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The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer’s Disease

Leticia Forny-Germano, Fernanda G. De Felice, Marcelo Nunes do Nascimento Vieira

Frontiers in Neuroscience · 2019 · Review · CC BY

doi:10.3389/fnins.2018.01027

Abstract

Cross-talk between adipose tissue and central nervous system (CNS) underlies the increased risk of obese people to develop brain diseases such as cognitive and mood disorders. Detailed mechanisms for how peripheral changes caused by adipose tissue accumulation in obesity impact the CNS to cause brain dysfunction are poorly understood. Adipokines are a large group of substances secreted by the white adipose tissue to regulate a wide range of homeostatic processes including, but not limited to, energy metabolism and immunity. Obesity is characterized by a generalized change in the levels of circulating adipokines due to abnormal accumulation and dysfunction of adipose tissue. Altered adipokine levels underlie complications of obesity as well as the increased risk for the development of obesity-related comorbidities such as type 2 diabetes, cardiovascular and neurodegenerative diseases. Here, we review the literature for the role of adipokines as key mediators of the communication between periphery and CNS in health and disease. We will focus on the actions of leptin and adiponectin, two of the most abundant and well studied adipokines, in the brain, with particular emphasis on how altered signaling of these adipokines in obesity may lead to cognitive dysfunction and augmented risk for Alzheimer's disease. A better understanding of adipokine biology in brain disorders may prove of major relevance to diagnostic, prevention and therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Lifestyle, nutrition and lack or inefficient exercise to control body weight is making the global population more susceptible to obesity. Food with high sugar and carbohydrate contents are in general cheaper and more readily available for the current busy lives. These factors contribute to a widespread epidemic of overweight and obesity, metabolic disorders characterized by the accumulation of peripheral and/or visceral adipose tissue. Obesity is a well established risk factor for a number of other chronic disorders, including type 2 diabetes, cardiovascular diseases, arthritis and some types of cancer. More recently, attention has been drawn to the impact of obesity on central nervous system (CNS) functioning, as growing evidence indicate that the obese population are more susceptible to some neurological conditions. Overweight and, in particular, central obesity during midlife have been associated to a higher risk of developing cognitive disorders, including Alzheimer’s disease (AD), later in life. In addition, overweight and obese individuals are at higher risk for developing mood disorders, such as major depression disorder (MDD) and bipolar disorder (BD) (; reviewed in;;; ). These evidences indicate that changes in the organism that accompany overweight and obesity can ultimately lead to CNS dysfunction. However, the pathophysiological mechanisms and molecular players underlying this connection are poorly known.

The obese body accumulates adipose tissues broadly classified in white (WAT) and brown adipose tissue (BAT). Initially considered a fat storage organ, it is now established that the WAT is an endocrine organ secreting a group of substances that act in a pleiotropic manner exerting autocrine, paracrine or endocrine effects on processes in the periphery and CNS. This class of WAT-derived substances are named adipocytokines or adipokines. Adipokines comprehend a wide range of molecules including hormones, cytokines and growth factors, and exert a variety of distinct functions in the organism ranging from control of metabolism homeostasis to immune system regulation and behavior. Abnormal production and secretion of adipokines resulting from aberrant accumulation of WAT in obesity leads to dysregulation of important homeostatic systems, resulting in the complications of obesity and in an increased risk for comorbidities such as insulin resistance and type-2 diabetes, hypertension, atherosclerosis and other cardiovascular diseases, and neurological disorders such as depression and AD.

In the following sections, we review the literature for studies on the role of adipokines as the possible mediators of signals from the periphery to the CNS in obesity-associated brain dysfunctions. Specifically, we will focus on two of the most abundant and well studied adipokines – leptin and adiponectin – and their interaction with cognitive processes of the CNS in health and disease.

Adipokines in Obesity and Related Diseases

Disproportional accumulation of white adipose tissue in overweight and obesity is accompanied by a generalized change in the circulating levels of several adipokines. Adipose dysfunction and adipokine dysregulation are thought to be responsible for or, at least, be an important contributor to the increased risk of obese people to develop a number of related diseases. For instance, increased levels of proinflammatory adipokines such as interleukin (IL)-1β, IL-6, TNFα and leptin, and decreased levels of anti-inflammatory adipokines, such as adiponectin, in obesity produce a chronic state of low-grade inflammation which promotes the development of insulin resistance and type-2 diabetes, hypertension, atherosclerosis and other cardiovascular diseases, and some types of cancer. Moreover, since adiponectin also acts as an insulin-sensitizing hormone in muscle and liver, lower levels of adiponectin further contribute to peripheral insulin resistance in obesity. Lastly, increased circulating levels of leptin in obesity lead to hypothalamic leptin resistance, turning down anorexigenic and energy expenditure signals and further contributing to aggravate obesity.

The CNS is not exempt from negative effects of obesity, as adipose dysfunction associated with obesity have been linked to altered brain metabolism, neuroinflammation, neuronal dysfunction, brain atrophy, impaired mood and cognitive decline. Studies associating obesity to morphometric changes in brain structure are somehow controversial. While the vast majority demonstrates obesity to be associated with lower gray matter and whole brain volumes, fewer publications showed no association. This controversy has been recently addressed in a meta-analysis study which found obesity to be consistently associated with lower gray matter volumes in brain areas associated with executive functions, including medial prefrontal cortex, left temporal lobe and bilateral cerebellum. These findings were further validated in the same study in an independent dataset.

Obesity has also been linked to cognitive disorders. Obese individuals are under greater risk to develop age-related cognitive decline, vascular dementia, mild cognitive impairment (MCI) and AD. Furthermore, animal models of obesity also develop cognitive decline. Mechanisms proposed to underlie obesity-associated risk for cognitive disorders include development of brain inflammation and central insulin resistance. Peripheral inflammation in obesity results from secretion of proinflammatory cytokines by adipocytes and adipose tissue-resident activated macrophages. Proinflammatory cytokines such as TNFα, interleukin (IL)-1β and IL-6, have been shown to cross the blood–brain barrier (BBB) and may act in concert with proinflammatory factors produced locally by microglial cells to foster brain inflammation in AD. Importantly, such cytokines has been shown to modulate synaptic plasticity and cognition both in health and disease states. Moreover, as occurs in peripheral tissues in obesity and type 2 diabetes, proinflammatory cytokines, in particular TNFα, mediate the development of neuronal insulin resistance. Since both insulin and cytokine signaling in the brain regulate synaptic plasticity, learning and memory, neuroinflammation and neuronal insulin resistance may be key mediators of obesity-associated cognitive decline (reviewed in ).

The increased risk for obese individuals to develop CNS pathology reflects the capacity of adipose tissue to communicate with the brain and impact brain function. It is not clear yet how this cross-talk occurs, but growing evidence indicate that adipokines are involved. Adipokines may impact brain physiology through different mechanisms. Some adipokines such as leptin and TNFα can cross the BBB and act directly in the brain while other adipokines would act on endothelial brain cells, regulating BBB permeability and the access of other circulating mediators into the brain. Importantly, in pathological states such as inflammation, the BBB integrity is compromised allowing the penetration of adipokines and other substances to which the brain is normally inaccessible. Finally, local expression of adipokines such as leptin and adiponectin have been reported in the mammalian brain. Advances on adipokine research have been providing information to understand how obesity affect brain function to cause brain atrophy, cognitive dysfunction, mood disorders and increase the risk for neurological diseases.

In the following sections, we will examine key aspects of leptin and adiponectin – the two most abundant and well studied adipokines – regarding their roles in brain physiology and their involvement in obesity-related cognitive dysfunction, dementia and AD (Figure 1).

Leptin in the Brain

The discovery of leptin in 1994 is considered the cornerstone for adipokine research. Leptin is classically related to the central control of food intake and energy homeostasis. However, other neurophysiological functions have been attributed to leptin, including brain development neurogenesis, neuronal protection, mood and stress regulation, reproduction and reproductive behaviors.

Leptin is mainly produced by adipose tissue, more specifically by visceral white adipocytes in rodent and by subcutaneous adipose tissue in human. However, local expression of leptin mRNA and protein in CNS has been reported. Circulating levels of leptin are dynamic and susceptible to different regulatory factors such as metabolism, body fat mass, circadian cycle and sexual dimorphisms. Leptin crosses the BBB by binding to specific receptors or interacting with BBB. The partially saturate influx of leptin through BBB indicates that membrane proteins facilitate leptin uptake where the entrance is limited by transport dynamics. There is evidence that leptin transport into the brain can be mediated by megalin at the choroid plexus epithelium and by short LepR isoforms in tanycytes. Therefore, levels of leptin in the brain are subject to regulation by local leptin production, circulating leptin levels and leptin transport across BBB through different mechanisms.

Leptin receptors (LepR or ObR) were first detected in 1995 at the mouse choroid plexus. Posterior studies revealed that alternative splicing during LepR-coding db gene expression result in six different LepR isoforms (LepRa-f). Long leptin receptor (LepRb) is the isoform which best bind to leptin and activate intracellular pathways. LepRs are tyrosine-kinase receptors that undergo autophosphorylation upon leptin binding to activate different signaling cascades, including JAK/STAT, ERK/MAPK and IRS/PI3K pathways. STAT (signal transducer and activator of transcription) is a family of transcription factor which, upon phosphorylation, migrate to the nucleus and regulate transcription of target genes such as the suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B). STAT3 is the major signaling pathway recruited by leptin and, due to its responsive property, STAT3 phosphorylation became an alternative way to identify leptin-responsive cells and infer leptin sensitivity.

LepRb is the main isoform of leptin receptor expressed in the brain. Robust expression comprehends the arcuate nucleus (ARC), the paraventricular nucleus and the dorsomedial, lateral and ventromedial regions of the hypothalamus. Extrahypothalamic sites also express leptin receptors including hippocampus, cortex, midbrain and hindbrain. A transgenic mouse expressing LepRb-cre in combination with cre-inducible enhanced green fluorescent protein (EGFP) and farnesylated EGFP (EGFPf) was used to reveal a detailed distribution of LepRb expressing neurons as well as their projection sites throughout the brain. Regions found to contain LepRb expressing neurons were consistent with those previously determined by examination of LepRb mRNA expression via in situ hybridization, but this study further identified projections sites of LepRb neurons in the brain. LepRb neurons and projection were observed throughout the prefrontal cortex, while more discrete, circumscribed regions containing both LepRb neurons and projections were found in insular, temporal, auditory, somatosensory and visual cortices. The hippocampus displayed few LepRb neurons along with projections from LepRb neurons mostly concentrated in CA1–3 regions and, to a lower extent, in the dentate.

The wide variety of leptin effects in the CNS likely reflects the peculiar distribution of leptin receptors through different brain structures as well as the particular signaling cascades activated by these receptors in distinct regions.

In the following sections, we review key aspects of brain leptin signaling that are relevant for its role in cognitive decline and AD (Table 1).

Leptin in Synaptic Function and Memory

Synaptic plasticity is a crucial event for learning and memory process. Long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are pivotal mechanisms in hippocampal memory formation and consolidation. At the molecular level, LTP and LTD are regulated by insertion or removal of NMDA- and AMPA-type glutamate receptors from post-synaptic terminals, thereby modulating synaptic transmission strength.

There is substantial evidence indicating that leptin regulates hippocampal synaptic plasticity and memory. LepRs in hippocampal neurons are closely associated with somato-dendritic and synaptic regions, indicating the potential for leptin to modulate synaptic function. Recent studies demonstrate that leptin activation of JAK2/STAT3 signaling pathway induces transcription of genes related to LTD. Moreover, learning and memory formation are modulated by JAK2/STAT5 signaling, a pathway also subject to regulation by leptin receptor signaling in the hippocampus. Two different LepR-deficient rodent strains (Zucker rats and db/db mice) show impaired LTP in the CA1 region of the hippocampus, which is accompanied by poor performance in the water maze spatial memory test. Conversely, leptin treatment has been shown to improve learning and memory performances in different models (;; reviewed in ).

Leptin was shown to regulated synaptic plasticity by targeting NMDA- and AMPA-receptors trafficking, particularly in the CA1 region of the hippocampus. Schaffer collaterals (SCs) and temporoammonic (TA) projections to CA1 pyramidal neurons exhibit an age-dependent response to leptin. Interestingly, these functionally distinct circuits appear to respond differently to leptin exposure. In SC-CA1 synapses, leptin was shown to induce depression of synaptic transmission in young rodents hippocampus whereas, in adult animals, leptin promote synaptic strengthening and LTP. Different effects were observed in TA-CA1 synapses, where leptin induces LTP in young, promote LTD in the adult but had no effect on synaptic transmission in aged rat hippocampus. Importantly, the age- and regional-variability of leptin effects on hippocampal synaptic plasticity appears to be driven by the composition of NMDARs subtypes, and to be achieved by regulating the traffic of different subsets of AMPARs toward and away from synapses. Leptin regulation of synaptic plasticity involves several downstream targets, including JAK2-STAT3, PTEN, PI3K, ERK, and CaMKII (for more comprehensive reviews, see; ).

Leptin Resistance

Several studies demonstrated that leptin responsiveness decreases with obesity, aging and neurodegenerative diseases, a phenomenon called leptin resistance. Leptin resistance affects a range of processes such as food intake, insulin sensitivity, inflammation and cognition. In obesity, leptin resistance leads to increased production of leptin by adipocytes and hyperleptinemia, in an attempt of the organism to compensate for low leptin responsiveness. Decreased leptin signaling in the CNS may be related to defective leptin transport across BBB, LepR downregulation and/or deficient leptin signaling downstream LepRs.

Triglycerides can impair BBB leptin transport causing central leptin deficiency. Furthermore, it was recently demonstrated that triglycerides can cross the BBB to directly induce hypothalamic leptin and insulin receptor resistance, leading to decreased satiety and cognitive impairment in mice. Interestingly, triglycerides increased leptin binding in different brain regions, suggesting an allosteric or post-receptor rather than a competitive mechanism of inhibition of LepR signaling by triglycerides. In light of longitudinal studies linking increased mid-life triglyceride levels to the risk for AD, the above results suggest that triglycerides may contribute to AD pathogenesis and progression by suppressing leptin signaling in the brain. Deficient leptin transport across BBB by megalin leading to reduced leptin entry into the brain has also been described in aged mice and in mouse models of AD.

At the intracellular level, leptin signaling is negatively regulated by the suppressor of SOCS3 and by the PTP1B. SOCS3 binds to LepR and JAK2 to inhibit their activities, whereas PTP1B dephosphorylates tyrosine residues deactivating LepR and JAK2. PTP1B have been linked to central leptin resistance in humans as well as in a variety of animal models of obesity and aging. SOCS3 and PTP1B were also found upregulated in the brains of AD mouse models and AD patients. Therefore, targeting PTP1B and SOCS3 may prove valuable to overcome central leptin resistance in obesity, aging, and AD.

Central leptin resistance can also be mediated by downregulation of LepRs expression. In this regard, LepR levels were found to be decreased in the hippocampus of AD patients, whereas leptin levels were upregulated both in CSF and locally in the hippocampus, possibly due to a compensatory mechanism for receptor dysfunction. Age-dependent changes in LepR expression levels were also reported in Tg2576 and APP/PS1 mouse models of AD. Although the results from these studies are hard to interpret, they are consistent with an impact of AD phenotypes in LepR expression in brain areas relevant to cognition and memory.

Taken together, the results described above indicate that impaired brain leptin signaling may play a role in AD pathophysiology, and that restoring leptin signaling may constitute a valid approach to restore synaptic function and cognition in AD.

Leptin Signaling, Obesity, and Alzheimer’s Disease

Several studies indicate that over-weight and obesity during mid-age increases risk to develop AD. In contrast, high weight in late-life was shown to be protective against AD and cognitive decline. Surprisingly, weight loss in late age is related to higher risk for dementia and AD. This apparently paradoxical influence of body weight on dementia and AD risk is far from being understood. Interestingly, a similarly complex relation is observed between overweight/obesity and other neurodegenerative diseases. For instance, in amyotrophic lateral sclerosis (ALS) patients, mild obesity is associated with increased survival rates, whereas morbid obesity increases mortality rates. The influence of body weight on the clinical outcomes of dementia, AD and other neurodegenerative diseases suggest that adipose tissue dysfunction and adipokines dysregulation may play a broad role across the spectrum of neurodegenerative diseases. Moreover, the explanation for this puzzling and somehow paradoxical influence of adiposity on brain diseases may lie in how weight changes impact production and action of adipokines such as leptin and adiponectin.

Evidence regarding how leptin levels are affected in AD are controversial. Several studies show decreased leptin levels in CSF and plasma in AD patients whereas increased leptin levels and unaffected levels in CSF and cerebral tissue were also reported. Conflicting findings can be associate to variations in dementia score, post-mortem neuropathological analyses to confirm dementia, sample size, stratification in sex, age, and others.

Leptin signaling was found to interact with several mechanisms associated with AD physiopathology. Aβ disrupt leptin signaling leading to down-regulation of hippocampal leptin and LepR expression. Conversely, leptin was reported to be neuroprotective in AD models by suppressing Aβ accumulation and toxicity and attenuating tau pathology. Leptin administration reduce Aβ levels in the Tg2576 mouse model of AD. The anti-amyloidogenic effect of leptin involve inhibition of APP processing by down regulating β-amyloid precursor protein (APP) cleaving enzyme (BACE1) and increase in APOE-dependent Aβ uptake, and seems to be mediated by activation of AMP-activated protein kinase (AMPK).

Tau phosphorylation can be suppressed by leptin modulation of GSK3β activity. Importantly, leptin treatment also improve memory performance in different mouse models of AD. In a rat model of intracerebroventricular Aβ injection, chronic leptin administration rescued Aβ-induced impairment of spatial memory and late-phase LTP. Leptin was further shown to enhance hippocampal neurogenesis in AD mice. Collectively, the above studies provide initial validation for the potential therapeutic applications of leptin signaling enhancement in AD brains.

Adiponectin

Adiponectin is a 30 KDa adipokine encoded by the AdipoQ gene, mainly produced and secreted by adipocytes and highly abundant in human plasma. Adiponectin is known to increase insulin sensitivity of target organs such as liver and muscle, ultimately regulating peripheral glucose and fatty acid metabolism. Besides being a metabolic regulator, adiponectin is also known for its anti-inflammatory and anti-oxidant activity. These characteristics make adiponectin a protective factor in conditions such as obesity, type 2 diabetes and cardiovascular diseases. Levels of circulating adiponectin are decreased in obesity and metabolic syndrome, likely contributing to the development of insulin resistance. Low levels of adiponectin have also been linked to several types of cancer and cardiovascular diseases.

Adiponectin naturally self-associate to form different types of aggregates. In plasma, adiponectin exists as trimers, hexamers or high molecular weight (HMW) multimers. Adiponectin trimers are mainly stabilized by non-covalent interactions, whereas larger aggregates require crosslinking between subunits by disulfide bonds. In addition, adiponectin also circulates as biologically active globular fragment generated through proteolysis of full-length adiponectin. Importantly, these post-translational modifications affect biological activity, as distinct adiponectin complexes present tissue-specificity and may activate different signaling pathways (for reviews, see; ).

Adiponectin acts through binding to three different receptors: adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2) and T-cadherin. AdipoR1 and AdipoR2 are the most abundant sites for adiponectin binding and mediate most of adiponectin actions through the organism. Activation of AdipoRs by adiponectin leads to the recruitment of the adaptor protein APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) which, in turn, mediates downstream adiponectin signaling through a number of different pathways including AMPK, PI3K-Akt, MAPK-Erk1/2, PPARα, p38-MAPK, PTEN and JNK. APPL1 also plays a crucial role in the insulin sensitization effect of adiponectin by interacting with and facilitating the binding of IRS1/2 to the insulin receptor.

Adiponectin in the Brain

Data from epidemiological studies demonstrate that diabetes, obesity, and metabolic syndrome increase the risk of developing cognitive problems and dementia. More recently, evidence indicate that insulin signaling dysfunction and chronic neuroinflammation are key factors in cognitive decline, MCI and AD (;, reviewed in;; ). In face of these observations, adiponectin has gained attention in the context of such CNS disorders due to its potentially protective actions as an anti-inflammatory and insulin sensitizing hormone.

Adiponectin is present in human and mouse CSF, albeit in much lower concentrations than in blood. However, the source(s) for adiponectin in CNS are not completely clear. Initial studies suggested that adiponectin expression was limited to adipocytes and, to a lower extent, other peripheral tissues such as liver, muscle, placenta, and epithelium. More recently, however, some studies reported adiponectin expression at both mRNA and protein levels in the chicken and mammalian brain. Whether peripheral adiponectin crosses the BBB to reach the brain is a matter of debate. While some studies conclude that adiponectin does not cross the BBB, other studies found evidence suggesting that peripheral adiponectin does reach the brain through the BBB. This is an important open question with physiological and potential translational relevance, since adiponectin-based therapies to treat brain conditions would possibly consist of peripheral administration and require adiponectin to reach the CNS. Therefore, further studies are required to clarify whether or not peripheral adiponectin can reach the brain tissue through BBB.

Adiponectin receptors are also expressed in different structures of the brain. The hypothalamus is the best documented site for AdipoRs expression in the mammalian brain, but there is also evidence for expression in endothelial brain cells, cerebral cortex, brain stem and hippocampus reviewed in. Interestingly, a study in post mortem human brains also revealed intense immunostaining for AdipoR1 in the nucleus basalis magnocellularis (NBM), a small structure rich in cholinergic neurons projecting diffusely to the whole neocortex and other brain areas, and that is severely affected in AD.

Adiponectin functions in the brain are highly diversified. It has been shown to act locally in the brain to control key processes of brain physiology including neuronal excitability and synaptic plasticity, neuroprotection, neurogenesis and regulation of glial cells activation. More recently, adiponectin was found to modulate glucose metabolism in hippocampal neurons, increasing glucose uptake, glycolysis and ATP production rates. Adiponectin also acts on brain to regulate peripheral and systemic processes such as thermogenesis, energy expenditure and reproduction. Finally, central adiponectin has been shown to regulate behaviors like food intake, locomotor activity as well as cognition, anxiety and mood. This variety of central effects of adiponectin likely reflects the wide distribution of different adiponectin receptors throughout the brain. For the purpose of this review, the following sections will focus on roles of adiponectin that are most likely relevant to cognitive dysfunction and AD, namely synaptic regulation, insulin sensitivity, neuroinflammation, neuroprotection and neurogenesis (Table 2).

Adiponectin in Synaptic Function and Memory

Synapse loss is the best pathological correlate for clinical manifestations of cognitive dysfunction in AD. Compelling evidence indicate that Aβ oligomers, toxins that accumulate in AD brains, target synapses impairing synaptic function and plasticity and causing synapse loss (reviewed in;; ) Aβ oligomers inhibit LTP and promote LTD of hippocampal synapses in vitro and in vivo.

Interestingly, recent data indicate that adiponectin signaling directly regulates synaptic function and plasticity, preserving and enhancing cognitive functions in a number of different models. Intracerebroventricular administration of adiponectin in anesthetized rats potentiates high frequency stimulation (HFS)-induced LTP and suppresses low-frequency stimulation (LFS)-induced LTD. Furthermore, adiponectin administration alone induced a chemical LTP, independent of presynaptic stimulus. Osmotin, a plant-derived homolog of adiponectin capable of activate AdipoRs, improves LTP impairment and ameliorates memory deficits in a mouse model of AD. This effect appears to be mediated by AdipoR1 and the Nogo66 receptor 1 (NgR1) and involve promotion of neurite outgrowth and increasing of dendritic spine and synapse density in the hippocampus. Adiponectin-deficient mice displays increased excitability of hippocampal dentate gyrus (DG) granule neurons, associated with impaired extinction of contextual fear memory. Adiponectin and its mimetic drug AdipoRon restored fear memory extinction via AdipoR2 activation and inhibition of DG neuron excitability. Aged adiponectin-deficient mice have reduced levels of synaptic proteins suggesting synapse loss, and also performs poorly in spatial memory and contextual fear conditioning tests. Importantly, both adiponectin and osmotin treatments ameliorate learning and memory deficits in AD animal models. Caloric restriction increases circulating adiponectin levels and improve cognition in mice probably via regulation of the AMPK signaling pathway in mouse hippocampus. Finally, a recent clinical study found that individuals with higher adiponectin levels tend to perform better in a delayed word recall test, supporting the notion that adiponectin is a protective factor against cognitive decline and represents a promising therapeutic strategy in cognitive disorders.

Collectively, these recent studies consistently established a previously ignored ability of adiponectin to regulate hippocampal synaptic function and plasticity and to improve cognitive function, learning and memory. This further support a protective role for adiponectin in AD, suggesting that diminished brain adiponectin signaling in obesity may favor AD onset and progression and that adiponectin signaling may be an interesting target in AD therapy.

Adiponectin in Central Insulin Signaling

Neuronal insulin signaling is important for synaptic plasticity and memory, mainly by regulating glutamate receptors trafficking. Impaired insulin signaling is well documented both in human AD patients and in a variety of AD animal models and is considered an important mechanism for neuronal dysfunction and cognitive impairment in AD Synaptotoxicity of Aβ oligomers is accompanied by insulin receptor dysfunction in vitro and in vivo and can be prevented by treatment with insulin sensitizing drugs and by insulin itself. These discoveries encouraged several groups to evaluate the efficacy of different classes of anti-diabetic drugs in AD models, and positive preclinical results paved the way for human clinical trials (for comprehensive reviews, see;; ). In this context, interest has recently been directed to the insulin-sensitizing actions of adiponectin to correct aberrant insulin signaling in AD. Impaired brain insulin signaling was observed, along with several other AD-like pathological features, in adiponectin knockout mice and in AdipoR1 deficient mice. Conversely, adiponectin increases insulin sensitivity in SH-SY5Y neuronal cell line modeling insulin resistance, through AdipoR1 receptor activation of AMPK. These data indicate that adiponectin has the potential to restore neuronal insulin signaling, with possible therapeutic implications for AD and other neurodegenerative diseases. However, further translational studies using proper animal models of AD are required to validate adiponectin signaling as a therapeutic approach to overcome brain insulin resistance in AD.

Adiponectin in Neuroinflammation

Adiponectin is well known for its anti-inflammatory activity in peripheral tissues, which include suppression of macrophage activation and secretion of pro-inflammatory cytokines. For that, adiponectin is considered a protective factor against pathological processes such as peripheral insulin resistance and cardiovascular diseases, whereas low levels of adiponectin in obesity contributes to chronic inflammation and obesity-associated risk for related diseases (For recent reviews, see; ).

Alzheimer’s disease is also characterized by a chronic state of low-grade inflammation in the brain. This response is mediated by microglial cells activation and secretion of pro-inflammatory cytokines TNFα, IL-6, and IL-1β (;;; reviewed in; ). Proinflammatory cytokines trigger a series of detrimental events in the AD brain, including neuronal insulin resistance, endoplasmic reticulum stress, synaptotoxicity and neurodegeneration.

Adiponectin-knockout mice develop a series of pathological features in the brain resembling AD, including insulin resistance, reduced levels of synaptic proteins and the presence of neuroinflammatory markers such as microgliosis, astrogliosis and elevated levels of the pro-inflammatory cytokines TNFα and IL-1β. Environmental enrichment, housing conditions that promote physical activity, cognitive engagement and social interactions, has been shown to improve cognitive functions and be protective in AD mouse models. These effects are at least in part due to modulation of microglial response to the insult of Aβ oligomers. Interestingly, it was recently shown that beneficial effects of environmental enrichment to the brain are mediated by adiponectin, and involves the promotion of an anti-inflammatory activation state of microglia with decreased production of pro-inflammatory cytokines. The same group also showed that globular adiponectin directly inhibits microglia pro-inflammatory profile in vivo and in vitro in a mechanism involving AdipoR1 and NF-κB. Adiponectin also modulates microglial activation profile under Aβ toxicity in vitro, via PPARγ activation. Further evidence for the anti-inflammatory actions of adiponectin in the CNS come from a study showing that CTRP9, an AdipoR1 agonist, attenuates neuroinflammation in a mouse model of intracerebral hemorrhage through a AdipoR1/AMPK/NFκB signaling mechanism. Moreover, AdipoRon treatment suppresses macrophage recruitment in a model of spinal cord injury. Finally, it has been proposed that adiponectin can also modulate neuroinflammation by reducing expression of pro-inflammatory cytokines by brain endothelial cells. These evidences support a role for adiponectin in mitigating brain inflammation, and suggest that adiponectin deficiency in obesity may trigger neuroinflammatory events leading to AD and other related CNS disorders.

Adiponectin in Neuroprotection and Neurogenesis

Neurodegeneration in AD is mediated by overactivation of glutamate receptors and excessive neuronal calcium influx, a process called excitotoxicity. Excitotoxicity can be triggered by toxic amyloid-β aggregates in vitro and in vivo, and represents an important pathological mechanism in synaptic failure and neuronal death in AD (reviewed in ). Excitotoxicity is commonly associated with mitochondrial dysfunction and oxidative stress, and also occurs in other pathological conditions such as stroke and brain and spinal cord injuries.

In the past few years, a growing number of studies demonstrated the neuroprotective properties of adiponectin and other AdipoRs agonists against a variety of neuronal toxic insults in vitro and in vivo. In vitro, adiponectin was shown to protect SH-SY5Y human neuroblastoma cells against oxidative stress and cytotoxicity induced by Aβ and MPP+, an inhibitor of mitochondrial complex I. Adiponectin neuroprotection was also observed in a model of kainic acid (KA)-induced excitotoxicity in primary cultures of rat hippocampal neurons. A series of studies also reported neuroprotective roles of adiponectin and AdipoRs in different models of hemorrhagic and ischemic stroke. Cellular mechanisms reported to underlie adiponectin and AdipoRs neuroprotection include suppression of oxidative stress, apoptosis and inflammation, and involve a remarkable variety of intracellular targets, including antioxidant enzymes, AMPK, JNK/PI3K/Akt, PKA, GSK3β, NFkappaB, Bax/Bcl-2 and caspase 3. These neuroprotective actions of adiponectin may be therapeutically applicable in neurodegenerative diseases.

The antidepressant effects of physical exercise are well known and widely used in the clinic as a non-pharmacological treatment for depression. Recently, adiponectin was shown to play a crucial role in antidepressant effects of exercise, by mediating exercise-induced hippocampal neurogenesis. The neurogenic and neurotrophic effects of adiponectin signaling were further demonstrated by intracerebroventricular injection of adiponectin in adiponectin-deficient mice. Remarkably, chronic intraperitoneal administration of the AdipoRs agonist AdipoRon in an anxiety/depression mouse model reversed depression-like state by modulating several CNS processes, including neurogenesis. This study is of particular translational relevance since AdipoRon, a small-molecule adiponectin-mimetic drug, showed central activity while administered peripherally. It has been suggested that, for its neurogenic and antidepressant actions, adiponectin can be explored as a pharmacological surrogate for physical exercise to treat depression and, possibly, other brain disorders.

Adiponectin in Alzheimer’s Disease

Recent studies indicate that adiponectin signaling deficiency is sufficient to induce an AD-like phenotype in mice. Aged adiponectin-knockout mice recapitulate several aspects of AD pathology, including increased Aβ levels and deposition, tau hyperphosporylation, neuroinflammation, synapse loss, neuronal apoptosis and impaired insulin signaling. Importantly, aged adiponectin knockout mice also performed poorly in spatial memory and fear conditioning behavioral tests. These observations were further corroborated by another recent study showing that gene-therapy induced suppression of AdipoR1 also produces an AD-like phenotype, which includes impaired spatial memory and learning, increased levels of Aβ aggregates and hyperphosphorylated tau, insulin signaling dysfunction, neuroinflammation and neurodegeneration markers. Collectively, these studies make strong case for a role for adiponectin deficiency in AD pathogenesis. The NBM is a cholinergic nucleus in the basal forebrain which is severely affected in AD and other neurodegenerative diseases. It is well documented that neuronal loss of NBM cholinergic neurons contributes to cholinergic dysfunction and, most importantly, it correlates with clinical measures of dementia (;;; reviewed in ). Interestingly, NBM was found to be a prominent site of expression of AdipoR1. Therefore, it is possible that adiponectin deficiency contributes to the onset and progression of AD by promoting NBM dysfunction and degeneration. This hypothesis, however, remain to be tested.

Conversely, impairment in adiponectin function is also observed in amyloid-based AD models, whereas activating adiponectin signaling reduces AD-like pathology. In APP/PS1 mice, changes in AdipoRs expression levels were less responsive to a stress-inducing paradigm as compared to wild-type mice. In the same model, the adiponectin-homolog osmotin ameliorated AD-like neuropathological features such as Aβ production and aggregation, synaptic dysfunction and impaired LTP, memory and cognitive deficits. AdipoR1 silencing abolished osmotin beneficial effects and further aggravated brain pathology in AD-mice. Osmotin was further shown to reduce Aβ deposition in cultured SH-SY5Y human neuroblastoma cells overexpressing APP. Osmotin effects were mediated by activation of AMPK, an enzyme downregulated by Aβ oligomers in hippocampal neurons. In a rat model of streptozotocin-induced brain pathology, intracerebroventricular injection of adiponectin rescued cognitive deficits and attenuated GSK3β-mediated tau hyperphosphorylation in AD-relevant sites. These results suggest boosting adiponectin signaling, particularly through AdipoR1, as a potential therapeutic approach in AD. In this regard, chronic treatment with donepezil, an acetylcholinesterase inhibitor widely use to treat AD, was recently shown to increase serum levels of adiponectin. Moreover, thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone, PPARγ agonists used for decades to treat type 2 diabetes due to its insulin sensitization activity were recently repurposed to treat AD. The insulin-sensitizing effect of TZDs is in part mediated by induction of peripheral adiponectin and AdipoRs expression. Therefore, it is possible that adiponectin mediate part of the observed beneficial effects of donepezil and TZDs.

AdipoRon, an orally bioavailable small-molecule agonist of adiponectin receptors, was shown to modulate hippocampal synaptic transmission and to facilitate fear memory extinction in rodents. AdipoRon was further shown to regulate activity of dopaminergic neurons in the ventral-tegmental area and to act as an antidepressant and metabolic regulator in a mouse model of depression. Importantly, central AdipoRon effects were obtained by peripheral administration, and it was shown that it crosses the BBB to activate AdipoRs in the brain. However, to our knowledge, there are no available data on AdipoRon effects in AD models. It should be interesting to investigate the efficacy of this adiponectin-mimetic drug with translational potential in AD models.

Studies relating adiponectin levels to AD in humans are controversial. Increased baseline adiponectin levels in plasma have been associated with a higher risk of women, but not men, to develop AD and other types of dementia. Furthermore, elevated adiponectin levels were reported in the plasma and CSF of subjects with MCI and sporadic AD, whereas plasma levels of adiponectin positively correlated with the degree of dementia. The correlation between high blood adiponectin and AD has been replicated and supported by meta-analysis study. However, while the studies described above suggest increased adiponectin levels to be associated with AD and dementia, opposite results have also been reported. One study found lower levels of circulating adiponectin in MCI and AD subjects. Moreover, adiponectin levels failed to predict progression of cognitive dysfunction from normal to MCI and from MCI to AD. One larger study also reported low levels of plasma adiponectin to be associated with MCI, even though this association was observed in men, but not in women. In line with these observations, it has been shown that, in diabetic patients, low plasma levels of adiponectin correlate with lower gray-matter volume and reduced glucose utilization in temporal regions of the brain, similarly to what is observed in AD. Finally, a recent study reports that levels of adiponectin are higher in blood but lower in CSF of AD and MCI patients.

Available data regarding a possible association between adiponectin levels in blood and CSF to MCI and AD are conflicting and inconclusive. Therefore, further studies are warranted to reveal the potential use of adiponectin measurement for diagnostic purposes and its clinical relevance for the physiopathology of these neurological conditions. Worth mentioning, some studies found that the association between adiponectin levels and dementia can be sex-specific. This may be of particular relevance in the case of AD, where a considerable sexual dichotomy is observed with women being at a significantly higher risk to develop the disease.

Concluding Remarks

Obesity is pandemic in present days. Beyond its intrinsic complications, and the obvious social and psychological impact, obesity harms extend to a wide range of associated health conditions to which it represents a major risk factor. More recently, growing attention is being given to the impact of obesity on CNS function, as accumulating evidence indicate higher incidence of neurological disorders in the obese population. The mechanisms by which fat accumulation and adipose tissue dysfunction in obesity result in CNS pathology are poorly understood. It is widely accepted that dissection of such mechanisms will greatly improve our knowledge on the cross-talk between peripheral metabolism and brain physiology, and may provide novel targets for therapeutic intervention for prevention and/or treatment of neurological dysfunctions associated with obesity.

Adipokines are secreted factors which carry regulatory signals from adipose tissue through systemic circulation to control a wide range of physiological functions throughout the human body. Not surprisingly, adipokine dysregulation in obesity results in the disruption of homeostasis in a variety of organs and systems, and underlie obesity complications and risk for associated chronic conditions. In this context, adipokines emerged as strong candidates to represent the mediators of pathological signals from adipose tissue to CNS in metabolic disorders.

The studies reviewed here provide evidence supporting a role of leptin and adiponectin, two highly abundant and well characterized adipokines, as key mediators of obesity-related CNS dysfunctions (Figure 1). We found consistent evidence that leptin and adiponectin, as well as their receptors, are present in the brain and function as important regulators of different aspects of brain physiology. Importantly, leptin (Table 1) and adiponectin (Table 2) signaling have been shown to interfere with a range of neuropathological events covering those most commonly present in neurodegenerative diseases and, in particular, in AD. These include amyloidogenesis, tau hyperphosphorylation, neuroinflammation, oxidative stress, endoplasmic reticulum stress, insulin resistance, synaptic dysfunction and cognitive impairment. Remarkably, the phenotype of adiponectin- or adiponectin receptor-deficient mice recapitulates the majority of AD neuropathological hallmarks. Therefore, dysregulated adiponectin and leptin signaling may mediate the detrimental impact of obesity on CNS and raise the risk for cognitive decline and AD. Importantly, restoring proper leptin and adiponectin signaling in the brain may constitute beneficial, disease-modifying therapeutic interventions in such neurological conditions (Figure 1).

Author Contributions

LF-G and MV wrote the manuscript. MV designed the figure. LF-G, FDF, and MV planned the scope and reviewed the final manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 306

  1. 1.

    Ahima R. S. (2012 ). Adipose tissue as an endocrine organ. Obesity 14 242S–249S.

    Not in our library10.1038/oby.2006.317

  2. 2.

    Ahima R. S. Blüher M. Mantzoros C. S. Dhar M. Wayman G. A. Zhu M. (2017 ). Adiposity and cognitive decline: underlying mechanisms. Nature 30 203–217.

    Not in our library10.3233/jad-2012-120487

  3. 3.

    Ahima R. S. Prabakaran D. Flier J. S. (1998 ). Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J. Clin. Invest. 101 1020–1027.

    Not in our library10.1172/jci1176

  4. 4.

    Ahuja C. S. Wilson J. R. Nori S. Kotter M. R. N. Druschel C. Curt A. (2017 ). Traumatic spinal cord injury. Nat. Rev. Dis. Primers 3:17018.

    Not in our library10.1038/nrdp.2017.18

  5. 5.

    Alhurani R. E. Vassilaki M. Aakre J. Mielke M. M. Kremers W. K. Machulda M. M. (2016 ). Decline in weight and incident mild cognitive impairment: mayo clinic study of aging. JAMA Neurol. 73 439–446.

    Not in our library10.1001/jamaneurol.2015.4756

  6. 6.
    Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus · 2015
    No notice
  7. 7.

    Allison M. B. Myers M. G. (2014 ). Connecting leptin signaling to biological function. J. Endocrinol. 223 T25–T35.

    Not in our library10.1530/joe-14-0404

  8. 8.

    Angelidis G. Dafopoulos K. Messini C. I. Valotassiou V. Tsikouras P. Vrachnis N. (2012 ). The emerging roles of adiponectin in female reproductive system-associated disorders and pregnancy. Reprod. Sci. 20 872–881.

    Not in our library10.1177/1933719112468954

  9. 9.

    Antoniades C. Antonopoulos A. S. Tousoulis D. Stefanadis C. (2009 ). Adiponectin: from obesity to cardiovascular disease. Obes. Rev. 10 269–279.

    Not in our library10.1111/j.1467-789x.2009.00571.x

  10. 10.

    Arendt T. Bigl V. Arendt A. Tennstedt A. (1983 ). Loss of neurons in the nucleus basalis of Meynert in Alzheimer’s disease, paralysis agitans and Korsakoff’s disease. Acta Neuropathol. 61 101–108.

    Not in our library10.1007/bf00697388

  11. 11.

    Arita Y. Kihara S. Ouchi N. Takahashi M. Maeda K. Miyagawa J. (1999 ). Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257 79–83.

    Not in our library10.1006/bbrc.1999.0255

  12. 12.

    Arnold S. E. Arvanitakis Z. Macauley-Rambach S. L. Koenig A. M. Wang H.-Y. Ahima R. S. (2018 ). Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14 168–181.

    Not in our library10.1038/nrneurol.2017.185

  13. 13.

    Arshad N. Lin T. S. Yahaya M. F. (2018 ). Metabolic syndrome and its effect on the brain: possible mechanism. CNS Neurol. Disord. Drug Targets 17 595–603.

    Not in our library10.2174/1871527317666180724143258

  14. 14.

    Baker L. D. Cross D. J. Minoshima S. Belongia D. Watson G. S. Craft S. (2011 ). Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 68 51–57.

    Not in our library10.1001/archneurol.2010.225

  15. 15.

    Balland E. Dam J. Langlet F. Caron E. Steculorum S. Messina A. (2014 ). Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 19 293–301.

    Not in our library10.1016/j.cmet.2013.12.015

  16. 16.

    Bamberger M. E. Harris M. E. McDonald D. R. Husemann J. Landreth G. E. (2003 ). A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 23 2665–2674.

    Not in our library10.1523/jneurosci.23-07-02665.2003

  17. 17.

    Banks W. (2005 ). Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr. Pharm. Des. 11 973–984.

    Not in our library10.2174/1381612053381684

  18. 18.

    Banks W. A. Coon A. B. Robinson S. M. Moinuddin A. Shultz J. M. Nakaoke R. (2004 ). Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53 1253–1260.

    Not in our library10.2337/diabetes.53.5.1253

  19. 19.

    Banks W. A. Farr S. A. Salameh T. S. Niehoff M. L. Rhea E. M. Morley J. E. (2018 ). Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance. Int. J. Obes. 42 391–397.

    Not in our library10.1038/ijo.2017.231

  20. 20.

    Banks W. A. Kastin A. J. Huang W. Jaspan J. B. Maness L. M. (1996 ). Leptin enters the brain by a saturable system independent of insulin. Peptides 17 305–311.

    Not in our library10.1016/0196-9781(96)00025-3

  21. 21.

    Bao Y. Giovannucci E. L. Kraft P. Stampfer M. J. Ogino S. Ma J. (2013 ). A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. J. Natl. Cancer Inst. 105 95–103.

    Not in our library10.1093/jnci/djs474

  22. 22.

    Baranowska-Bik A. Bik W. Styczynska M. Chodakowska-Zebrowska M. Barcikowska M. Wolinska-Witort E. (2015 ). Plasma leptin levels and free leptin index in women with Alzheimer’s disease. Neuropeptides 52 73–78.

    Not in our library10.1016/j.npep.2015.05.006

  23. 23.

    Barrett-Connor E. Edelstein S. L. Corey-Bloom J. Wiederholt W. C. (1996 ). Weight loss precedes dementia in community-dwelling older adults. J. Am. Geriatr. Soc. 44 1147–1152.

    Not in our library10.1111/j.1532-5415.1996.tb01362.x

  24. 24.

    Bartolome F. Antequera D. Tavares E. Pascual C. Maldonado R. Camins A. (2017 ). Obesity and neuroinflammatory phenotype in mice lacking endothelial megalin. J. Neuroinflammation 14:26.

    Not in our library10.1186/s12974-017-0800-2

  25. 25.
    The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease · 2018
    No notice
  26. 26.

    Beattie E. C. Carroll R. C. Yu X. Morishita W. Yasuda H. von Zastrow M. (2000 ). Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat. Neurosci. 3 1291–1300.

    Not in our library10.1038/81823

  27. 27.

    Bell S. P. Liu D. Samuels L. R. Saraf A. A. Gifford K. A. Hohman T. J. (2017 ). Late-life body mass index, rapid weight loss, Apolipoprotein E ε4 and the risk of cognitive decline and incident dementia. J. Nutr. Health Aging 21 1259–1267.

    Not in our library10.1007/s12603-017-0906-3

  28. 28.

    Bhat A. H. Dar K. B. Anees S. Zargar M. A. Masood A. Sofi M. A. (2015 ). Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed. Pharmacother. 74 101–110.

    Not in our library10.1016/j.biopha.2015.07.025

  29. 29.

    Bigalke B. Schreitmüller B. Sopova K. Paul A. Stransky E. Gawaz M. (2011 ). Adipocytokines and CD34+ progenitor cells in Alzheimer’s disease. PLoS One 6:e20286.

    Not in our library10.1371/journal.pone.0020286

  30. 30.

    Bjørbaek C. Kahn B. B. (2004 ). Leptin signaling in the central nervous system and the periphery. Recent Prog. Horm. Res. 59 305–331.

    Not in our library10.1210/rp.59.1.305

  31. 31.

    Bliss T. V. P. Collingridge G. L. (1993 ). A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361 31–39.

    Not in our library10.1038/361031a0

  32. 32.

    Bluher M. (2016 ). Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance? Clin. Sci. 130 1603–1614.

    Not in our library10.1042/cs20160005

  33. 33.

    Bomfim T. R. Forny-Germano L. Sathler L. B. Brito-Moreira J. Houzel J.-C. Decker H. (2012 ). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. J. Clin. Invest. 122 1339–1353.

    Not in our library10.1172/jci57256

  34. 34.

    Bonda D. J. Stone J. G. Torres S. L. Siedlak S. L. Perry G. Kryscio R. (2014 ). Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance. J. Neurochem. 128 162–172.

    Not in our library10.1111/jnc.12380

  35. 35.

    Bouret S. G. (2010 ). Neurodevelopmental actions of leptin. Brain Res. 1350 2–9.

    Not in our library10.1016/j.brainres.2010.04.011

  36. 36.

    Buchman A. S. Wilson R. S. Bienias J. L. Shah R. C. Evans D. A. Bennet D. A. (2005 ). Change in body mass index and risk of incident Alzheimer disease. Neurology 65 892–897.

    Not in our library10.1212/01.wnl.0000176061.33817.90

  37. 37.

    Cao B. Chen Y. Brietzke E. Cha D. Shaukat A. Pan Z. (2018 ). Leptin and adiponectin levels in major depressive disorder: a systematic review and meta-analysis. J. Affect. Disord. 238 101–110.

    Not in our library10.1016/j.jad.2018.05.008

  38. 38.

    Caprio M. Fabbrini E. Isidori A. M. Aversa A. Fabbri A. (2001 ). Leptin in reproduction. Trends Endocrinol. Metab. 12 65–72.

    Not in our library10.1016/s1043-2760(00)00352-0

  39. 39.

    Caron A. Lee S. Elmquist J. K. Gautron L. (2018 ). Leptin and brain–adipose crosstalks. Nat. Rev. Neurosci. 19 153–165.

    Not in our library10.1038/nrn.2018.7

  40. 40.

    Carro E. Spuch C. Trejo J. L. Antequera D. Torres-Aleman I. (2005 ). Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J. Neurosci. 25 10884–10893.

    Not in our library10.1523/jneurosci.2909-05.2005

  41. 41.

    Cezaretto A. Suemoto C. K. Bensenor I. Lotufo P. A. de Almeida-Pititto B. Ferreira S. R. G. (2018 ). Association of adiponectin with cognitive function precedes overt diabetes in the Brazilian Longitudinal Study of Adult Health: ELSA. Diabetol. Metab. Syndr. 10:54.

    Not in our library10.1186/s13098-018-0354-1

  42. 42.

    Chabry J. Nicolas S. Cazareth J. Murris E. Guyon A. Glaichenhaus N. (2015 ). Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: relevance to depressive-like behavior. Brain Behav. Immun. 50 275–287.

    Not in our library10.1016/j.bbi.2015.07.018

  43. 43.

    Chakrabarti S. (2014 ). Altered serum levels of adipokines and insulin in probable Alzheimer’s disease. J. Alzheimers Dis. 41 525–533.

    Not in our library10.3233/jad-140006

  44. 44.
    Adiponectin Potentially Contributes to the Antidepressive Effects of Baduanjin Qigong Exercise in Women with Chronic Fatigue Syndrome-Like Illness · 2017
    Not checked
  45. 45.
    Adiponectin is Protective against Oxidative Stress Induced Cytotoxicity in Amyloid-Beta Neurotoxicity · 2012
    No notice
  46. 46.

    Chandrasekar B. Boylston W. H. Venkatachalam K. Webster N. J. G. Prabhu S. D. Valente A. J. (2008 ). Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-κB/PTEN suppression. J. Biol. Chem. 283 24889–24898.

    Not in our library10.1074/jbc.m804236200

  47. 47.

    Chehab F. F. (2014 ). Leptin and reproduction: past milestones, present undertakings and future endeavors. J. Endocrinol. 223 T37–T48.

    Not in our library10.1530/joe-14-0413

  48. 48.

    Chen B. Liao W.-Q. Xu N. Xu H. Wen J.-Y. Yu C.-A. (2009 ). Adiponectin protects against cerebral ischemia–reperfusion injury through anti-inflammatory action. Brain Res. 1273 129–137.

    Not in our library10.1016/j.brainres.2009.04.002

  49. 49.

    Cheng A. Uetani N. Simoncic P. D. Chaubey V. P. Lee-Loy A. McGlade C. J. (2002 ). Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2 497–503.

    Not in our library10.1016/s1534-5807(02)00149-1

  50. 50.

    Cheng K. K. Y. Lam K. S. L. Wang Y. Huang Y. Carling D. Wu D. (2007 ). Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 56 1387–1394.

    Not in our library10.2337/db06-1580

  51. 51.

    Cisternas P. Martinez M. Ahima R. S. William Wong G. Inestrosa N. C. (2018 ). Modulation of glucose metabolism in hippocampal neurons by adiponectin and resistin. Mol. Neurobiol. [Epub ahead of print].

    Not in our library10.1007/s12035-018-1271-x

  52. 52.

    Coope A. Milanski M. Araújo E. P. Tambascia M. Saad M. J. A. Geloneze B. (2008 ). AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus. FEBS Lett. 582 1471–1476.

    Not in our library10.1016/j.febslet.2008.03.037

  53. 53.

    De Felice F. G. (2013 ). Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J. Clin. Invest. 123 531–539.

    Not in our library10.1172/jci64595

  54. 54.

    De Felice F. G. Ferreira S. T. (2014 ). Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 63 2262–2272.

    Not in our library10.2337/db13-1954

  55. 55.

    De Felice F. G. Lourenco M. V. (2015 ). Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease. Front. Aging Neurosci. 7:94

    Not in our library10.3389/fnagi.2015.00094

  56. 56.

    De Felice F. G. Vieira M. N. N. Bomfim T. R. Decker H. Velasco P. T. Lambert M. P. (2009 ). Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc. Natl. Acad. Sci. U.S.A. 106 1971–1976.

    Not in our library10.1073/pnas.0809158106

  57. 57.

    de Git K. C. G. Adan R. A. H. (2015 ). Leptin resistance in diet-induced obesity: the role of hypothalamic inflammation. Obes. Rev. 16 207–224.

    Not in our library10.1111/obr.12243

  58. 58.

    de la Monte S. M. (2017 ). Insulin resistance and neurodegeneration: progress towards the development of new therapeutics for Alzheimer’s disease. Drugs 77 47–65.

    Not in our library10.1007/s40265-016-0674-0

  59. 59.

    de la Monte S. M. Longato L. Tong M. Wands J. R. (2009 ). Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. Curr. Opin. Investig. Drugs 10 1049–1060.

    Not in our library

  60. 60.

    DeKosky S. T. Scheff S. W. (1990 ). Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27 457–464.

    Not in our library10.1002/ana.410270502

  61. 61.

    Denver R. J. Bonett R. M. Boorse G. C. (2011 ). Evolution of leptin structure and function. Neuroendocrinology 94 21–38.

    Not in our library10.1159/000328435

  62. 62.
    The LepR-mediated leptin transport across brain barriers controls food reward · 2018
    Not checked
  63. 63.

    Dietrich M. O. Spuch C. Antequera D. Rodal I. de Yébenes J. G. Molina J. A. (2008 ). Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol. Aging 29 902–912.

    Not in our library10.1016/j.neurobiolaging.2007.01.008

  64. 64.

    Doherty G. H. Beccano-Kelly D. Yan S. D. Gunn-Moore F. J. Harvey J. (2013 ). Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β. Neurobiol. Aging 34 226–237.

    Not in our library10.1016/j.neurobiolaging.2012.08.003

  65. 65.

    Dong X. Wang Y. Qin Z. (2009 ). Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol. Sin. 30 379–387.

    Not in our library10.1038/aps.2009.24

  66. 66.

    Elfeky M. Kaede R. Okamatsu-Ogura Y. Kimura K. (2016 ). Adiponectin inhibits LPS-induced HMGB1 release through an AMP kinase and Heme Oxygenase-1-dependent pathway in RAW 264 macrophage cells. Mediators Inflamm. 2016:5701959.

    Not in our library10.1155/2016/5701959

  67. 67.

    Elfeky M. Yoneshiro T. Okamatsu-Ogura Y. Kimura K. (2018 ). Adiponectin suppression of late inflammatory mediator, HMGB1-induced cytokine expression in RAW264 macrophage cells. J. Biochem. 163 143–153.

    Not in our library10.1093/jb/mvx069

  68. 68.

    Elias M. F. Elias P. K. Sullivan L. M. Wolf P. A. D’Agostino R. B. (2005 ). Obesity, diabetes and cognitive deficit: the Framingham Heart Study. Neurobiol. Aging 26 11–16.

    Not in our library10.1016/j.neurobiolaging.2005.08.019

  69. 69.

    Elmquist J. K. Bjørbæk C. Ahima R. S. Flier J. S. Saper C. B. (1998 ). Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395 535–547.

    Not in our library

  70. 70.

    Elmquist J. K. Coppari R. Balthasar N. Ichinose M. Lowell B. B. (2005 ). Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J. Comp. Neurol. 493 63–71.

    Not in our library10.1002/cne.20786

  71. 71.

    Emmerzaal T. L. Kiliaan A. J. Gustafson D. R. (2014 ). 2003-2013: a decade of body mass index, Alzheimer’s disease, and dementia. J. Alzheimers Dis. 43 739–755.

    Not in our library10.3233/jad-141086

  72. 72.

    Engin A. (2017 ). Diet-induced obesity and the mechanism of leptin resistance. Adv. Exp. Med. Biol. 960 381–397.

    Not in our library10.1007/978-3-319-48382-5_16

  73. 73.

    Espeland M. A. Luchsinger J. A. Baker L. D. Neiberg R. Kahn S. E. Arnold S. E. (2017 ). Effect of a long-term intensive lifestyle intervention on prevalence of cognitive impairment. Neurology 88 2026–2035.

    Not in our library10.1212/wnl.0000000000003955

  74. 74.

    Farr S. A. Banks W. A. Morley J. E. (2006 ). Effects of leptin on memory processing. Peptides 27 1420–1425.

    Not in our library10.1016/j.peptides.2005.10.006

  75. 75.

    Fasshauer M. Blüher M. (2015 ). Adipokines in health and disease. Trends Pharmacol. Sci. 36 461–470.

    Not in our library10.1016/j.tips.2015.04.014

  76. 76.

    Ferreira S. T. Clarke J. R. Bomfim T. R. De Felice F. G. (2014 ). Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement. 10 S76–S83.

    Not in our library10.1016/j.jalz.2013.12.010

  77. 77.

    Ferreira S. T. Klein W. L. (2011 ). The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol. Learn. Mem. 96 529–543.

    Not in our library10.1016/j.nlm.2011.08.003

  78. 78.

    Fewlass D. C. Noboa K. Pi-Sunyer F. X. Johnston J. M. Yan S. D. Tezapsidis N. (2004 ). Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J. 18 1870–1878.

    Not in our library10.1096/fj.04-2572com

  79. 79.

    Forny-Germano L. Lyra e Silva N. M. Batista A. F. Brito-Moreira J. Gralle M. Boehnke S. E. (2014 ). Alzheimer’s disease-like pathology induced by amyloid-β oligomers in nonhuman primates. J. Neurosci. 34 13629–13643.

    Not in our library10.1523/jneurosci.1353-14.2014

  80. 80.

    Friedemann C. Heneghan C. Mahtani K. Thompson M. Perera R. Ward A. M. (2012 ). Cardiovascular disease risk in healthy children and its association with body mass index: systematic review and meta-analysis. BMJ 345:e4759.

    Not in our library10.1136/bmj.e4759

  81. 81.

    Friedman J. (2016 ). The long road to leptin. J. Clin. Invest. 126 4727–4734.

    Not in our library10.1172/jci91578

  82. 82.

    Frisardi V. Solfrizzi V. Seripa D. Capurso C. Santamato A. Sancarlo D. (2010 ). Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res. Rev. 9 399–417.

    Not in our library10.1016/j.arr.2010.04.007

  83. 83.

    Fruebis J. Tsao T.-S. Javorschi S. Ebbets-Reed D. Erickson M. R. S. Yen F. T. (2001 ). Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc. Natl. Acad. Sci. U.S.A. 98 2005–2010.

    Not in our library10.1073/pnas.98.4.2005

  84. 84.

    Furigo I. C. Melo H. M. Lyra E. Silva N. M. Ramos-Lobo A. M. Teixeira P. D. S. (2018 ). Brain STAT5 signaling modulates learning and memory formation. Brain Struct. Funct. 223 2229–2241.

    Not in our library10.1007/s00429-018-1627-z

  85. 85.

    Gallo V. Wark P. A. Jenab M. Pearce N. Brayne C. Vermeulen R. (2013 ). Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis: the EPIC cohort. Neurology 80 829–838.

    Not in our library10.1212/wnl.0b013e3182840689

  86. 86.

    Gao S. Nguyen J. T. Hendrie H. C. Unverzagt F. W. Hake A. Smith-Gamble V. (2011 ). Accelerated weight loss and incident dementia in an elderly African-American cohort. J. Am. Geriatr. Soc. 59 18–25.

    Not in our library10.1111/j.1532-5415.2010.03169.x

  87. 87.

    García-Casares N. García-Arnés J. A. Rioja J. Ariza M. J. Gutiérrez A. Alfaro F. (2016 ). Alzheimer’s like brain changes correlate with low adiponectin plasma levels in type 2 diabetic patients. J. Diabetes Complications 30 281–286.

    Not in our library10.1016/j.jdiacomp.2015.12.001

  88. 88.

    García-García I. Michaud A. Dadar M. Zeighami Y. Neseliler S. Collins D. L. (2018 ). Neuroanatomical differences in obesity: meta-analytic findings and their validation in an independent dataset. Int. J. Obes. [Epub ahead of print].

    Not in our library10.1038/s41366-018-0164-4

  89. 89.

    Garza J. C. Guo M. Zhang W. Lu X.-Y. (2008 ). Leptin increases adult hippocampal neurogenesis in Vivo and in Vitro. J. Biol. Chem. 283 18238–18247.

    Not in our library10.1074/jbc.m800053200

  90. 90.

    Gong Y. Ishida-Takahashi R. Villanueva E. C. Fingar D. C. Münzberg H. Myers M. G. (2007 ). The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J. Biol. Chem. 282 31019–31027.

    Not in our library10.1074/jbc.m702838200

  91. 91.

    Greco S. J. Bryan K. J. Sarkar S. Zhu X. Smith M. A. Ashford J. W. (2010 ). Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer’s disease. J. Alzheimers Dis. 19 1155–1167.

    Not in our library10.3233/jad-2010-1308

  92. 92.

    Greco S. J. Sarkar S. Johnston J. M. Zhu X. Su B. Casadesus G. (2008 ). Leptin reduces Alzheimer’s disease-related tau phosphorylation in neuronal cells. Biochem. Biophys. Res. Commun. 376 536–541.

    Not in our library10.1016/j.bbrc.2008.09.026

  93. 93.

    Gruol D. L. (2015 ). IL-6 regulation of synaptic function in the CNS. Neuropharmacology 96 42–54.

    Not in our library10.1016/j.neuropharm.2014.10.023

  94. 94.

    Gunstad J. Paul R. H. Cohen R. A. Tate D. F. Spitznagel M. B. Gordon E. (2007 ). Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr. Psychiatry 48 57–61.

    Not in our library10.1016/j.comppsych.2006.05.001

  95. 95.

    Guo F. Jiang T. Song W. Wei H. Wang F. Liu L. (2015 ). Electroacupuncture attenuates cerebral ischemia-reperfusion injury in diabetic mice through adiponectin receptor 1-mediated phosphorylation of GSK-3β. Mol. Neurobiol. 51 685–695.

    Not in our library10.1007/s12035-014-8765-y

  96. 96.

    Gustafson D. R. Bäckman K. Lissner L. Carlsson L. Waern M. Östling S. (2012 ). Leptin and dementia over 32 years-The Prospective Population Study of Women. Alzheimers Dement. 8 272–277.

    Not in our library10.1016/j.jalz.2011.05.2411

  97. 97.

    Harvey J. (2015 ). “Leptin and Alzheimer’s disease,” in Diet and Nutrition in Dementia and Cognitive Decline, eds Martin C. Preedy V. (San Diego, CA: Academic Press), 457–467.

    Not in our library

  98. 98.

    Haslam D. W. James W. P. T. (2005 ). Obesity. Lancet 366 1197–1209.

    Not in our library10.1016/s0140-6736(05)67483-1

  99. 99.

    Hassing L. B. Dahl A. K. Thorvaldsson V. Berg S. Gatz M. Pedersen N. L. (2009 ). Overweight in midlife and risk of dementia: a 40-year follow-up study. Int. J. Obes. 33 893–898.

    Not in our library10.1038/ijo.2009.104

  100. 100.

    Hendrickx H. McEwen B. S. van der Ouderaa F. (2005 ). Metabolism, mood and cognition in aging: the importance of lifestyle and dietary intervention. Neurobiol. Aging 26 1–5.

    Not in our library10.1016/j.neurobiolaging.2005.10.005

  101. 101.

    Heneka M. T. Carson M. J. El Khoury J. Landreth G. E. Brosseron F. Feinstein D. L. (2015 ). Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14 388–405.

    Not in our library10.1016/s1474-4422(15)70016-5

  102. 102.

    Hileman S. M. Pierroz D. D. Masuzaki H. Bjørbæk C. El-Haschimi K. Banks W. A. (2002 ). Characterization of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology 143 775–783.

    Not in our library10.1210/endo.143.3.8669

  103. 103.

    Hill J. O. Wyatt H. R. Peters J. C. (2012 ). Energy balance and obesity. Circulation 126 126–132.

    Not in our library10.1161/circulationaha.111.087213

  104. 104.

    Holden K. F. Lindquist K. Tylavsky F. A. Rosano C. Harris T. B. Yaffe K. (2009 ). Serum leptin level and cognition in the elderly: findings from the Health ABC Study. Neurobiol. Aging 30 1483–1489.

    Not in our library10.1016/j.neurobiolaging.2007.11.024

  105. 105.
    The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development · 2018
    No notice
  106. 106.

    Hotamisligil G. S. (2017 ). Foundations of immunometabolism and implications for metabolic health and disease. Immunity 47 406–420.

    Not in our library10.1016/j.immuni.2017.08.009

  107. 107.

    Hotta K. Funahashi T. Bodkin N. L. Ortmeyer H. K. Arita Y. Hansen B. C. (2001 ). Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50 1126–1133.

    Not in our library10.2337/diabetes.50.5.1126

  108. 108.

    Hoyda T. D. Fry M. Ahima R. S. Ferguson A. V. (2007 ). Adiponectin selectively inhibits oxytocin neurons of the paraventricular nucleus of the hypothalamus. J. Physiol. 585 805–816.

    Not in our library10.1113/jphysiol.2007.144519

  109. 109.

    Hube F. Lietz U. Igel M. Jensen P. B. Tornqvist H. Joost H. G. (1996 ). Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm. Metab. Res. 28 690–693.

    Not in our library10.1055/s-2007-979879

  110. 110.

    Hughes T. F. Ganguli M. (2009 ). Modifiable midlife risk factors for late-life cognitive impairment and dementia. Curr. Psychiatry Rev. 5 73–92.

    Not in our library10.2174/157340009788167347

  111. 111.

    Iraizoz I. Guijarro J. L. Gonzalo L. M. de Lacalle S. (1999 ). Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia. Acta Neuropathol. 98 186–196.

    Not in our library10.1007/s004010051068

  112. 112.

    Irving A. J. Harvey J. (2013 ). Leptin regulation of hippocampal synaptic function in health and disease. Philos. Trans. R. Soc. B Biol. Sci. 369:20130155.

    Not in our library10.1098/rstb.2013.0155

  113. 113.

    Iwahara N. Hisahara S. Kawamata J. Matsumura A. Yokokawa K. Saito T. (2017 ). Role of suppressor of cytokine signaling 3 (SOCS3) in altering activated microglia phenotype in APPswe/PS1dE9 mice. J. Alzheimers Dis. 55 1235–1247.

    Not in our library10.3233/jad-160887

  114. 114.

    Jeon B. T. Shin H. J. Kim J. B. Kim Y. K. Lee D. H. Kim K. H. (2009 ). Adiponectin protects hippocampal neurons against kainic acid-induced excitotoxicity. Brain Res. Rev. 61 81–88.

    Not in our library10.1016/j.brainresrev.2009.05.002

  115. 115.

    Jeong H.-G. Min B. J. Lim S. Kim T. H. Lee J. J. Park J. H. (2012 ). Plasma adiponectin elevation in elderly individuals with subsyndromal depression. Psychoneuroendocrinology 37 948–955.

    Not in our library10.1016/j.psyneuen.2011.11.002

  116. 116.

    Johnson D. Wilkins C. Morris J. (2006 ). Accelerated weight loss may precede diagnosis in alzheimer disease. Arch. Neurol. 63 1312–1317.

    Not in our library10.1001/archneur.63.9.1312

  117. 117.

    Johnston J. M. Hu W. T. Fardo D. W. Greco S. J. Perry G. Montine T. J. (2014 ). Low plasma leptin in cognitively impaired ADNI subjects: gender differences and diagnostic and therapeutic potential. Curr. Alzheimer Res. 11 165–174.

    Not in our library10.2174/1567205010666131212114156

  118. 118.

    Joo S. H. Yun S. H. Kang D. W. Hahn C. T. Lim H. K. Lee C. U. (2018 ). Body mass index in mild cognitive impairment according to age, sex, cognitive intervention, and hypertension and risk of progression to Alzheimer’s disease. Front. Psychiatry 9:142.

    Not in our library10.3389/fpsyt.2018.00142

  119. 119.

    Jung T. W. Lee J. Y. Shim W. S. Kang E. S. Kim J. S. Ahn C. W. (2006 ). Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity. Biochem. Biophys. Res. Commun. 343 564–570.

    Not in our library10.1016/j.bbrc.2006.02.186

  120. 120.

    Jürgensen S. Antonio L. L. Mussi G. E. A. Brito-Moreira J. Bomfim T. R. De Felice F. G. (2011 ). Activation of D1/D5 dopamine receptors protects neurons from synapse dysfunction induced by amyloid-β oligomers. J. Biol. Chem. 286 3270–3276.

    Not in our library10.1074/jbc.m110.177790

  121. 121.

    Kaminski T. Smolinska N. Maleszka A. Kiezun M. Dobrzyn K. Czerwinska J. (2014 ). Expression of adiponectin and its receptors in the porcine hypothalamus during the oestrous cycle. Reprod. Domest. Anim. 49 378–386.

    Not in our library10.1111/rda.12282

  122. 122.

    Kamogawa K. Kohara K. Tabara Y. Uetani E. Nagai T. Yamamoto M. (2010 ). Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study. Dement. Geriatr. Cogn. Disord. 30 432–439.

    Not in our library10.1159/000321985

  123. 123.

    Kerwin D. R. Gaussoin S. A. Chlebowski R. T. Kuller L. H. Vitolins M. Coker L. H. (2011 ). Interaction between body mass index and central adiposity and risk of incident cognitive impairment and dementia: results from the women’s health initiative memory study. J. Am. Geriatr. Soc. 59 107–112.

    Not in our library10.1111/j.1532-5415.2010.03219.x

  124. 124.

    Khemka V. K. Bagchi D. Bandyopadhyay K. Bir A. Chattopadhyay M. Biswas A. (2014a ). Altered serum levels of adipokines and insulin in probable Alzheimer’s disease. J. Alzheimers Dis. 41 525–533.

    Not in our library10.3233/jad-140006

  125. 125.

    Khemka V. K. Ganguly A. Bagchi D. Ghosh A. Bir A. Biswas A. (2014b ). Raised serum proinflammatory cytokines in Alzheimer’s disease with depression. Aging Dis. 5 170–176.

    Not in our library10.14336/ad.2014.0500170

  126. 126.

    Kiliaan A. J. Arnoldussen I. A. C. Gustafson D. R. (2014 ). Adipokines: a link between obesity and dementia? Lancet Neurol. 13 913–923.

    Not in our library10.1016/s1474-4422(14)70085-7

  127. 127.

    Kim B. Feldman E. L. (2015 ). Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome. Exp. Mol. Med. 47:e149.

    Not in our library10.1038/emm.2015.3

  128. 128.

    Kim M. W. Abid N. B. Jo M. H. Jo M. G. Yoon G. H. Kim M. O. (2017 ). Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies. Sci. Rep. 7:12435.

    Not in our library10.1038/s41598-017-12632-9

  129. 129.

    King A. Brain A. Hanson K. Dittmann J. Vickers J. Fernandez-Martos C. (2018 ). Disruption of leptin signalling in a mouse model of Alzheimer’s disease. Metab. Brain Dis. 33 1097–1110.

    Not in our library10.1007/s11011-018-0203-9

  130. 130.

    Kivipelto M. Ngandu T. Fratiglioni L. Viitanen M. Kåreholt I. Winblad B. (2005 ). Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch. Neurol. 62 1556–1560.

    Not in our library10.1001/archneur.62.10.1556

  131. 131.

    Kleinert M. Clemmensen C. Hofmann S. M. Moore M. C. Renner S. Woods S. C. (2018 ). Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 14 140–162.

    Not in our library10.1038/nrendo.2017.161

  132. 132.

    Komatsu M. Ohfusa H. Sato Y. Yajima H. Yamauchi K. Aizawa T. (2004 ). Strong inverse correlation between serum adiponectin level and heart rate-corrected QT interval in an apparently healthy population: a suggestion for a direct antiatherogenic effect of adiponectin. Diabetes Care 27 1237–1238.

    Not in our library10.2337/diacare.27.5.1237

  133. 133.

    Kubota N. Yano W. Kubota T. Yamauchi T. Itoh S. Kumagai H. (2007 ). Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6 55–68.

    Not in our library10.1016/j.cmet.2007.06.003

  134. 134.

    Kusminski C. M. McTernan P. G. Schraw T. Kos K. O’Hare J. P. Ahima R. (2007 ). Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum. Diabetologia 50 634–642.

    Not in our library10.1007/s00125-006-0577-9

  135. 135.

    Lambert M. P. Barlow A. K. Chromy B. A. Edwards C. Freed R. Liosatos M. (1998 ). Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U.S.A. 95 6448–6453.

    Not in our library10.1073/pnas.95.11.6448

  136. 136.

    Lee B.-C. Lee J. (2014 ). Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim. Biophys. Acta 1842 446–462.

    Not in our library10.1016/j.bbadis.2013.05.017

  137. 137.

    Lee G. H. Proenca R. Montez J. M. Carroll K. M. Darvishzadeh J. G. Lee J. I. (1996 ). Abnormal splicing of the leptin receptor in diabetic mice. Nature 379 632–635.

    Not in our library10.1038/379632a0

  138. 138.

    Lee M.-H. Klein R. L. El-Shewy H. M. Luttrell D. K. Luttrell L. M. (2008 ). The adiponectin receptors AdipoR1 and AdipoR2 activate ERK1/2 through a Src/Ras-dependent pathway and stimulate cell growth †. Biochemistry 47 11682–11692.

    Not in our library10.1021/bi801451f

  139. 139.

    Lehr S. Hartwig S. Lamers D. Famulla S. Müller S. Hanisch F.-G. (2012 ). Identification and validation of novel adipokines released from primary human adipocytes. Mol. Cell. Proteomics 11:M111.010504.

    Not in our library10.1074/mcp.m111.010504

  140. 140.

    Lehtisalo J. Lindström J. Ngandu T. Kivipelto M. Ahtiluoto S. Ilanne-Parikka P. (2016 ). Association of long-term dietary fat intake, exercise, and weight with later cognitive function in the Finnish Diabetes Prevention Study. J. Nutr. Health Aging 20 146–154.

    Not in our library10.1007/s12603-015-0565-1

  141. 141.

    Lengyel E. Makowski L. DiGiovanni J. Kolonin M. G. (2018 ). Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4 374–384.

    Not in our library10.1016/j.trecan.2018.03.004

  142. 142.

    Li A. Yau S. Machado S. Yuan T.-F. So K.-F. (2015 ). Adult neurogenic and antidepressant effects of adiponectin: a potential replacement for exercise? CNS Neurol. Disord. Drug Targets 14 1129–1144.

    Not in our library10.2174/1871527315666151111125533

  143. 143.

    Li S. Hong S. Shepardson N. E. Walsh D. M. Shankar G. M. Selkoe D. (2009 ). Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62 788–801.

    Not in our library10.1016/j.neuron.2009.05.012

  144. 144.

    Li S. Stys P. K. (2000 ). Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J. Neurosci. 20 1190–1198.

    Not in our library10.1523/jneurosci.20-03-01190.2000

  145. 145.

    Li X.-L. Aou S. Oomura Y. Hori N. Fukunaga K. Hori T. (2002 ). Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 113 607–615.

    Not in our library10.1016/s0306-4522(02)00162-8

  146. 146.

    Licinio J. Mantzoros C. Negrão A. B. Cizza G. Wong M.-L. Bongiorno P. B. (1997 ). Human leptin levels are pulsatile and inversely related to pituitary–adrenal function. Nat. Med. 3 575–579.

    Not in our library10.1038/nm0597-575

  147. 147.

    Lieb W. Beiser A. S. Vasan R. S. Tan Z. S. Au R. Harris T. B. (2009 ). Association of plasma leptin levels with incident Alzheimer’s disease and MRI measures of brain aging: the Framingham study. JAMA 302 2565–2572.

    Not in our library10.1001/jama.2009.1836

  148. 148.
    Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease · 2015
    No notice
  149. 149.

    Liu Y. Palanivel R. Rai E. Park M. Gabor T. V. Scheid M. P. (2015 ). Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes 64 36–48.

    Not in our library10.2337/db14-0267

  150. 150.

    Liu C. Feng X. Li Q. Wang Y. Li Q. Hua M. (2016 ). Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: a systematic review and meta-analysis. Cytokine 86 100–109.

    Not in our library10.1016/j.cyto.2016.06.028

  151. 151.

    Liu M. Liu F. (2014 ). Regulation of adiponectin multimerization, signaling and function. Best Pract. Res. Clin. Endocrinol. Metab. 28 25–31.

    Not in our library10.1016/j.beem.2013.06.003

  152. 152.

    Lourenco M. V. Clarke J. R. Frozza R. L. Bomfim T. R. Forny-Germano L. Batista A. F. (2013 ). TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s β-amyloid oligomers in mice and monkeys. Cell Metab. 18 831–843.

    Not in our library10.1016/j.cmet.2013.11.002

  153. 153.

    Lu X.-Y. Kim C. S. Frazer A. Zhang W. (2006 ). Leptin: a potential novel antidepressant. Proc. Natl. Acad. Sci. U.S.A. 103 1593–1598.

    Not in our library10.1073/pnas.0508901103

  154. 154.

    Luo X. McGregor G. Irving A. J. Harvey J. (2015 ). Leptin induces a novel form of NMDA receptor-dependent LTP at hippocampal temporoammonic-CA1 synapses. eNeuro 2:ENEURO.0007–ENEURO.15.

    Not in our library10.1523/eneuro.0007-15.2015

  155. 155.

    Luppino F. de Wit L. Bouvy P. Et A. (2010 ). Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch. Gen. Psychiatry 67 220–229.

    Not in our library10.1001/archgenpsychiatry.2010.2

  156. 156.

    Ma J.-J. Shang J. Wang H. Sui J.-R. Liu K. Du J.-X. (2016 ). Serum adiponectin levels are inversely correlated with leukemia: a meta-analysis. J. Cancer Res. Ther. 12 897–902.

    Not in our library10.4103/0973-1482.186695

  157. 157.

    Ma L. Wang R. Dong W. Zhao Z. (2018 ). Caloric restriction can improve learning and memory in C57/BL mice probably via regulation of the AMPK signaling pathway. Exp. Gerontol. 102 28–35.

    Not in our library10.1016/j.exger.2017.11.013

  158. 158.

    Maddineni S. Metzger S. Ocón O. Hendricks G. Ramachandran R. (2005 ). Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression. Endocrinology 146 4250–4256.

    Not in our library10.1210/en.2005-0254

  159. 159.

    Maioli S. Lodeiro M. Merino-Serrais P. Falahati F. Khan W. Puerta E. (2015 ). Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer’s disease. Aging Cell 14 122–129.

    Not in our library10.1111/acel.12281

  160. 160.

    Malenka R. C. Bear M. F. (2004 ). LTP and LTD. Neuron 44 5–21.

    Not in our library10.1016/j.neuron.2004.09.012

  161. 161.

    Malinowski J. M. Bolesta S. (2000 ). Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. Clin. Ther. 22 1151–1168.

    Not in our library10.1016/s0149-2918(00)83060-x

  162. 162.

    Man H. Y. Ju W. Ahmadian G. Wang Y. T. (2000 ). Intracellular trafficking of AMPA receptors in synaptic plasticity. Cell. Mol. Life Sci. 57 1526–1534.

    Not in our library10.1007/pl00000637

  163. 163.

    Mansur R. B. Brietzke E. McIntyre R. S. (2015 ). Is there a “metabolic-mood syndrome”? A review of the relationship between obesity and mood disorders. Neurosci. Biobehav. Rev. 52 89–104.

    Not in our library10.1016/j.neubiorev.2014.12.017

  164. 164.

    Mao X. Kikani C. K. Riojas R. A. Langlais P. Wang L. Ramos F. J. (2006 ). APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat. Cell Biol. 8 516–523.

    Not in our library10.1038/ncb1404

  165. 165.

    Marqués-Iturria I. Pueyo R. Garolera M. Segura B. Junqué C. García-García I. (2013 ). Frontal cortical thinning and subcortical volume reductions in early adulthood obesity. Psychiatry Res. Neuroimaging 214 109–115.

    Not in our library10.1016/j.pscychresns.2013.06.004

  166. 166.

    Marwarha G. Dasari B. Jaya Prasanthi R. P. Schommer J. Ghribi O. (2010 ). β-amyloid regulates leptin expression and tau phosphorylation through the mTORC1 signaling pathway. J. Neurochem. 115 373–384.

    Not in our library10.1111/j.1471-4159.2010.06929.x

  167. 167.

    Mather A. A. Cox B. J. Enns M. W. Sareen J. (2009 ). Associations of obesity with psychiatric disorders and suicidal behaviors in a nationally representative sample. J. Psychosom. Res. 66 277–285.

    Not in our library10.1016/j.jpsychores.2008.09.008

  168. 168.

    McCrimmon R. J. Ryan C. M. Frier B. M. (2012 ). Diabetes and cognitive dysfunction. Lancet 379 2291–2299.

    Not in our library10.1016/s0140-6736(12)60360-2

  169. 169.

    McGregor G. Clements L. Farah A. Irving A. J. Harvey J. (2018 ). Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin. Neurobiol. Aging 69 76–93.

    Not in our library10.1016/j.neurobiolaging.2018.05.007

  170. 170.

    McGregor G. Harvey J. (2017 ). Leptin regulation of synaptic function at hippocampal TA-CA1 and SC-CA1 synapses: implications for health and disease. Neurochem. Res. [Epub ahead of print].

    Not in our library10.1007/s11064-017-2362-1

  171. 171.

    McGregor G. Irving A. J. Harvey J. (2017 ). Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses. FASEB J. 31 3449–3466.

    Not in our library10.1096/fj.201601293rr

  172. 172.

    Mcguire M. J. Ishii M. (2016 ). Leptin dysfunction and Alzheimer’s disease: evidence from cellular, animal, and human studies. Cell. Mol. Neurobiol. 36 203–217.

    Not in our library10.1007/s10571-015-0282-7.leptin

  173. 173.

    McLean F. H. Grant C. Morris A. C. Horgan G. W. Polanski A. J. Allan K. (2018 ). Rapid and reversible impairment of episodic memory by a high-fat diet in mice. Sci. Rep. 8:11976.

    Not in our library10.1038/s41598-018-30265-4

  174. 174.

    Mercer J. G. Hoggard N. Williams L. M. Lawrence C. B. Hannah L. T. Trayhurn P. (2018 ). Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 387 113–116.

    Not in our library10.1016/0014-5793(96)00473-5

  175. 175.

    Miyatake Y. Shiuchi T. Ueta T. Taniguchi Y. Futami A. Sato F. (2015 ). Intracerebroventricular injection of adiponectin regulates locomotor activity in rats. J. Med. Investig. 62 199–203.

    Not in our library10.2152/jmi.62.199

  176. 176.

    Miyoshi Y. Funahashi T. Kihara S. Taguchi T. Tamaki Y. Matsuzawa Y. (2003 ). Association of serum adiponectin levels with breast cancer risk. Clin. Cancer Res. 9 5699–5704.

    Not in our library

  177. 177.

    Mody N. Agouni A. Mcilroy G. D. Platt B. Delibegovic M. (2011 ). Susceptibility to diet-induced obesity and glucose intolerance in the APPSWE/PSEN1A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal. Diabetologia 54 2143–2151.

    Not in our library10.1007/s00125-011-2160-2

  178. 178.

    Morash B. Li A. Murphy P. R. Wilkinson M. Ur E. (1999 ). Leptin gene expression in the brain and pituitary gland. Endocrinology 140 5995–5998.

    Not in our library10.1210/endo.140.12.7288

  179. 179.

    Morrison C. D. White C. L. Wang Z. Lee S.-Y. Lawrence D. S. Cefalu W. T. (2007 ). Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology 148 433–440.

    Not in our library10.1210/en.2006-0672

  180. 180.

    Moult P. Harvey J. (2009 ). Regulation of glutamate receptor trafficking by leptin. Biochem. Soc. Trans. 37 1364–1368.

    Not in our library10.1042/bst0371364

  181. 181.

    Moult P. R. Cross A. Santos S. D. Carvalho A.-L. Lindsay Y. Connolly C. N. (2010 ). Leptin regulates AMPA receptor trafficking via PTEN inhibition. J. Neurosci. 30 4088–4101.

    Not in our library10.1523/jneurosci.3614-09.2010

  182. 182.

    Moult P. R. Harvey J. (2011 ). NMDA receptor subunit composition determines the polarity of leptin-induced synaptic plasticity. Neuropharmacology 61 924–936.

    Not in our library10.1016/j.neuropharm.2011.06.021

  183. 183.

    Moult P. R. Milojkovic B. Harvey J. (2009 ). Leptin reverses long-term potentiation at hippocampal CA1 synapses. J. Neurochem. 108 685–696.

    Not in our library10.1111/j.1471-4159.2008.05810.x

  184. 184.

    Myers M. G. Cowley M. A. Münzberg H. (2008 ). Mechanisms of leptin action and leptin resistance. Annu. Rev. Physiol. 70 537–556.

    Not in our library10.1146/annurev.physiol.70.113006.100707

  185. 185.

    Myers M. G. Heymsfield S. B. Haft C. Kahn B. B. Laughlin M. Leibel R. L. (2012 ). Defining clinical leptin resistance - challenges and opportunities. Cell Metab. 15 150–156.

    Not in our library10.1016/j.cmet.2012.01.002

  186. 186.

    Myers M. G. Leibel R. L. Seeley R. J. Schwartz M. W. (2010 ). Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol. Metab. 21 643–651.

    Not in our library10.1016/j.tem.2010.08.002

  187. 187.

    Nägga K. Gustavsson A.-M. Stomrud E. Lindqvist D. van Westen D. Blennow K. (2018 ). Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later. Neurology 90 e73–e81.

    Not in our library10.1212/wnl.0000000000004749

  188. 188.

    Nelson T. E. Engberink A. O. Hernandez R. Puro A. Huitron-Resendiz S. Hao C. (2012 ). Altered synaptic transmission in the hippocampus of transgenic mice with enhanced central nervous systems expression of interleukin-6. Brain Behav. Immun. 26 959–971.

    Not in our library10.1016/j.bbi.2012.05.005

  189. 189.

    Neumeier M. Weigert J. Buettner R. Wanninger J. Schäffler A. Müller A. M. (2007 ). Detection of adiponectin in cerebrospinal fluid in humans. Am. J. Physiol. Endocrinol. Metab. 293 E965–E969.

    Not in our library10.1152/ajpendo.00119.2007

  190. 190.

    Ng R. C. L. Chan K. H. (2017 ). Potential neuroprotective effects of adiponectin in Alzheimer’s disease. Int. J. Mol. Sci. 18 1–13.

    Not in our library10.3390/ijms18030592

  191. 191.
    Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice · 2016
    No notice
  192. 192.
    Obesity and cognitive decline: role of inflammation and vascular changes · 2014
    No notice
  193. 193.

    Nicolas S. Cazareth J. Zarif H. Guyon A. Heurteaux C. Chabry J. (2017 ). Globular adiponectin limits microglia pro-inflammatory phenotype through an AdipoR1/NF-κB signaling pathway. Front. Cell. Neurosci. 11:352.

    Not in our library10.3389/fncel.2017.00352

  194. 194.

    Nicolas S. Debayle D. Béchade C. Maroteaux L. Gay A.-S. Bayer P. (2018 ). Adiporon, an adiponectin receptor agonist acts as an antidepressant and metabolic regulator in a mouse model of depression. Transl. Psychiatry 8:159.

    Not in our library10.1038/s41398-018-0210-y

  195. 195.

    Nicolas S. Veyssière J. Gandin C. Zsürger N. Pietri M. Heurteaux C. (2015 ). Neurogenesis-independent antidepressant-like effects of enriched environment is dependent on adiponectin. Psychoneuroendocrinology 57 72–83.

    Not in our library10.1016/j.psyneuen.2015.03.017

  196. 196.

    Nie J.-M. Li H.-F. (2017 ). Metformin in combination with rosiglitazone contribute to the increased serum adiponectin levels in people with type 2 diabetes mellitus. Exp. Ther. Med. 14 2521–2526.

    Not in our library10.3892/etm.2017.4823

  197. 197.

    Oania R. McEvoy L. K. (2015 ). Plasma leptin levels are not predictive of dementia in patients with mild cognitive impairment. Age Ageing 44 53–58.

    Not in our library10.1093/ageing/afu160

  198. 198.

    Odegaard J. I. Chawla A. (2013 ). Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339 172–177.

    Not in our library10.1126/science.1230721

  199. 199.

    Ohashi K. Yuasa D. Shibata R. Murohara T. Ouchi N. (2015 ). Adiponectin as a target in obesity-related inflammatory state. Endocr. Metab. Immune Disord. Drug Targets 15 145–150.

    Not in our library10.2174/1871530315666150316122709

  200. 200.

    Okada-Iwabu M. Yamauchi T. Iwabu M. Honma T. Hamagami K. Matsuda K. (2013 ). A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503 493–499.

    Not in our library10.1038/nature12656

  201. 201.

    Oomura Y. Hori N. Shiraishi T. Fukunaga K. Takeda H. Tsuji M. (2006 ). Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. Peptides 27 2738–2749.

    Not in our library10.1016/j.peptides.2006.07.001

  202. 202.

    Paganoni S. Deng J. Jaffa M. Cudkowicz M. E. Wills A.-M. (2011 ). Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve 44 20–24.

    Not in our library10.1002/mus.22114

  203. 203.

    Pákáski M. Fehér A. Juhász A. Drótos G. Fazekas O. C. Kovács J. (2013 ). Serum adipokine levels modified by donepezil treatment in Alzheimer’s disease. J. Alzheimers Dis. 38 371–377.

    Not in our library10.3233/jad-131139

  204. 204.
    Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis · 2018
    No notice
  205. 205.

    Palta P. Carlson M. C. Crum R. M. Colantuoni E. Sharrett A. R. Yasar S. (2018 ). Diabetes and cognitive decline in older adults: the ginkgo evaluation of memory study. J. Gerontol. Ser. A 73 123–130.

    Not in our library10.1093/gerona/glx076

  206. 206.

    Pan W. Tu H. Kastin A. J. (2006 ). Differential BBB interactions of three ingestive peptides: obestatin, ghrelin, and adiponectin. Peptides 27 911–916.

    Not in our library10.1016/j.peptides.2005.12.014

  207. 207.

    Pan W. W. Myers M. G. Jr. (2018 ). Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19 95–105.

    Not in our library10.1038/nrn.2017.168

  208. 208.

    Pannacciulli N. Del Parigi A. Chen K. Le D. S. N. T. Reiman E. M. Tataranni P. A. (2006 ). Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage 31 1419–1425.

    Not in our library10.1016/j.neuroimage.2006.01.047

  209. 209.

    Park H.-K. Ahima R. S. (2015 ). Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64 24–34.

    Not in our library10.1016/j.metabol.2014.08.004

  210. 210.

    Patterson C. M. Leshan R. L. Jones J. C. Myers M. G. (2011 ). Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res. 1378 18–28.

    Not in our library10.1016/j.brainres.2011.01.010

  211. 211.

    Paula-Lima A. C. Brito-Moreira J. Ferreira S. T. (2013 ). Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer’s disease. J. Neurochem. 126 191–202.

    Not in our library10.1111/jnc.12304

  212. 212.

    Paz-Filho G. Wong M.-L. Licinio J. (2010 ). The procognitive effects of leptin in the brain and their clinical implications. Int. J. Clin. Pract. 64 1808–1812.

    Not in our library10.1111/j.1742-1241.2010.02536.x

  213. 213.

    Pei J.-J. Sersen E. Iqbal K. Grundke-Iqbal I. (1994 ). Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. Brain Res. 655 70–76.

    Not in our library10.1016/0006-8993(94)91598-9

  214. 214.

    Pérez-González R. Alvira-Botero M. X. Robayo O. Antequera D. Garzón M. Martín-Moreno A. M. (2014 ). Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice. Gene Ther. 21 298–308.

    Not in our library10.1038/gt.2013.85

  215. 215.

    Pérez-González R. Antequera D. Vargas T. Spuch C. Bolós M. Carro E. (2011 ). Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer’s disease. J. Alzheimers Dis. 24 17–25.

    Not in our library10.3233/jad-2011-102070

  216. 216.

    Platzer M. Fellendorf F. T. Bengesser S. A. Birner A. Dalkner N. Hamm C. (2018 ). Adiponectin is decreased in bipolar depression. World J. Biol. Psychiatry [Epub ahead of print].

    Not in our library10.1080/15622975.2018.1500033

  217. 217.

    Pousti F. Ahmadi R. Mirahmadi F. Hosseinmardi N. Rohampour K. (2018 ). Adiponectin modulates synaptic plasticity in hippocampal dentate gyrus. Neurosci. Lett. 662 227–232.

    Not in our library10.1016/j.neulet.2017.10.042

  218. 218.

    Psilopanagioti A. Papadaki H. Kranioti E. F. Alexandrides T. K. Varakis J. N. (2009 ). Expression of adiponectin and adiponectin receptors in human pituitary gland and brain. Neuroendocrinology 89 38–47.

    Not in our library10.1159/000151396

  219. 219.

    Qi Y. Takahashi N. Hileman S. M. Patel H. R. Berg A. H. Pajvani U. B. (2004 ). Adiponectin acts in the brain to decrease body weight. Nat. Med. 10 524–529.

    Not in our library10.1038/nm1029

  220. 220.

    Qiu G. Wan R. Hu J. Mattson M. P. Spangler E. Liu S. (2011 ). Adiponectin protects rat hippocampal neurons against excitotoxicity. Age 33 155–165.

    Not in our library10.1007/s11357-010-9173-5

  221. 221.

    Raji C. A. Ho A. J. Parikshak N. Becker J. T. Lopez O. L. Kuller L. H. (2010 ). Brain structure and obesity. Hum. Brain Mapp. 31 353–364.

    Not in our library10.1002/hbm.20870

  222. 222.

    Ramos-Lobo A. M. Donato J. (2017 ). The role of leptin in health and disease. Temperature 4 258–291.

    Not in our library10.1080/23328940.2017.1327003

  223. 223.
    Tumor Necrosis Factor and Interleukin-1 β Modulate Synaptic Plasticity during Neuroinflammation · 2018
    No notice
  224. 224.

    Rosengren A. Skoog I. Gustafson D. Wilhelmsen L. (2005 ). Body mass index, other cardiovascular risk factors, and hospitalization for dementia. Arch. Intern. Med. 165 321–326.

    Not in our library10.1001/archinte.165.3.321

  225. 225.

    Ryu J. Galan A. K. Xin X. Dong F. Abdul-Ghani M. A. Zhou L. (2014 ). APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the Insulin Receptor. Cell Rep. 7 1227–1238.

    Not in our library10.1016/j.celrep.2014.04.006

  226. 226.

    Saad M. F. Damani S. Gingerich R. L. Riad-Gabriel M. G. Khan A. Boyadjian R. (1997 ). Sexual dimorphism in plasma leptin concentration. J. Clin. Endocrinol. Metab. 82 579–584.

    Not in our library10.1210/jcem.82.2.3739

  227. 227.

    Saltiel A. R. Olefsky J. M. (1996 ). Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45 1661–1669.

    Not in our library10.2337/diab.45.12.1661

  228. 228.

    Saltiel A. R. Olefsky J. M. (2017 ). Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127 1–4.

    Not in our library10.1172/jci92035

  229. 229.

    Sarlus H. Heneka M. T. (2017 ). Microglia in Alzheimer’s disease. J. Clin. Invest. 127 3240–3249.

    Not in our library10.1172/jci90606

  230. 230.

    Schwartz M. W. Seeley R. J. Campfield L. A. Burn P. Baskin D. G. (1996 ). Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98 1101–1106.

    Not in our library10.1172/jci118891

  231. 231.

    Scott M. M. Lachey J. L. Sternson S. M. Lee C. E. Elias C. F. Friedman J. M. (2009 ). Leptin targets in the mouse brain. J. Comp. Neurol. 514 518–532.

    Not in our library10.1002/cne.22025

  232. 232.

    Seixas da Silva G. S. Melo H. M. Lourenco M. V. Lyra e Silva N. M. de Carvalho M. B. Alves-Leon S. (2017 ). Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons. J. Biol. Chem. 292 7395–7406.

    Not in our library10.1074/jbc.m116.753525

  233. 233.

    Shah S. A. Yoon G. H. Chung S. S. Abid M. N. Kim T. H. Lee H. Y. (2017 ). Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer’s disease neuropathological deficits. Mol. Psychiatry 22 407–416.

    Not in our library10.1038/mp.2016.23

  234. 234.

    Shankar G. M. Li S. Mehta T. H. Garcia-Munoz A. Shepardson N. E. Smith I. (2008 ). Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 14 837–842.

    Not in our library10.1038/nm1782

  235. 235.

    Shanley L. J. Irving A. J. Harvey J. (2001 ). Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J. Neurosci. 21:RC186.

    Not in our library10.1523/jneurosci.21-24-j0001.2001

  236. 236.
    Overweight is not associated with cortical thickness alterations in children · 2015
    Not checked
  237. 237.

    Shen L.-H. Miao J. Zhao Y.-J. Zhao Y.-J. Liang W. (2014 ). Expression of brain adiponectin in a murine model of transient cerebral ischemia. Int. J. Clin. Exp. Med. 7 4590–4596.

    Not in our library

  238. 238.

    Skeberdis V. A. Lan J.-Y. Zheng X. Zukin R. S. Bennett M. V. L. (2001 ). Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proc. Natl. Acad. Sci. U.S.A. 98 3561–3566.

    Not in our library10.1073/pnas.051634698

  239. 239.

    Song J. Choi S.-M. Kim B. C. (2017 ). Adiponectin regulates the polarization and function of microglia via PPAR-γ signaling under amyloid β toxicity. Front. Cell. Neurosci. 11:64.

    Not in our library10.3389/fncel.2017.00064

  240. 240.

    Song W. Guo F. Zhong H. Liu L. Yang R. Wang Q. (2015 ). Therapeutic window of globular adiponectin against cerebral ischemia in diabetic mice: the role of dynamic alteration of adiponectin/adiponectin receptor expression. Sci. Rep. 5:17310.

    Not in our library10.1038/srep17310

  241. 241.

    Song W. Huo T. Guo F. Wang H. Wei H. Yang Q. (2013 ). Globular adiponectin elicits neuroprotection by inhibiting NADPH oxidase-mediated oxidative damage in ischemic stroke. Neuroscience 248 136–144.

    Not in our library10.1016/j.neuroscience.2013.05.063

  242. 242.

    Spranger J. Verma S. Göhring I. Bobbert T. Seifert J. Sindler A. L. (2006 ). Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells. Diabetes 55 141–147.

    Not in our library

  243. 243.

    Steen E. Terry B. M. Rivera E. J. Cannon J. L. Neely T. R. Tavares R. (2005 ). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J. Alzheimers Dis. 7 63–80.

    Not in our library10.3233/jad-2005-7107

  244. 244.

    Stewart R. Liolitsa D. (1999 ). Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet. Med. 16 93–112.

    Not in our library10.1046/j.1464-5491.1999.00027.x

  245. 245.

    Stewart R. Masaki K. Xue Q. Peila R. Petrovitch H. White L. R. (2005 ). A 32-year prospective study of change in body weight and incident dementia: the honolulu-asia aging study. Arch. Neurol. 62 55–60.

    Not in our library10.1001/archneur.62.1.55

  246. 246.

    Sun F. Lei Y. You J. Li C. Sun L. Garza J. (2018 ). Adiponectin modulates ventral tegmental area dopamine neuron activity and anxiety-related behavior through AdipoR1. Mol. Psychiatry [Epub ahead of print].

    Not in our library10.1038/s41380-018-0102-9

  247. 247.

    Suyama S. Maekawa F. Maejima Y. Kubota N. Kadowaki T. Yada T. (2016 ). Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. Sci. Rep. 6:30796.

    Not in our library10.1038/srep30796

  248. 248.

    Takemura Y. Ouchi N. Shibata R. Aprahamian T. Kirber M. T. Summer R. S. (2007 ). Adiponectin modulates inflammatory reactions via calreticulin receptor–dependent clearance of early apoptotic bodies. J. Clin. Invest. 117 375–386.

    Not in our library10.1172/jci29709

  249. 249.

    Talbot K. Wang H.-Y. Kazi H. Han L.-Y. Bakshi K. P. Stucky A. (2012 ). Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122 1316–1338.

    Not in our library10.1172/jci59903

  250. 250.

    Tartaglia L. A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. (1995 ). Identification and expression cloning of a leptin receptor, OB-R. Cell 83 1263–1271.

    Not in our library10.1016/0092-8674(95)90151-5

  251. 251.

    Teixeira A. L. Diniz B. S. Campos A. C. Miranda A. S. Rocha N. P. Talib L. L. (2013 ). Decreased levels of circulating adiponectin in mild cognitive impairment and Alzheimer’s disease. Neuromolecular Med. 15 115–121.

    Not in our library10.1007/s12017-012-8201-2

  252. 252.

    Terry R. D. Masliah E. Salmon D. P. Butters N. DeTeresa R. Hill R. (1991 ). Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30 572–580.

    Not in our library10.1002/ana.410300410

  253. 253.

    Thundyil J. Pavlovski D. Sobey C. G. Arumugam T. V. (2012 ). Adiponectin receptor signalling in the brain. Br. J. Pharmacol. 165 313–327.

    Not in our library10.1111/j.1476-5381.2011.01560.x

  254. 254.

    Tong J.-Q. Zhang J. Hao M. Yang J. Han Y.-F. Liu X.-J. (2015 ). Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats. Horm. Behav. 73 125–130.

    Not in our library10.1016/j.yhbeh.2015.06.013

  255. 255.

    Trayhurn P. Thomas M. E. Duncan J. S. Rayner D. V. (1995 ). Effects of fasting and refeeding on ob gene expression in white adipose tissue of lean and obese (OBlob) mice. FEBS Lett. 368 488–490.

    Not in our library10.1016/0014-5793(95)00719-p

  256. 256.

    Tsuchida A. Yamauchi T. Takekawa S. Hada Y. Ito Y. Maki T. (2005 ). Peroxisome proliferator–activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue. Diabetes 54 3358–3370.

    Not in our library10.2337/diabetes.54.12.3358

  257. 257.

    Une K. Takei Y. A. Tomita N. Asamura T. Ohrui T. Furukawa K. (2010 ). Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer’s disease. Eur. J. Neurol. 18 1006–1009.

    Not in our library10.1111/j.1468-1331.2010.03194.x

  258. 258.

    van Boxtel M. P. J. Baars L. Jolles J. (2007 ). Obesity, blood pressure and cognitive function: a reply to Waldstein and Katzel. Int. J. Obes. 31:1186.

    Not in our library10.1038/sj.ijo.0803558

  259. 259.

    van Himbergen T. M. Beiser A. S. Ai M. Seshadri S. Otokozawa S. Au R. (2012 ). Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease: results from the Framingham heart study. Arch. Neurol. 69 594–600.

    Not in our library10.1001/archneurol.2011.670

  260. 260.

    Vannucchi G. Toni C. Maremmani I. Perugi G. (2014 ). Does obesity predict bipolarity in major depressive patients? J. Affect. Disord. 155 118–122.

    Not in our library10.1016/j.jad.2013.10.035

  261. 261.

    Várhelyi Z. P. Kálmán J. Oláh Z. Ivitz E. V. Fodor E. K. Sántha M. (2017 ). Adiponectin receptors are less sensitive to stress in a transgenic mouse model of Alzheimer’s disease. Front. Neurosci. 11:199

    Not in our library10.3389/fnins.2017.00199

  262. 262.

    Veit R. Kullmann S. Heni M. Machann J. Häring H.-U. Fritsche A. (2014 ). Reduced cortical thickness associated with visceral fat and BMI. Neuroimage 6 307–311.

    Not in our library10.1016/j.nicl.2014.09.013

  263. 263.

    Vemuri P. Knopman D. S. Lesnick T. G. Przybelski S. A. Mielke M. M. Graff-Radford J. (2017 ). Evaluation of amyloid protective factors and Alzheimer disease neurodegeneration protective factors in elderly individuals. JAMA Neurol. 74 718–726.

    Not in our library10.1001/jamaneurol.2017.0244

  264. 264.

    Vieira M. N. N. Beckman D. (2017 ). Training microglia to resist Alzheimer’s disease. J. Neurosci. 37 477–479.

    Not in our library10.1523/jneurosci.3345-16.2017

  265. 265.

    Vieira M. N. N. Lima-Filho R. A. S. De Felice F. G. (2018 ). Connecting Alzheimer’s disease to diabetes: underlying mechanisms and potential therapeutic targets. Neuropharmacology 136 160–171.

    Not in our library10.1016/j.neuropharm.2017.11.014

  266. 266.

    Vieira M. N. N. Lyra e Silva N. M. Ferreira S. T. De Felice F. G. (2017 ). Protein tyrosine phosphatase 1B (PTP1B): a potential target for Alzheimer’s therapy? Front. Aging Neurosci. 9:7

    Not in our library10.3389/fnagi.2017.00007

  267. 267.

    Vogelzangs N. Kritchevsky S. B. Beekman A. T. F. Brenes G. A. Newman A. B. Satterfield S. (2010 ). Obesity and onset of significant depressive symptoms: results from a community-based cohort of older men and women. J. Clin. Psychiatry 71 391–399.

    Not in our library10.4088/jcp.08m04743blu

  268. 268.

    Waki H. Yamauchi T. Kamon J. Ito Y. Uchida S. Kita S. (2003 ). Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J. Biol. Chem. 278 40352–40363.

    Not in our library10.1074/jbc.m300365200

  269. 269.

    Walker D. G. Whetzel A. M. Lue L.-F. (2015 ). Expression of suppressor of cytokine signaling (SOCS) genes in human elderly and Alzheimer’s disease brains and human microglia. Neuroscience 302 121–137.

    Not in our library10.1016/j.neuroscience.2014.09.052

  270. 270.

    Wang H.-W. Pasternak J. F. Kuo H. Ristic H. Lambert M. P. Chromy B. (2002 ). Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 924 133–140.

    Not in our library10.1016/s0006-8993(01)03058-x

  271. 271.

    Wang M. Y. Zhou Y. T. Newgard C. B. Unger R. H. (1996 ). A novel leptin receptor isoform in rat. FEBS Lett. 392 87–90.

    Not in our library10.1016/0014-5793(96)00790-9

  272. 272.

    Wang R. Reddy P. H. (2017 ). Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimers Dis. 57 1041–1048.

    Not in our library10.3233/jad-160763

  273. 273.

    Wang S. Zhou Y. Yang B. Li L. Yu S. Chen Y. (2016 ). C1q/tumor necrosis factor-related protein-3 attenuates brain injury after intracerebral hemorrhage via AMPK-dependent pathway in rat. Front. Cell. Neurosci. 10:237.

    Not in our library10.3389/fncel.2016.00237

  274. 274.

    Wang Y. Lam K. S. L. Yau M. Xu A. (2008 ). Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem. J. 409 623–633.

    Not in our library10.1042/bj20071492

  275. 275.

    Waterson M. J. Horvath T. L. (2015 ). Neuronal regulation of energy homeostasis: beyond the hypothalamus and feeding. Cell Metab. 22 962–970.

    Not in our library10.1016/j.cmet.2015.09.026

  276. 276.

    Wauman J. Tavernier J. (2011 ). Leptin receptor signaling: pathways to leptin resistance. Front. Biosci. 16 2771–2793.

    Not in our library10.2741/3885

  277. 277.

    White C. L. Whittington A. Barnes M. J. Wang Z. Bray G. A. Morrison C. D. (2009 ). HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. Am. J. Physiol. Endocrinol. Metab. 296 E291–E299.

    Not in our library10.1152/ajpendo.90513.2008

  278. 278.

    Whitehouse P. J. Martino A. M. Antuono P. G. Lowenstein P. R. Coyle J. T. Price D. L. (1986 ). Nicotinic acetylcholine binding sites in Alzheimer’s disease. Brain Res. 371 146–151.

    Not in our library10.1016/0006-8993(86)90819-x

  279. 279.

    Whitmer R. A. Gunderson E. P. Barrett-Connor E. Quesenberry C. P. Yaffe K. (2005 ). Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 330:1360.

    Not in our library10.1136/bmj.38446.466238.e0

  280. 280.

    Whitmer R. A. Gustafson D. R. Barrett-Connor E. Haan M. N. Gunderson E. P. Yaffe K. (2008 ). Central obesity and increased risk of dementia more than three decades later. Neurology 71 1057–1064.

    Not in our library10.1212/01.wnl.0000306313.89165.ef

  281. 281.

    Winocur G. Greenwood C. E. Piroli G. G. Grillo C. A. Reznikov L. R. Reagan L. P. (2005 ). Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity. Behav. Neurosci. 119 1389–1395.

    Not in our library10.1037/0735-7044.119.5.1389

  282. 282.

    Xu H. Gelyana E. Rajsombath M. Yang T. Li S. Selkoe D. (2016 ). Environmental enrichment potently prevents microglia-mediated neuroinflammation by human amyloid β-protein oligomers. J. Neurosci. 36 9041–9056.

    Not in our library10.1523/jneurosci.1023-16.2016

  283. 283.

    Xu L. Rensing N. Yang X.-F. Zhang H. X. Thio L. L. Rothman S. M. (2008 ). Leptin inhibits 4-aminopyridine-and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents. J. Clin. Invest. 118 272–280.

    Not in our library10.1172/jci33009

  284. 284.

    Xu W. L. Atti A. R. Gatz M. Pedersen N. L. Johansson B. Fratiglioni L. (2011 ). Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology 76 1568–1574.

    Not in our library10.1212/wnl.0b013e3182190d09

  285. 285.

    Xu Z. P. Gan G. S. Liu Y. M. Xiao J. S. Liu H. X. Mei B. (2018 ). Adiponectin attenuates streptozotocin-induced tau hyperphosphorylation and cognitive deficits by rescuing PI3K/Akt/GSK-3β pathway. Neurochem. Res. 43 316–323.

    Not in our library10.1007/s11064-017-2426-2

  286. 286.

    Yamauchi T. Hara K. Kubota N. Terauchi Y. Tobe K. Froguel P. (2003a ). Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. Curr. Drug Targets Immune Endocr. Metabol. Disord. 3 243–254.

    Not in our library10.2174/1568008033340090

  287. 287.

    Yamauchi T. Kamon J. Ito Y. Tsuchida A. Yokomizo T. Kita S. (2003b ). Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423 762–769.

    Not in our library10.1038/nature01705

  288. 288.

    Yamauchi T. Kamon J. Minokoshi Y. Ito Y. Waki H. Uchida S. (2002 ). Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8 1288–1295.

    Not in our library10.1038/nm788

  289. 289.

    Yamauchi T. Kamon J. Waki H. Terauchi Y. Kubota N. Hara K. (2001 ). The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7 941–946.

    Not in our library10.1038/90984

  290. 290.

    Yamauchi T. Nio Y. Maki T. Kobayashi M. Takazawa T. Iwabu M. (2007 ). Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13 332–339.

    Not in our library10.1038/nm1557

  291. 291.

    Yang B. Wang S. Yu S. Chen Y. Li L. Zhang H. (2017 ). C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling. Brain Res. 1657 176–184.

    Not in our library10.1016/j.brainres.2016.11.016

  292. 292.

    Yang W.-S. Lee W.-J. Funahashi T. Tanaka S. Matsuzawa Y. Chao C.-L. (2001 ). Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J. Clin. Endocrinol. Metab. 86 3815–3819.

    Not in our library10.1210/jcem.86.8.7741

  293. 293.

    Yarchoan M. Arnold S. E. (2014 ). Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63 2253–2261.

    Not in our library10.2337/db14-0287

  294. 294.

    Yau S. Y. Li A. Hoo R. L. C. Ching Y. P. Christie B. R. Lee T. M. C. (2014 ). Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc. Natl. Acad. Sci. U.S.A. 111 15810–15815.

    Not in our library10.1073/pnas.1415219111

  295. 295.

    Yin H. Tian S. Huang R. Cai R. Guo D. Lin H. (2018 ). Low plasma leptin and high soluble leptin receptor levels are associated with mild cognitive impairment in type 2 diabetic patients. Front. Aging Neurosci. 10:132.

    Not in our library10.3389/fnagi.2018.00132

  296. 296.

    Yokota T. Oritani K. Takahashi I. Ishikawa J. Matsuyama A. Ouchi N. (2000 ). Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96 1723–1732.

    Not in our library

  297. 297.

    Yokum S. Ng J. Stice E. (2011 ). Relation of regional gray and white matter volumes to current BMI and future increases in BMI: a prospective MRI study. Int. J. Obes. 36 656–664.

    Not in our library10.1038/ijo.2011.175

  298. 298.

    Yoon G. Shah S. A. Ali T. Kim M. O. (2018 ). The adiponectin homolog osmotin enhances neurite outgrowth and synaptic complexity via AdipoR1/NgR1 signaling in Alzheimer’s disease. Mol. Neurobiol. 55 6673–6686.

    Not in our library10.1007/s12035-017-0847-1

  299. 299.

    Yu J. G. Javorschi S. Hevener A. L. Kruszynska Y. T. Norman R. A. Sinha M. (2002 ). The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51 2968–2974.

    Not in our library10.2337/diabetes.51.10.2968

  300. 300.

    Zabolotny J. M. Bence-Hanulec K. K. Stricker-Krongrad A. Haj F. Wang Y. Minokoshi Y. (2002 ). PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2 489–495.

    Not in our library10.1016/s1534-5807(02)00148-x

  301. 301.

    Zhang D. Wang X. Lu X.-Y. (2016 ). Adiponectin exerts neurotrophic effects on dendritic arborization, spinogenesis, and neurogenesis of the dentate gyrus of male mice. Endocrinology 157 2853–2869.

    Not in our library10.1210/en.2015-2078

  302. 302.

    Zhang D. Wang X. Wang B. Garza J. C. Fang X. Wang J. (2017 ). Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors. Mol. Psychiatry 22 1044–1055.

    Not in our library10.1038/mp.2016.58

  303. 303.

    Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J. M. (1994 ). Positional cloning of the mouse obese gene and its human homologue. Nature 372 425–432.

    Not in our library10.1038/372425a0

  304. 304.

    Zhao L. Chen S. Sherchan P. Ding Y. Zhao W. Guo Z. (2018 ). Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice. J. Neuroinflammation 15:215.

    Not in our library10.1186/s12974-018-1256-8

  305. 305.

    Zhao W.-Q. Chen H. Quon M. J. Alkon D. L. (2004 ). Insulin and the insulin receptor in experimental models of learning and memory. Eur. J. Pharmacol. 490 71–81.

    Not in our library10.1016/j.ejphar.2004.02.045

  306. 306.

    Zhou Q. Xiang H. Li A. Lin W. Huang Z. Guo J. (2018 ). Activating adiponectin signaling with exogenous AdipoRon reduces myelin lipid accumulation and suppresses macrophage recruitment after spinal cord injury. J. Neurotrauma [Epub ahead of print].

    Not in our library10.1089/neu.2018.5783

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