Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

1The number of overweight and obese people worldwide has increased over recent years, giving rise to a global obesity epidemic. According to the World Health Organization (WHO), in 2014, more than 1.9 billion adults were overweight, of which over 600 million were classified as clinically obese. Perhaps even more alarmingly, 42 million children under the age of 5 were overweight or obese in 2013. Obesity is a major risk factor for associated comorbidities such as cardiovascular diseases, type 2 diabetes mellitus, cancer and musculoskeletal disorders, and is associated with an increased overall mortality relative to non-obese individuals.

2Obesity results from the dysregulation of energy metabolism. The central nervous system (CNS) plays a key role in sensing and controlling the energy status of the organism, and the hypothalamus in particular has emerged as an integrating, superordinate master regulator of whole-body energy homeostasis. Obesity has long been considered to be the result of a lack of discipline and effort to reduce calorie intake and to increase physical activity, which has led to a fundamental and still present social weight-related stigmatization of affected individuals. However, extensive research in both humans and various murine model systems over recent decades has revealed that a complex interplay of genes and environmental factors that impact CNS control of food intake and energy homeostasis pave the way for the development of obesity. In this review and its accompanying poster, we provide a snapshot of the hypothalamic neurocircuits that regulate the homeostatic control of energy metabolism and feeding. We also give an overview of the pleiotropic factors involved in the regulation and dysregulation of the homeostatic hypothalamic system in the context of obesity, including hypothalamic inflammation as well as insulin and leptin resistance. Later, we discuss the impact of a maternal high-fat diet and obesity on offspring and highlight the importance of mitochondrial dynamics and genetic factors involved in the development of obesity at the level of the hypothalamic neurocircuits. Thereby, most of the molecular insights summarized in this article are derived from studies in rodent model organisms. Finally, we provide our outlook on recent perspectives on CNS-dependent control of feeding behavior and metabolism, and future therapeutic approaches to tackle dysfunctional regulation of central energy homeostasis.

3The hypothalamus is one of the best-studied and most important brain regions involved in the central control of feeding and energy expenditure. In particular, the arcuate nucleus (ARC) within the hypothalamus is critical for the regulation of feeding and metabolism. The ARC is located near to the median eminence (ME; see poster), a circumventricular organ that is rich in fenestrated capillaries that lead to a ‘leaky’ blood-brain barrier (BBB). The ME facilitates transport of peripheral hormonal and nutrient signals and their sensing by the ARC neurons. Thereby, the ARC integrates hormonal and nutritional metabolic signals from the peripheral circulation as well as peripheral and central neuronal inputs to generate a coordinated feedback response.

4There are two distinct, functionally antagonistic types of neurons in the ARC: the orexigenic (appetite-stimulating) neuropeptide Y (NPY) and agouti-related peptide (AgRP)-expressing AgRP/NPY neurons and the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC)-expressing POMC neurons (see poster). POMC neurons project mainly to second-order neurons in the paraventricular hypothalamic nucleus (PVN), but also to the dorsomedial hypothalamus (DMH), the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH) (see poster). These second-order neurons further process the received information and project to multiple neurocircuits outside of the hypothalamus (extrahypothalamic), leading to an integrated response on energy intake and expenditure, respectively. Neurons within the PVN control sympathetic outflow to peripheral organs and secrete a variety of regulatory neuropeptides. Destruction of the PVN leads to overeating and obesity, pointing to the important role of PVN neurons for the inhibitory control of food intake. Moreover, destruction of the VMH results in hyperphagia and obesity, whereas deletion of the DMH and the LH produces a hypophagic, lean phenotype.

5Upon nutrient ingestion, POMC is cleaved to α-melanocyte-stimulating hormone (α-MSH) which is released from POMC-axons to activate melanocortin 3 and 4 receptors (MC3/4R) on downstream neurons, including neurons in the PVN (see poster; Healthy postprandial or feeding state), resulting in a decrease in food intake and an increase in energy expenditure. Although MC4R expression is widely distributed among different brain regions, within the hypothalamus, the PVN displays the highest MC4R expression and is considered to host the predominant energy-intake-regulating MC4R population within the CNS (see; for reviews). Consistent with this, studies in mice have shown that disruption of the MC4R, and specifically in the PVN, results in obesity as a result of hyperphagia and reduced energy expenditure, along with deteriorations in glucose homeostasis. Downstream mediators likely to be involved in transducing the effects of MC4R activation on food intake regulation are brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). While food intake is believed to be inhibited via hypothalamic melanocortinergic neurons in a constant manner, energy expenditure is increased upon MC4R activation due to an increased activity of the sympathetic nervous system leading to brown adipose tissue (BAT) activation.

6Fasting, on the other hand, induces the activation of AgRP/NPY neurons that project also to the PVN and the LH (see poster; Healthy fasting state). AgRP/NPY neurons co-release NPY and AgRP. NPY directly stimulates food intake via activation of NPY Y1 and Y5 receptors. Furthermore, NPY reduces energy expenditure via a Y1-receptor-mediated reduction in tyrosine hydroxylase expression in the PVN and the brainstem, which leads to a decreased sympathetic output to the BAT and concomitantly reduced BAT activity. AgRP acts as an inverse agonist of MC3/4R, thereby preventing the anorexigenic effect of α-MSH on second-order neurons. Furthermore, AgRP/NPY neurons directly inhibit POMC neurons via inhibitory γ-aminobutyric acid (GABA) action at the level of the ARC. Interestingly, while optogenetic activation of AgRP→POMC synaptic connections strongly inhibited POMC neuron activity, suppression of POMC neuron activity by AgRP neurons was shown not to be required for acute feeding induction. However, exclusive activation of the ARC→PVN connection strongly induces feeding. GABA release from AgRP/NPY projections to extrahypothalamic neurons, specifically in the parabrachial nucleus (PBN), also plays a role in the stimulation of food intake, although the exclusive activation of the AgRP/NPY→PBN interconnection is not sufficient to induce feeding. Recently, a study involving optogenetic activation of AgRP neurons demonstrated that distinct AgRP neuron subpopulations project to different brain regions and that activation of some projections – including those to the PVN and LH, but not to the PBN – are able to independently induce feeding similar to somatic activation of AgRP neurons.

7Of note, POMC and AgRP/NPY neurons also receive activating glutamatergic feedback input from other hypothalamic nuclei such as the VMH and the PVN, whereas PVN neurons receive inhibitory innervation from LH neurons that promote feeding, resulting in a finely tuned response regulating food intake. Strikingly, it has very recently been demonstrated that the visual and olfactory sensing of food without ingestion of any nutrients is sufficient to reverse the effects of fasting on POMC and AgRP/NPY neurons.

8As mentioned above, intrahypothalamic projections from ARC neurons to the PVN not only play a role in the regulation of food intake, but also in energy expenditure: POMC neurons increase while AgRP/NPY neurons decrease metabolic activity in BAT (for reviews, see; ). Thus, in the fasting state, energy expenditure is decreased, and following food intake, energy expenditure is increased. Of note, we recently demonstrated that AgRP/NPY neuron activation regulates BAT glucose uptake through specific projections to the bed nucleus of the stria terminalis (BNST), a forebrain structure involved in the control of neuroendocrine and autonomic responses, as well as feeding and reward behavior. Thereby, this structure interconnects key nuclei of the limbic system with hypothalamic and brainstem structures in both rodents and humans (for reviews, see; ).

9Hypothalamic nuclei also project to and receive input from other extrahypothalamic brain regions such as the nucleus of the solitary tract (NTS) to regulate food intake and energy expenditure (for reviews, see;;;;; ). Furthermore, hypothalamic neurocircuits are directly connected to the mesolimbic reward system, comprising the ventral tegmental area (VTA) and the nucleus accumbens (NAc), which control the ‘hedonic’ aspects of food intake. Decreased glucose levels, such as those that occur in the fasting state, activate glutamate and orexin co-expressing neurons in the LH, which project to and excite dopaminergic neurons in the VTA. In addition, activation of inhibitory GABAergic LH neurons that project to the VTA (see poster, Fasting state) leads to increased food intake and specifically consummatory behavior, which refers to the drive to receive a caloric reward. In line with this, two recent studies showed that activation of GABAergic projection from the LH to the VTA enhances compulsive ‘sucrose seeking’ and therefore feeding-related behavior. Thus, homeostatic inputs from the hypothalamus are integrated with hedonic feeding signals from mesolimbic pathways and signals from superordinate decision-making centers such as the amygdala, the hippocampus and the prefrontal cortex to generate an orchestrated response on feeding, glucose metabolism and energy homeostasis regulation. Although extensive research in rodent models in recent years has made a vast contribution to deciphering the underlying mechanisms of food-related reward stimuli and decision making, the interplay of the different components of the reward system contributing to food-related reward in humans are far more complex. Indeed, a number of mostly fMRI-based studies have shed light on the complexity of feeding-related reward mechanisms and brain structures involved in humans.

10In summary, the hypothalamus plays a key role in the regulation of appetite and food intake both in humans and rodents. Furthermore, brain regions such as the amygdala and the striatum as well as the VTA, with its dopaminergic projections, are involved in both human and rodent food-related reward. However, distinct from rodents, in humans, reward and behavioral drives are strongly impacted and directed by cognition.

11Both POMC and AgRP/NPY neurons express receptors for peripheral metabolic hormones such as insulin and leptin. Insulin is secreted from pancreatic β-cells upon nutrient ingestion and plays an important role in the peripheral regulation of energy and glucose homeostasis. It specifically controls peripheral glucose metabolism by suppressing hepatic glucose production (HGP) via direct action on hepatic insulin receptors. However, insulin is also a major factor in the regulation of glucose and energy homeostasis at the level of the hypothalamus (see poster, Healthy feeding state). Activation of insulin receptors on POMC neurons causes membrane hyperpolarization and reduced firing of these neurons while increasing POMC mRNA expression. However, a recent publication demonstrated that purified insulin actually excites POMC neurons. Interestingly, disruption of insulin signaling from POMC neurons did not affect energy or glucose homeostasis. However, deletion of both insulin and leptin receptors from POMC neurons deteriorates glucose homeostasis and specifically leads to systemic insulin resistance and impaired fertility in mice. Concomitant insulin and leptin action on POMC neurons also increases the browning of white fat, a process that favors enhanced metabolic activity. Furthermore, a very recent study has shown that insulin action on POMC neurons controls adipose-tissue lipolysis and prevents high-fat-diet-induced liver steatosis. On AgRP/NPY neurons, insulin action is required for the suppressive effect of insulin on HGP. Insulin induces a hyperpolarization and a decreased firing rate of AgRP neurons, thus reducing the release of AgRP and other neurotransmitters, affecting peripheral hepatic innervation, and finally leading to increased interleukin (IL)-6 expression in the liver parenchymal cells (; for a review, see ). In the liver, IL-6 action leads to decreased expression of glucose-6-phosphatase and subsequently to reduced gluconeogenesis.

12Adipose tissue-derived leptin, encoded by the LEP gene (previously known as ob), is released into the plasma in levels proportional to whole-body fat stores and is induced by insulin. Leptin plays a crucial role in the central regulation of food intake and energy homeostasis at multiple levels: it directly excites POMC neurons and induces POMC expression, while exerting an inhibitory effect on AgRP/NPY neurons and the expression of AGRP (see poster, feeding state). Thus, the net effect of leptin action within the hypothalamus is to inhibit food intake and to increase energy expenditure. Of note, although the actions of insulin and leptin are interconnected at the level of the hypothalamus and both together are required for a complete anorexigenic and glucoregulatory effect, leptin and insulin act on different subpopulations of POMC neurons, the characterization of which is urgently needed to decipher their precise function.

13In addition to the ARC, the VMH represents another effector site for leptin and insulin action in the control of energy homeostasis, and recent studies have sought to establish the physiological relevance of these pathways. Mice with insulin receptor deletion in VMH-specific steroidogenic-factor-1 (SF-1) neurons are protected from diet-induced obesity and deterioration of glucose metabolism and, furthermore, display increased POMC neuron activity under high-fat diet conditions. This indicates that high-fat-diet-induced insulin-dependent activation of VMH neurons contributes to obesity development. On the other hand, enhanced leptin receptor signaling in SF-1 neurons within the VMH results in improved glucose homeostasis while body weight is not significantly affected. In the DMH, leptin action leads to increased energy expenditure via enhanced sympathetic activation of the BAT, thereby, impacting body weight control independent of food intake.

14Insulin also acts on dopaminergic neurons of the mesolimbic reward system. Here, insulin negatively modulates reward-related behavior such as the desire for high-fat or high-sugar food and reduces hedonic feeding. Likewise, leptin reduces food intake upon injection into the VTA, and ablation of leptin receptors in this area increases the rewarding aspect of highly palatable food (; for reviews, see; ). Intriguingly, a recent study revealed that insulin promotes dopamine release in reward centers in a dynamic fashion. While insulin enhances dopamine release upon food restriction, this effect is lost with an obesogenic diet, indicating that insulin alters food choices depending on the nutritional status of the organism.

15Overall, leptin and insulin are major players in the central regulation of energy and glucose homeostasis at various levels within and outside the hypothalamus. Since leptin and insulin receptors are distributed differentially in distinct subsets of central nuclei, a key outstanding challenge is to unequivocally decipher the distinct roles of the different neuronal subsets that express the leptin or insulin receptor, or both together, in terms of central regulation of feeding and glucose control, energy expenditure and reward mechanisms.

16Gastrointestinal hormones have also emerged as important regulators of CNS-dependent energy control. Ghrelin, which is predominantly secreted from the stomach during starvation, robustly stimulates feeding by activating AgRP/NPY neurons, in addition to promoting body weight gain and adiposity via direct effects on PVN neurons (see poster, Healthy fasting state).

17Other hormones, including glucagon-like peptide 1 (GLP-1), peptide YY3-36 (PYY3-36) and cholecystokinin (CCK), are released from the intestine upon nutrient ingestion and exert anorexigenic effects in various brain regions (such as the ARC, the NTS, the DMH, the VMH and the PVN, see poster, Healthy feeding state) and by modulating vagal afferents, the peripheral components of the gut-brain axis. However, GLP-1 also acts as a neurotransmitter in the brain (for simplicity, GLP-1 is not depicted separately in the poster). This hormone is produced in distinct neuronal populations within the NTS and centrally influences not only food intake, body weight and glucose homeostasis at the level of the ARC and the PBN, but also appears to have a major impact on food reward behavior by directly acting on the VTA and the nucleus accumbens (NAc). Thereby, GLP-1 reduces food reward behavior and, if food choice is provided, selectively reduces intake of high-fat chow while increasing low-fat chow intake. Overall, central GLP-1 receptor activation seems to influence food intake, glucose and energy homeostasis at various levels within the CNS (for reviews, see;;; ). However, more research is needed to unravel the exact molecular mechanisms and cellular effectors of GLP-1 receptor-mediated actions. In light of its multiple beneficial effects on body weight regulation, GLP-1 receptor agonists were very recently approved for the treatment of humans that are obese or overweight.

18Obesity is associated with chronic low-grade inflammation and resistance to leptin and insulin action not only in the periphery but also in the CNS (see poster, Obese feeding state). Research in murine model organisms has contributed substantially to our present understanding of the hypothalamic mechanisms associated with and contributing to the development of obesity, as outlined below. As an early event in obesity development and even within a few days of ingesting a high-fat, calorie-dense diet, an increased amount of saturated fatty acids (FAs) from the periphery crosses the BBB and induces an inflammatory response in hypothalamic neurons. This involves activation of microglia, the tissue-resident macrophages in the CNS. Local inflammation in the mediobasal hypothalamus (encompassing the ARC, the anterior part of the PVN and the ME) promotes endoplasmic reticulum (ER) stress in hypothalamic neurons, leading to insulin and leptin resistance. It has recently been demonstrated that constitutive activation of the proinflammatory c-Jun N-terminal kinase 1 (JNK1) pathway in AgRP neurons increases spontaneous firing in these cells, along with neuronal and systemic leptin resistance, resulting in hyperphagia (overeating), increased weight gain and adiposity. Furthermore, constitutive activation of the inflammatory inhibitor of nuclear factor kappa-B kinase 2 (IKK2) pathway blunts the response of AgRP neurons to insulin and impairs systemic glucose homeostasis. Thus, hypothalamic inflammation impairs the effects of insulin and leptin, contributing not only to hyperphagia and obesity development but also to the associated dysregulation of glucose homeostasis.

19Although POMC and AgRP neurons in the ARC develop insulin resistance in response to a high-fat diet, SF-1-expressing neurons in the VMH increase their insulin sensitivity, leading to an impairment of the glutamatergic innervation of SF-1 neurons to anorexigenic POMC neurons, resulting in impaired POMC activation. In line with this, ablation of the insulin receptor on SF-1 neurons restores POMC activity and results in a protection from high-fat-diet-induced obesity and the associated deterioration in glucose tolerance. Similarly, in the obese state, leptin sensitivity is retained in the DMH and increased leptin action on these neurons contributes to obesity-associated hypertension presumably via an increase in sympathetic outflow.

20Leptin and insulin resistance in the CNS can also result from overactivation of signal transducer and activator of transcription 3/suppressor of cytokine signaling 3 (STAT3/SOCS3), an intracellular pathway that is activated by leptin. Chronic activation of STAT3, e.g. due to elevated leptin resulting from growing adiposity, leads to increased SOCS3 activation, which in turn inhibits STAT3 signaling in a negative feedback manner resulting in resistance, not only to leptin, but also to insulin. Thus, obesity is associated with selective insulin and leptin resistance at the level of the CNS, whereby leptin and insulin action are attenuated in certain neuronal populations while others become more leptin- and insulin-sensitive, thus further promoting hyperphagia, weight gain and a dysregulation in glucose homeostasis. These findings have given rise to the concept of differential neuronal hormone resistance and hypersensitivity – termed ‘selective hormone resistance’.

21Collectively, numerous studies in humans have confirmed findings obtained from rodent model organisms that clearly point towards a major role of central insulin resistance in the dysregulation of energy homeostasis and the development of obesity in humans. However, high-fat-diet-induced obesity is not only associated with a central resistance to insulin and leptin. There is also evidence for the impaired ability of ghrelin to induce food intake at the level of the ARC AgRP/NPY neurons, which could be an adaptive response to prevent further food intake in obese individuals (see poster, Obese fasting state). However, ghrelin-mediated activation of the PVN is retained in obesity, which suggests that ghrelin might increase adiposity independent of food intake. Of note, circulating ghrelin levels are lowered in obese humans, presumably again as an adaptive mechanism.

22The number of obese women of reproductive age is increasing worldwide at an alarming rate. Several observational clinical studies over past decades have revealed a clear association between maternal obesity and the development of metabolic disorders in the offspring (for reviews, see; ). However, the molecular mechanisms that prime offspring of obese mothers for the development of obesity have only recently been investigated in non-human primate and rodent model organisms. An elegant study in non-human primates recently demonstrated that high-fat diet intake in obese mothers leads to an overconsumption of high-fat and sucrose-dense (palatable) food, possibly related to an impairment in dopamine signaling and dopaminergic fiber projections to the prefrontal cortex. Consistent with this, studies in rat offspring revealed altered food choice towards energy-dense food and associated obesity development as well as alterations in the dopaminergic mesolimbic system and resulting perturbations in reward responses, including an increased response to a fat-enriched reward. Strikingly, a maternal diet rich in saturated fatty acids during gestation and lactation leads to hypothalamic inflammation in rodent offspring. In line with this, maternal high-fat diet intake has also been shown to induce inflammation in the offspring in non-human primates.

23In rodents, maternal high-fat diet has been shown to impair leptin signaling at the level of the ARC, leading to an attenuated leptin-induced appetite suppression. Furthermore, it has been recently discovered that maternal high-fat feeding during lactation in mice severely alters the projections of POMC and AgRP neurons to second-order neurons, resulting in increased obesity and impaired glucose homeostasis in the offspring (; for review, see ). In the light of the worldwide growing epidemic of overweight and obese children, more research in this field is desperately needed to better understand which maternal-derived factors and underlying mechanisms increase the risk for obesity in the following generation and how these risk factors can be tackled.

24Mitochondria have emerged as important players in the development of a number of metabolic disorders including obesity, type 2 diabetes mellitus, and cardiovascular diseases. Mitochondria regulate cellular energy and fuel metabolism in a highly dynamic fashion, enabling fast adaptation to changes in cellular energy supply and demand. In the hypothalamus, mitochondrial reactive oxygen species (ROS) have emerged as important signaling molecules that indicate positive or negative energy states at the level of AgRP/NPY and POMC neurons (see poster). In the negative energy or fasting state, when systemic glucose levels are low, the activation of AgRP/NPY by ghrelin leads to an induction of long-chain fatty acid β-oxidation and concomitant ROS production in AgRP/NPY neurons, which activates uncoupling protein (UCP)2 expression. UCP2, in turn, reduces intracellular ROS levels, enabling a sustained energy supply from β-oxidation without ROS generation and thereby promoting sustained AgRP/NPY firing, which results in increased food intake. In the positive postprandial energy state, when systemic glucose levels are high, glucose is taken up and oxidized by POMC neurons, leading to the generation of ATP and ROS, and, in turn, to depolarization and increased firing of these neurons, promoting satiety and a decrease in food intake. Fluctuating hypothalamic ROS levels not only direct hunger and satiety and ultimately food intake, but also energy expenditure and peripheral glucose utilization. Upon exposure to a high-fat diet, ROS levels plateau, resulting in impaired satiety signaling in POMC neurons (see poster, Obese feeding state). Mitochondria also constantly adapt to changes in cellular energy levels and fuel availability via conformational changes, so-called ‘fission and fusion’ events and via interaction with the ER. Mitofusins (MFNs), highly conserved mitochondrial transmembrane GTPases, are of central importance for the regulation of these processes. There are two mammalian mitofusins, MFN1 and MFN2. Both have been implicated in mitochondrial fusion processes, while MFN2 also specifically controls ER morphology and its interaction with mitochondria. One study has shown that deletion of MFN1 or MNF2 in AgRP/NPY neurons protects mice from high-fat diet-induced obesity. Deletion of MFN2 in POMC neurons resulted in deprived mitochondria-ER contacts, leptin-resistance, hyperphagia, reduced energy expenditure and morbid obesity. Interestingly, POMC-specific knockout of MFN1 did not result in any alteration of energy, or glucose homeostasis. This striking difference in POMC-specific MFN2 versus MNF1 deletion on the metabolic outcome phenotype might indicate the importance of ER integrity and coordinated ER-mitochondrial interactions for proper POMC function.

25Taken together, these findings demonstrate the crucial role of mitochondrial function and dynamics not only in the regulation of basal biodynamic processes such as satiety, hunger and whole-body metabolism but also in disease development, suggesting that mitochondrial dynamics could represent novel therapeutic targets in obesity treatment. In support of this, berberine, a natural plant product, used in Chinese medicine, inhibits mitochondrial respiration and has been shown to effectively improve energy and glucose metabolism in insulin-resistant, obese rodents and humans. In addition, Metformin, a first-line treatment in type 2 diabetes with neutral effects on body weight, is supposed to exert its antidiabetic effects, at least in part, via inhibition of mitochondrial respiration. Consistent with this, direct application of metformin to the brain in rodents has been shown to decrease food intake and improve glucose metabolism.

26In accordance with their role in anorexic signaling pathways, mutations in the MC4R and POMC genes, which encode the melanocortin 4 receptor and pro-opiomelanocortin, respectively, result in hyperphagia and obesity in humans and rodents. The most severe form of obesity in mice and humans results from a deficiency in the genes encoding leptin (LEP) or the leptin-receptor (LEPR). Importantly, leptin-deficiency-associated obesity successfully resolves upon treatment with recombinant leptin, clearly indicating the major physiological role of leptin in the regulation of whole-body energy homeostasis. Remarkably, mutations underlying monogenetic obesity in humans have been identified not only in the POMC/MC4R genes, but also in transcription factors and neurotransmitters that modulate the activity of the homeostatic melanocortin circuitry, such as single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (encoded by NTRK2), highlighting their important role in the physiological regulation of energy homeostasis.

27Interestingly, genome-wide association studies in humans have revealed a robust association of single nucleotide polymorphisms (SNPs) with excess weight and obesity, not only in or near to the BDNF gene (for a review, see ) but also in intron 1 of the fat mass and obesity-associated protein (FTO) gene (;;; for a review, see ). It was recently shown that deletion of Fto in rodents impairs dopaminergic control of behavioral and neural responses and alters methylation of several neural mRNAs, leading to an altered protein expression level of the encoded proteins and an overall changed dopaminergic midbrain circuitry response, pointing to a role of the FTO gene in complex behaviors like reward-based decision-making. The notion that FTO controls dopaminergic signaling has since been confirmed in human fMRI studies. Overall, ongoing and future research exploring genetic variants in obese humans will allow the identification of novel candidate genes leading to the discovery of potential new drug targets for the treatment of obesity.

28A recent report in rodents demonstrated that AgRP neurons are activated by uridine-diphosphate (UDP), which is synthesized from circulating uridine in the CNS by the nucleotide salvage pathway. UDP acts on AgRP neurons via the purinergic receptor 6 (P2Y6) to promote feeding. In the context of obesity, uridine levels are elevated in the circulation, indicating that the uridine/UDP system might be another mechanism that promotes the vicious cycle of increased weight gain along with exaggerated food intake. Consistent with this model, AgRP-neuron-specific P2Y6-deficient mice are protected from high-fat-diet-induced adiposity and insulin resistance (see poster, Obese fasting state).

29A recent study conducted in mice challenged the idea that POMC neurons are solely anorexigenic by showing that activation of the cannabinoid receptor 1 on POMC neurons leads to the release of β-endorphin, an opioid neuropeptide, which in turn promotes feeding. This anorexigenic-to-orexigenic switch of POMC neurons might be responsible for cannabinoid-induced hyperphagia.

30Another concept that has recently come to light via studies of rodent model organisms is the active role of astrocytes (glial cells in the nervous system) in the regulation of feeding and glucose homeostasis. First, it was demonstrated that astrocytes are involved in leptin-dependent control of feeding, as ablation of leptin-receptor signaling in astrocytes blunted the anorexic effect of leptin and enhanced fasting and ghrelin-induced hyperphagia. Second, insulin-receptor signaling in astrocytes was demonstrated to play a crucial role in glucose uptake into the brain, glucose sensing in the hypothalamus, and feeding behavior, as astrocyte-specific deletion of the insulin receptor resulted in increased food intake and deteriorated glucose tolerance. In addition, it was recently shown in mice that activation of medial hypothalamic astrocytes directly leads to the inhibition of ghrelin-independent as well as ghrelin-induced food intake via the inhibition of AgRP/NPY neurons. The study also revealed that inhibition of AgRP/NPY neurons by astrocytes is mediated via increased extracellular levels of adenosine (derived from ATP that is released by astrocytes upon activation), which acts on the adenosine A1 receptor on synaptic AgRP/NPY endings, leading to silencing of AgRP/NPY neurons.

31Collectively, these new perspectives on novel regulatory mechanisms in the central control of energy and glucose metabolism highlight that we are only starting to understand how whole-body energy homeostasis is regulated and which neuronal and non-neuronal components are involved.

32The picture that researchers are gradually building of the CNS mechanisms underlying dysregulation of energy and glucose homeostasis is contributing to the development of new candidate therapies for obesity and related disorders. A very promising therapeutic strategy is emerging from pre-clinical and clinical studies with proglucagon-derived dual or triple co-agonists (for an overview of clinical and preclinical studies, see ). These poly-agonists, consisting of peptide hybrids of a GLP-1 receptor (GLP-1R) agonist and a glucagon receptor (GcgR) agonist (GcgR/GLP-1R) or a GLP-1R agonist together with an agonist for gastric inhibitory polypeptide (GIP) receptor, another important metabolic hormone in glucose homeostasis (GIPR/GLP-1R), exhibit higher efficacy in terms of body weight reduction and glycemic control while giving rise to fewer side effects compared with equimolar doses of mono-agonists in rodents and humans. Furthermore, preclinical studies with a GcgR/GIPR/GLP-1R triple agonist revealed even more promising results in terms of body weight and glucose control.

33Another encouraging therapeutic approach is the use of a selective MC4R agonist, which has been proven successful in the treatment of POMC-deficient obesity as well as in humans with non-genetic obesity and in non-human primates. However, Phase 2 and Phase 3 studies with a sufficient number of patients enrolled are needed to elucidate if these therapeutic approaches show real promise in terms of effectiveness and side effect profile.

34To tackle the growing obesity epidemic and its associated metabolic disorders, there is an urgent need to further decipher the CNS-level molecular mechanisms that lead to the dysregulation in energy homeostasis. This could set the stage for the development of new therapeutic strategies. One of the most intriguing mysteries that needs to be unraveled is how maternal metabolism impacts neurodevelopmental aspects of the fetus that predispose to obesity and metabolic dysfunction later in life. Moreover, it is becoming increasingly apparent that neuronal populations are not uniform but consist of clustered neurons with very different, unique entities that often result in opposing properties; thus, it is of high importance to fully characterize these neuronal sub-populations and to unravel their distinct features and projections to allow for specific therapeutic targeting. Another high priority question is how the well-known neuronal centers involved in feeding control, such as the hypothalamic nuclei, are regulated by and connected to superordinate brain centers including the reward system and sensory organs (e.g. the gustatory and olfactory systems). It is also important to unravel the role of non-neuronal, CNS-resident cell entities in the regulation of feeding and central metabolism. In summary, it is apparent that dysregulation of energy metabolism in the context of disease is far from being a single-track process allowing for easy and simple solution approaches. Therefore, a broadened view, integrating the different aspects of obesity development is a prerequisite to successfully fight obesity in the future.