Inter‐organ communication: a gatekeeper for metabolic health

Abstract

Multidirectional interactions between metabolic organs in the periphery and the central nervous system have evolved concomitantly with multicellular organisms to maintain whole‐body energy homeostasis and ensure the organism's adaptation to external cues. These interactions are altered in pathological conditions such as obesity and type 2 diabetes. Bioactive peptides and proteins, such as hormones and cytokines, produced by both peripheral organs and the central nervous system, are key messengers in this inter‐organ communication. Despite the early discovery of the first hormones more than 100 years ago, recent studies taking advantage of novel technologies have shed light on the multiple ways used by cells in the body to communicate and maintain energy balance. This review briefly summarizes well‐established concepts and focuses on recent advances describing how specific proteins and peptides mediate the crosstalk between gut, brain, and other peripheral metabolic organs in order to maintain energy homeostasis. Additionally, this review outlines how the improved knowledge about these inter‐organ networks is helping us to redefine therapeutic strategies in an effort to promote healthy living and fight metabolic disorders and other diseases.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 174

1. 1.

   Dinarello CA (2007 ) Historical insights into cytokines. Eur J Immunol 37(Suppl 1): S34–S45

   Not in our library10.1002/eji.200737772

2. 2.

   Ryan DG, Murphy MP, Frezza C, Prag HA, Chouchani ET, O'Neill LA, Mills EL (2019 ) Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat Metab 1: 16–33

   Not in our library10.1038/s42255-018-0014-7

3. 3.

   Myers Jr MG, Olson DP (2012 ) Central nervous system control of metabolism. Nature 491: 357–363

   Not in our library10.1038/nature11705

4. 4.

   Nogueiras R, Tschop MH, Zigman JM (2008 ) Central nervous system regulation of energy metabolism: ghrelin versus leptin. Ann N Y Acad Sci 1126: 14–19

   Not in our library10.1196/annals.1433.054

5. 5.

   Bartness TJ, Shrestha YB, Vaughan CH, Schwartz GJ, Song CK (2010 ) Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Mol Cell Endocrinol 318: 34–43

   Not in our library10.1016/j.mce.2009.08.031

6. 6.

   Bernard C (1853 ) Nouvelle fonction du foie considéré comme organe producteur de matière sucrée chez l'homme et les animaux. Paris: Baillère JB

   Not in our library

7. 7.

   Bayliss WM, Starling EH (1902 ) The mechanism of pancreatic secretion. J Physiol 28: 325–353

   Not in our library10.1113/jphysiol.1902.sp000920

8. 8.

   Tata JR (2005 ) One hundred years of hormones. EMBO Rep 6: 490–496

   Not in our library10.1038/sj.embor.7400444

9. 9.

   Cori CF, Cori GT (1946 ) Carbohydrate metabolism. Annu Rev Biochem 15: 193–218

   Not in our library10.1146/annurev.bi.15.070146.001205

10. 10.

    Meex RCR, Watt MJ (2017 ) Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 13: 509–520

    Not in our library10.1038/nrendo.2017.56

11. 11.

    Giudice J, Taylor JM (2017 ) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49–55

    Not in our library10.1016/j.coph.2017.05.005

12. 12.

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

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

13. 13.

    Villarroya F, Cereijo R, Villarroya J, Giralt M (2017 ) Brown adipose tissue as a secretory organ. Nat Rev Endocrinol 13: 26–35

    Not in our library10.1038/nrendo.2016.136

14. 14.

    Longo VD, Panda S (2016 ) Fasting, circadian rhythms, and time‐restricted feeding in healthy lifespan. Cell Metab 23: 1048–1059

    Not in our library10.1016/j.cmet.2016.06.001

15. 15.
    Circadian Rhythms and Hormonal Homeostasis: Pathophysiological Implications · 2017

    No notice
16. 16.

    Betz MJ, Enerback S (2015 ) Human brown adipose tissue: what we have learned so far. Diabetes 64: 2352–2360

    Not in our library10.2337/db15-0146

17. 17.

    Pedersen BK, Febbraio MA (2012 ) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8: 457–465

    Not in our library10.1038/nrendo.2012.49

18. 18.

    Rankin LC, Artis D (2018 ) Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell 173: 554–567

    Not in our library10.1016/j.cell.2018.03.013

19. 19.

    Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA et al (2002 ) Gut hormone PYY(3‐36) physiologically inhibits food intake. Nature 418: 650–654

    Not in our library10.1038/nature00887

20. 20.

    Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD et al (1996 ) A role for glucagon‐like peptide‐1 in the central regulation of feeding. Nature 379: 69–72

    Not in our library10.1038/379069a0

21. 21.

    Ronveaux CC, Tome D, Raybould HE (2015 ) Glucagon‐like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling. J Nutr 145: 672–680

    Not in our library10.3945/jn.114.206029

22. 22.

    Cheng CY, Chu JY, Chow BK (2011 ) Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology 36: 459–471

    Not in our library10.1038/npp.2010.178

23. 23.

    Chu JY, Cheng CY, Sekar R, Chow BK (2013 ) Vagal afferent mediates the anorectic effect of peripheral secretin. PLoS One 8: e64859

    Not in our library10.1371/journal.pone.0064859

24. 24.

    Tokarz VL, MacDonald PE, Klip A (2018 ) The cell biology of systemic insulin function. J Cell Biol 217: 2273–2289

    Not in our library10.1083/jcb.201802095

25. 25.

    Kersten S (2001 ) Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep 2: 282–286

    Not in our library10.1093/embo-reports/kve071

26. 26.

    Vieira E, Salehi A, Gylfe E (2007 ) Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50: 370–379

    Not in our library10.1007/s00125-006-0511-1

27. 27.
    Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood · 2016

    Not checked
28. 28.

    Gray SM, Meijer RI, Barrett EJ (2014 ) Insulin regulates brain function, but how does it get there? Diabetes 63: 3992–3997

    Not in our library10.2337/db14-0340

29. 29.

    Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller‐Wieland D, Kahn CR (2000 ) Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122–2125

    Not in our library10.1126/science.289.5487.2122

30. 30.

    Dodd GT, Michael NJ, Lee‐Young RS, Mangiafico SP, Pryor JT, Munder AC, Simonds SE, Bruning JC, Zhang ZY, Cowley MA et al (2018 ) Insulin regulates POMC neuronal plasticity to control glucose metabolism. Elife 7: e38704

    Not in our library10.7554/elife.38704

31. 31.

    Dodd GT, Lee‐Young RS, Bruning JC, Tiganis T (2018 ) TCPTP regulates insulin signaling in AgRP neurons to coordinate glucose metabolism with feeding. Diabetes 67: 1246–1257

    Not in our library10.2337/db17-1485

32. 32.

    O‐Sullivan I, Zhang W, Wasserman DH, Liew CW, Liu J, Paik J, DePinho RA, Stolz DB, Kahn CR, Schwartz MW et al (2015 ) FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat Commun 6: 7079

    Not in our library10.1038/ncomms8079

33. 33.

    Titchenell PM, Chu Q, Monks BR, Birnbaum MJ (2015 ) Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat Commun 6: 7078

    Not in our library10.1038/ncomms8078

34. 34.

    Obici S, Zhang BB, Karkanias G, Rossetti L (2002 ) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8: 1376–1382

    Not in our library10.1038/nm1202-798

35. 35.

    Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995 ) Leptin levels reflect body lipid content in mice: evidence for diet‐induced resistance to leptin action. Nat Med 1: 1311–1314

    Not in our library10.1038/nm1295-1311

36. 36.

    Ingalls AM, Dickie MM, Snell GD (1950 ) Obese, a new mutation in the house mouse. J Hered 41: 317–318

    Not in our library10.1093/oxfordjournals.jhered.a106073

37. 37.

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

    Not in our library10.1038/372425a0

38. 38.

    Pan WW, Myers Jr MG (2018 ) Leptin and the maintenance of elevated body weight. Nat Rev Neurosci 19: 95–105

    Not in our library10.1038/nrn.2017.168

39. 39.

    Stern JH, Rutkowski JM, Scherer PE (2016 ) Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 23: 770–784

    Not in our library10.1016/j.cmet.2016.04.011

40. 40.

    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002 ) Leptin stimulates fatty‐acid oxidation by activating AMP‐activated protein kinase. Nature 415: 339–343

    Not in our library10.1038/415339a

41. 41.

    D'Souza AM, Neumann UH, Glavas MM, Kieffer TJ (2017 ) The glucoregulatory actions of leptin. Mol Metab 6: 1052–1065

    Not in our library10.1016/j.molmet.2017.04.011

42. 42.

    Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA et al (2005 ) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217–225

    Not in our library10.1016/j.cmet.2005.09.001

43. 43.

    Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino‐Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ (2011 ) FGF19 as a postprandial, insulin‐independent activator of hepatic protein and glycogen synthesis. Science 331: 1621–1624

    Not in our library10.1126/science.1198363

44. 44.

    Potthoff MJ, Boney‐Montoya J, Choi M, He T, Sunny NE, Satapati S, Suino‐Powell K, Xu HE, Gerard RD, Finck BN et al (2011 ) FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB‐PGC‐1alpha pathway. Cell Metab 13: 729–738

    Not in our library10.1016/j.cmet.2011.03.019

45. 45.

    Ryan KK, Kohli R, Gutierrez‐Aguilar R, Gaitonde SG, Woods SC, Seeley RJ (2013 ) Fibroblast growth factor‐19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154: 9–15

    Not in our library10.1210/en.2012-1891

46. 46.

    Picard A, Soyer J, Berney X, Tarussio D, Quenneville S, Jan M, Grouzmann E, Burdet F, Ibberson M, Thorens B (2016 ) A genetic screen identifies hypothalamic Fgf15 as a regulator of glucagon secretion. Cell Rep 17: 1795–1806

    Not in our library10.1016/j.celrep.2016.10.041

47. 47.

    Ge X, Yang H, Bednarek MA, Galon‐Tilleman H, Chen P, Chen M, Lichtman JS, Wang Y, Dalmas O, Yin Y et al (2018 ) LEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metab 27: 461–469 e6

    Not in our library10.1016/j.cmet.2017.10.016

48. 48.

    Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (2001 ) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50: 1714–1719

    Not in our library10.2337/diabetes.50.8.1714

49. 49.

    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999 ) Ghrelin is a growth‐hormone‐releasing acylated peptide from stomach. Nature 402: 656–660

    Not in our library10.1038/45230

50. 50.

    Al Massadi O, Lopez M, Tschop M, Dieguez C, Nogueiras R (2017 ) Current understanding of the hypothalamic ghrelin pathways inducing appetite and adiposity. Trends Neurosci 40: 167–180

    Not in our library10.1016/j.tins.2016.12.003

51. 51.

    Chuang JC, Sakata I, Kohno D, Perello M, Osborne‐Lawrence S, Repa JJ, Zigman JM (2011 ) Ghrelin directly stimulates glucagon secretion from pancreatic alpha‐cells. Mol Endocrinol 25: 1600–1611

    Not in our library10.1210/me.2011-1001

52. 52.

    Tschop M, Smiley DL, Heiman ML (2000 ) Ghrelin induces adiposity in rodents. Nature 407: 908–913

    Not in our library10.1038/35038090

53. 53.

    Theander‐Carrillo C, Wiedmer P, Cettour‐Rose P, Nogueiras R, Perez‐Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schurmann A, Szanto I et al (2006 ) Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 116: 1983–1993

    Not in our library10.1172/jci25811

54. 54.

    Jackson MB, Ahima RS (2006 ) Neuroendocrine and metabolic effects of adipocyte‐derived hormones. Clin Sci (Lond) 110: 143–152

    Not in our library10.1042/cs20050243

55. 55.

    Steinberg GR, Kemp BE (2007 ) Adiponectin: starving for attention. Cell Metab 6: 3–4

    Not in our library10.1016/j.cmet.2007.06.008

56. 56.

    Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T et al (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

57. 57.

    Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM et al (2011 ) Receptor‐mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17: 55–63

    Not in our library10.1038/nm.2277

58. 58.

    Awazawa M, Ueki K, Inabe K, Yamauchi T, Kubota N, Kaneko K, Kobayashi M, Iwane A, Sasako T, Okazaki Y et al (2011 ) Adiponectin enhances insulin sensitivity by increasing hepatic IRS‐2 expression via a macrophage‐derived IL‐6‐dependent pathway. Cell Metab 13: 401–412

    Not in our library10.1016/j.cmet.2011.02.010

59. 59.

    Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B et al (2016 ) Asprosin, a fasting‐induced glucogenic protein hormone. Cell 165: 566–579

    Not in our library10.1016/j.cell.2016.02.063

60. 60.

    Duerrschmid C, He Y, Wang C, Li C, Bournat JC, Romere C, Saha PK, Lee ME, Phillips KJ, Jain M et al (2017 ) Asprosin is a centrally acting orexigenic hormone. Nat Med 23: 1444–1453

    Not in our library10.1038/nm.4432

61. 61.

    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA et al (2005 ) FGF‐21 as a novel metabolic regulator. J Clin Invest 115: 1627–1635

    Not in our library10.1172/jci23606

62. 62.

    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos‐Flier E (2007 ) Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5: 426–437

    Not in our library10.1016/j.cmet.2007.05.002

63. 63.

    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V et al (2007 ) Endocrine regulation of the fasting response by PPARalpha‐mediated induction of fibroblast growth factor 21. Cell Metab 5: 415–425

    Not in our library10.1016/j.cmet.2007.05.003

64. 64.

    BonDurant LD, Potthoff MJ (2018 ) Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr 38: 173–196

    Not in our library10.1146/annurev-nutr-071816-064800

65. 65.

    Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA et al (2009 ) FGF21 induces PGC‐1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 106: 10853–10858

    Not in our library10.1073/pnas.0904187106

66. 66.

    Lamy CM, Sanno H, Labouebe G, Picard A, Magnan C, Chatton JY, Thorens B (2014 ) Hypoglycemia‐activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab 19: 527–538

    Not in our library10.1016/j.cmet.2014.02.003

67. 67.

    Garretson JT, Szymanski LA, Schwartz GJ, Xue B, Ryu V, Bartness TJ (2016 ) Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol Metab 5: 626–634

    Not in our library10.1016/j.molmet.2016.06.013

68. 68.

    Geerling JJ, Boon MR, Kooijman S, Parlevliet ET, Havekes LM, Romijn JA, Meurs IM, Rensen PC (2014 ) Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies. J Lipid Res 55: 180–189

    Not in our library10.1194/jlr.r045013

69. 69.

    Zeng W, Pirzgalska RM, Pereira MM, Kubasova N, Barateiro A, Seixas E, Lu YH, Kozlova A, Voss H, Martins GG et al (2015 ) Sympathetic neuro‐adipose connections mediate leptin‐driven lipolysis. Cell 163: 84–94

    Not in our library10.1016/j.cell.2015.08.055

70. 70.

    Chi J, Wu Z, Choi CHJ, Nguyen L, Tegegne S, Ackerman SE, Crane A, Marchildon F, Tessier‐Lavigne M, Cohen P (2018 ) Three‐dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16‐dependent sympathetic neurite density. Cell Metab 27: 226–236 e3

    Not in our library10.1016/j.cmet.2017.12.011

71. 71.

    Jiang H, Ding X, Cao Y, Wang H, Zeng W (2017 ) Dense intra‐adipose sympathetic arborizations are essential for cold‐induced beiging of mouse white adipose tissue. Cell Metab 26: 686–692 e3

    Not in our library10.1016/j.cmet.2017.08.016

72. 72.

    Zhu Y, Gao Y, Tao C, Shao M, Zhao S, Huang W, Yao T, Johnson JA, Liu T, Cypess AM et al (2016 ) Connexin 43 mediates white adipose tissue beiging by facilitating the propagation of sympathetic neuronal signals. Cell Metab 24: 420–433

    Not in our library10.1016/j.cmet.2016.08.005

73. 73.

    Cannon B, Nedergaard J (2004 ) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359

    Not in our library10.1152/physrev.00015.2003

74. 74.

    Gesta S, Tseng YH, Kahn CR (2007 ) Developmental origin of fat: tracking obesity to its source. Cell 131: 242–256

    Not in our library10.1016/j.cell.2007.10.004

75. 75.

    Cypess AM, Kahn CR (2010 ) Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes 17: 143–149

    Not in our library10.1097/med.0b013e328337a81f

76. 76.

    Zhang W, Bi S (2015 ) Hypothalamic regulation of brown adipose tissue thermogenesis and energy homeostasis. Front Endocrinol (Lausanne) 6: 136

    Not in our library10.3389/fendo.2015.00136

77. 77.

    Sellayah D, Bharaj P, Sikder D (2011 ) Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab 14: 478–490

    Not in our library10.1016/j.cmet.2011.08.010

78. 78.

    Monda M, Viggiano AN, Viggiano A, Viggiano E, Lanza A, De Luca V (2005 ) Hyperthermic reactions induced by orexin A: role of the ventromedial hypothalamus. Eur J Neurosci 22: 1169–1175

    Not in our library10.1111/j.1460-9568.2005.04309.x

79. 79.

    Martins L, Seoane‐Collazo P, Contreras C, Gonzalez‐Garcia I, Martinez‐Sanchez N, Gonzalez F, Zalvide J, Gallego R, Dieguez C, Nogueiras R et al (2016 ) A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Rep 16: 2231–2242

    Not in our library10.1016/j.celrep.2016.07.045

80. 80.
    BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions · 2012

    No notice
81. 81.

    Zaretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA (2002 ) Chemical stimulation of the dorsomedial hypothalamus evokes non‐shivering thermogenesis in anesthetized rats. Brain Res 928: 113–125

    Not in our library10.1016/s0006-8993(01)03369-8

82. 82.

    Lee SJ, Sanchez‐Watts G, Krieger JP, Pignalosa A, Norell PN, Cortella A, Pettersen KG, Vrdoljak D, Hayes MR, Kanoski SE et al (2018 ) Loss of dorsomedial hypothalamic GLP‐1 signaling reduces BAT thermogenesis and increases adiposity. Mol Metab 11: 33–46

    Not in our library10.1016/j.molmet.2018.03.008

83. 83.

    Murano I, Barbatelli G, Giordano A, Cinti S (2009 ) Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat 214: 171–178

    Not in our library10.1111/j.1469-7580.2008.01001.x

84. 84.

    Bartness TJ, Vaughan CH, Song CK (2010 ) Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond) 34(Suppl 1): S36–S42

    Not in our library10.1038/ijo.2010.182

85. 85.

    Fedorenko A, Lishko PV, Kirichok Y (2012 ) Mechanism of fatty‐acid‐dependent UCP1 uncoupling in brown fat mitochondria. Cell 151: 400–413

    Not in our library10.1016/j.cell.2012.09.010

86. 86.
    Adipose tissues and thyroid hormones · 2014

    No notice
87. 87.

    Brent GA (2012 ) Mechanisms of thyroid hormone action. J Clin Invest 122: 3035–3043

    Not in our library10.1172/jci60047

88. 88.

    Bianco AC, McAninch EA (2013 ) The role of thyroid hormone and brown adipose tissue in energy homoeostasis. Lancet Diabetes Endocrinol 1: 250–258

    Not in our library10.1016/s2213-8587(13)70069-x

89. 89.

    Christoffolete MA, Linardi CC, de Jesus L, Ebina KN, Carvalho SD, Ribeiro MO, Rabelo R, Curcio C, Martins L, Kimura ET et al (2004 ) Mice with targeted disruption of the Dio2 gene have cold‐induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis. Diabetes 53: 577–584

    Not in our library10.2337/diabetes.53.3.577

90. 90.

    Wu J, Cohen P, Spiegelman BM (2013 ) Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 27: 234–250

    Not in our library10.1101/gad.211649.112

91. 91.

    Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F (2011 ) Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 286: 12983–12990

    Not in our library10.1074/jbc.m110.215889

92. 92.

    Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos‐Flier E et al (2012 ) FGF21 regulates PGC‐1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 26: 271–281

    Not in our library10.1101/gad.177857.111

93. 93.

    Keipert S, Kutschke M, Ost M, Schwarzmayr T, van Schothorst EM, Lamp D, Brachthauser L, Hamp I, Mazibuko SE, Hartwig S et al (2017 ) Long‐term cold adaptation does not require FGF21 or UCP1. Cell Metab 26: 437–446 e5

    Not in our library10.1016/j.cmet.2017.07.016

94. 94.

    Veniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, Moyer C, Lloyd DJ (2015 ) Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 21: 731–738

    Not in our library10.1016/j.cmet.2015.04.019

95. 95.

    Ameka M, Markan KR, Morgan DA, BonDurant LD, Idiga SO, Naber MC, Zhu Z, Zingman LV, Grobe JL, Rahmouni K et al (2019 ) Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci Rep 9: 630

    Not in our library10.1038/s41598-018-37198-y

96. 96.

    Worthmann A, John C, Ruhlemann MC, Baguhl M, Heinsen FA, Schaltenberg N, Heine M, Schlein C, Evangelakos I, Mineo C et al (2017 ) Cold‐induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med 23: 839–849

    Not in our library10.1038/nm.4357

97. 97.

    Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T et al (2006 ) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439: 484–489

    Not in our library10.1038/nature04330

98. 98.
    TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue · 2018

    No notice
99. 99.

    Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z et al (2018 ) Ablation of PM20D1 reveals N‐acyl amino acid control of metabolism and nociception. Proc Natl Acad Sci USA 115: E6937–E6945

    Not in our library10.1073/pnas.1803389115

100. 100.

     Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP et al (2016 ) The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166: 424–435

     Not in our library10.1016/j.cell.2016.05.071

101. 101.

     Glick Z (1982 ) Inverse relationship between brown fat thermogenesis and meal size: the thermostatic control of food intake revisited. Physiol Behav 29: 1137–1140

     Not in our library10.1016/0031-9384(82)90310-9

102. 102.

     Ud M, Saari T, Raiko J, Kudomi N, Maurer SF, Lahesmaa M, Fromme T, Amri EZ, Klingenspor M, Solin O et al (2018 ) Postprandial oxidative metabolism of human brown fat indicates thermogenesis. Cell Metab 28: 207–216 e3

     Not in our library10.1016/j.cmet.2018.05.020

103. 103.
     Brown Adipose Tissue as a Regulator of Energy Expenditure and Body Fat in Humans · 2013

     Not checked
104. 104.

     Kelsey R (2018 ) BAT is involved in control of satiation. Nat Rev Endocrinol 15: 1

     Not in our library10.1038/s41574-018-0136-8

105. 105.

     Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Ferno J, Salvador J, Escalada J et al (2014 ) GLP‐1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63: 3346–3358

     Not in our library10.2337/db14-0302

106. 106.

     Blouet C, Schwartz GJ (2012 ) Duodenal lipid sensing activates vagal afferents to regulate non‐shivering brown fat thermogenesis in rats. PLoS One 7: e51898

     Not in our library10.1371/journal.pone.0051898

107. 107.

     Li Y, Schnabl K, Gabler SM, Willershauser M, Reber J, Karlas A, Laurila S, Lahesmaa M, U Din M, Bast‐Habersbrunner A et al (2018 ) Secretin‐activated brown fat mediates prandial thermogenesis to induce satiation. Cell 175: 1561–1574 e12

     Not in our library10.1016/j.cell.2018.10.016

108. 108.

     Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Munzberg H, Zhang ZY, Kahn BB et al (2015 ) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160: 88–104

     Not in our library10.1016/j.cell.2014.12.022

109. 109.

     Dodd GT, Andrews ZB, Simonds SE, Michael NJ, DeVeer M, Bruning JC, Spanswick D, Cowley MA, Tiganis T (2017 ) A hypothalamic phosphatase switch coordinates energy expenditure with feeding. Cell Metab 26: 375–393 e7

     Not in our library10.1016/j.cmet.2017.07.013

110. 110.

     Febbraio MA (2017 ) Exercise metabolism in 2016: health benefits of exercise – more than meets the eye!. Nat Rev Endocrinol 13: 72–74

     Not in our library10.1038/nrendo.2016.218

111. 111.

     Goldstein MS (1961 ) Humoral nature of the hypoglycemic factor of muscular work. Diabetes 10: 232–234

     Not in our library10.2337/diab.10.3.232

112. 112.

     Hoffmann C, Weigert C (2017 ) Skeletal muscle as an endocrine organ: the role of myokines in exercise adaptations. Cold Spring Harb Perspect Med 7: a029793

     Not in our library10.1101/cshperspect.a029793

113. 113.

     Petersen AM, Petersen BK (2005 ) The anti‐inflammatory effect of exercise. J Appl Physiol (1985) 98: 1154–1162

     Not in our library10.1152/japplphysiol.00164.2004

114. 114.
     Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases · 2018

     No notice
115. 115.

     Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ et al (2012 ) A PGC1‐alpha‐dependent myokine that drives brown‐fat‐like development of white fat and thermogenesis. Nature 481: 463–468

     Not in our library10.1038/nature10777

116. 116.

     Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T et al (2014 ) Irisin stimulates browning of white adipocytes through mitogen‐activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 63: 514–525

     Not in our library10.2337/db13-1106

117. 117.

     Perakakis N, Triantafyllou GA, Fernandez‐Real JM, Huh JY, Park KH, Seufert J, Mantzoros CS (2017 ) Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 13: 324–337

     Not in our library10.1038/nrendo.2016.221

118. 118.

     Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US et al (2014 ) Irisin and FGF21 are cold‐induced endocrine activators of brown fat function in humans. Cell Metab 19: 302–309

     Not in our library10.1016/j.cmet.2013.12.017

119. 119.

     Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Goncalves RA, Clarke JR, Beckman D, Staniszewski A et al (2019 ) Exercise‐linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med 25: 165–175

     Not in our library10.1038/s41591-018-0275-4

120. 120.
     FNDC5/Irisin Is Not Only a Myokine but Also an Adipokine · 2013

     No notice
121. 121.

     Fiuza‐Luces C, Santos‐Lozano A, Joyner M, Carrera‐Bastos P, Picazo O, Zugaza JL, Izquierdo M, Ruilope LM, Lucia A (2018 ) Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat Rev Cardiol 15: 731–743

     Not in our library10.1038/s41569-018-0065-1

122. 122.

     Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA et al (2016 ) Running‐induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24: 332–340

     Not in our library10.1016/j.cmet.2016.05.025

123. 123.

     Virtanen KA (2014 ) BAT thermogenesis: linking shivering to exercise. Cell Metab 19: 352–354

     Not in our library10.1016/j.cmet.2014.02.013

124. 124.
     Exercise-induced ‘browning’ of adipose tissues · 2018

     No notice
125. 125.

     Suzuki WA (2016 ) How body affects brain. Cell Metab 24: 192–193

     Not in our library10.1016/j.cmet.2016.07.022

126. 126.

     Kahn BB, Flier JS (2000 ) Obesity and insulin resistance. J Clin Invest 106: 473–481

     Not in our library10.1172/jci10842

127. 127.

     Munzberg H, Flier JS, Bjorbaek C (2004 ) Region‐specific leptin resistance within the hypothalamus of diet‐induced obese mice. Endocrinology 145: 4880–4889

     Not in our library10.1210/en.2004-0726

128. 128.

     Balland E, Chen W, Dodd GT, Conductier G, Coppari R, Tiganis T, Cowley MA (2019 ) Leptin signaling in the arcuate nucleus reduces insulin's capacity to suppress hepatic glucose production in obese mice. Cell Rep 26: 346–355 e3

     Not in our library10.1016/j.celrep.2018.12.061

129. 129.

     Shi YC, Lau J, Lin Z, Zhang H, Zhai L, Sperk G, Heilbronn R, Mietzsch M, Weger S, Huang XF et al (2013 ) Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab 17: 236–248

     Not in our library10.1016/j.cmet.2013.01.006

130. 130.

     Okada‐Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura‐Someya T, Shirouzu M et al (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

131. 131.

     Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS (2004 ) Adiponectin acts in the brain to decrease body weight. Nat Med 10: 524–529

     Not in our library10.1038/nm1029

132. 132.

     Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, Bauer SM, Wade M, Singhal E, Cheng CC et al (2013 ) An FGF21‐adiponectin‐ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 17: 790–797

     Not in our library10.1016/j.cmet.2013.03.019

133. 133.

     BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga SO, Acevedo MR, Walsh SA, Ornitz DM, Potthoff MJ (2017 ) FGF21 regulates metabolism through adipose‐dependent and ‐independent mechanisms. Cell Metab 25: 935–944 e4

     Not in our library10.1016/j.cmet.2017.03.005

134. 134.

     Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos‐Flier E (2010 ) Obesity is a fibroblast growth factor 21 (FGF21)‐resistant state. Diabetes 59: 2781–2789

     Not in our library10.2337/db10-0193

135. 135.

     Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C, Phuong TMN, Gharakhanian R, Che N et al (2018 ) A strategy for discovery of endocrine interactions with application to whole‐body metabolism. Cell Metab 27: 1138–1155 e6

     Not in our library10.1016/j.cmet.2018.03.015

136. 136.

     Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC et al (2014 ) Meteorin‐like is a hormone that regulates immune‐adipose interactions to increase beige fat thermogenesis. Cell 157: 1279–1291

     Not in our library10.1016/j.cell.2014.03.065

137. 137.

     Lee JH, Kang YE, Kim JM, Choung S, Joung KH, Kim HJ, Ku BJ (2018 ) Serum Meteorin‐like protein levels decreased in patients newly diagnosed with type 2 diabetes. Diabetes Res Clin Pract 135: 7–10

     Not in our library10.1016/j.diabres.2017.10.005

138. 138.

     Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB (2010 ) Diet‐induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151: 4745–4755

     Not in our library10.1210/en.2010-0556

139. 139.

     Madsbad S (2014 ) The role of glucagon‐like peptide‐1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab 16: 9–21

     Not in our library10.1111/dom.12119

140. 140.

     Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, Matthews VB, Neill B, White DA, Murphy AJ et al (2015 ) Blocking IL‐6 trans‐signaling prevents high‐fat diet‐induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab 21: 403–416

     Not in our library10.1016/j.cmet.2015.02.006

141. 141.

     Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB (2005 ) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436: 356–362

     Not in our library10.1038/nature03711

142. 142.

     Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U et al (2006 ) Retinol‐binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 354: 2552–2563

     Not in our library10.1056/nejmoa054862

143. 143.

     McPherron AC, Lawler AM, Lee SJ (1997 ) Regulation of skeletal muscle mass in mice by a new TGF‐beta superfamily member. Nature 387: 83–90

     Not in our library10.1038/387083a0

144. 144.

     Argiles JM, Orpi M, Busquets S, Lopez‐Soriano FJ (2012 ) Myostatin: more than just a regulator of muscle mass. Drug Discov Today 17: 702–709

     Not in our library10.1016/j.drudis.2012.02.001

145. 145.

     LeBrasseur NK, Schelhorn TM, Bernardo BL, Cosgrove PG, Loria PM, Brown TA (2009 ) Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J Gerontol A Biol Sci Med Sci 64: 940–948

     Not in our library10.1093/gerona/glp068

146. 146.

     Zhao B, Wall RJ, Yang J (2005 ) Transgenic expression of myostatin propeptide prevents diet‐induced obesity and insulin resistance. Biochem Biophys Res Commun 337: 248–255

     Not in our library10.1016/j.bbrc.2005.09.044

147. 147.

     Shan T, Liang X, Bi P, Kuang S (2013 ) Myostatin knockout drives browning of white adipose tissue through activating the AMPK‐PGC1alpha‐Fndc5 pathway in muscle. FASEB J 27: 1981–1989

     Not in our library10.1096/fj.12-225755

148. 148.

     Zhang C, McFarlane C, Lokireddy S, Bonala S, Ge X, Masuda S, Gluckman PD, Sharma M, Kambadur R (2011 ) Myostatin‐deficient mice exhibit reduced insulin resistance through activating the AMP‐activated protein kinase signalling pathway. Diabetologia 54: 1491–1501

     Not in our library10.1007/s00125-011-2079-7

149. 149.

     Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P et al (1999 ) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose‐escalation trial. JAMA 282: 1568–1575

     Not in our library10.1001/jama.282.16.1568

150. 150.

     Hukshorn CJ, Saris WH, Westerterp‐Plantenga MS, Farid AR, Smith FJ, Campfield LA (2000 ) Weekly subcutaneous pegylated recombinant native human leptin (PEG‐OB) administration in obese men. J Clin Endocrinol Metab 85: 4003–4009

     Not in our library10.1210/jcem.85.11.6955

151. 151.

     Villarroya F, Vidal‐Puig A (2013 ) Beyond the sympathetic tone: the new brown fat activators. Cell Metab 17: 638–643

     Not in our library10.1016/j.cmet.2013.02.020

152. 152.

     Zhang C, Huang Z, Gu J, Yan X, Lu X, Zhou S, Wang S, Shao M, Zhang F, Cheng P et al (2015 ) Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal‐regulated kinase 1/2‐dependent signalling pathway. Diabetologia 58: 1937–1948

     Not in our library10.1007/s00125-015-3630-8

153. 153.

     Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA et al (2009 ) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet‐induced obese mice. Diabetes 58: 250–259

     Not in our library10.2337/db08-0392

154. 154.

     Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE (2013 ) The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 18: 333–340

     Not in our library10.1016/j.cmet.2013.08.005

155. 155.

     Kharitonenkov A, Adams AC (2014 ) Inventing new medicines: the FGF21 story. Mol Metab 3: 221–229

     Not in our library10.1016/j.molmet.2013.12.003

156. 156.

     Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R, Mohammadi M, Gerard RD, Dechow PC et al (2012 ) Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator‐activated receptor gamma. Proc Natl Acad Sci USA 109: 3143–3148

     Not in our library10.1073/pnas.1200797109

157. 157.

     Andersen A, Lund A, Knop FK, Vilsboll T (2018 ) Glucagon‐like peptide 1 in health and disease. Nat Rev Endocrinol 14: 390–403

     Not in our library10.1038/s41574-018-0016-2

158. 158.

     Seghieri M, Christensen AS, Andersen A, Solini A, Knop FK, Vilsboll T (2018 ) Future perspectives on GLP‐1 receptor agonists and GLP‐1/glucagon receptor co‐agonists in the treatment of NAFLD. Front Endocrinol (Lausanne) 9: 649

     Not in our library10.3389/fendo.2018.00649

159. 159.

     Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S et al (2010 ) Towards a knowledge‐based Human Protein Atlas. Nat Biotechnol 28: 1248–1250

     Not in our library10.1038/nbt1210-1248

160. 160.

     Lindskog C (2015 ) The potential clinical impact of the tissue‐based map of the human proteome. Expert Rev Proteomics 12: 213–215

     Not in our library10.1586/14789450.2015.1040771

161. 161.

     Cereijo R, Gavalda‐Navarro A, Cairo M, Quesada‐Lopez T, Villarroya J, Moron‐Ros S, Sanchez‐Infantes D, Peyrou M, Iglesias R, Mampel T et al (2018 ) CXCL14, a brown adipokine that mediates brown‐fat‐to‐macrophage communication in thermogenic adaptation. Cell Metab 28: 750–763 e6

     Not in our library10.1016/j.cmet.2018.07.015

162. 162.

     Yang Q, Vijayakumar A, Kahn BB (2018 ) Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol 19: 654–672

     Not in our library10.1038/s41580-018-0044-8

163. 163.

     Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M, Miao R, Lee S, Jiang L, Huck I, Kershaw EE et al (2017 ) Global analysis of plasma lipids identifies liver‐derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab 26: 509–522 e6

     Not in our library10.1016/j.cmet.2017.08.006

164. 164.

     Mills EL, Pierce KA, Jedrychowski MP, Garrity R, Winther S, Vidoni S, Yoneshiro T, Spinelli JB, Lu GZ, Kazak L et al (2018 ) Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 560: 102–106

     Not in our library10.1038/s41586-018-0353-2

165. 165.

     Chevalier C, Stojanovic O, Colin DJ, Suarez‐Zamorano N, Tarallo V, Veyrat‐Durebex C, Rigo D, Fabbiano S, Stevanovic A, Hagemann S et al (2015 ) Gut microbiota orchestrates energy homeostasis during cold. Cell 163: 1360–1374

     Not in our library10.1016/j.cell.2015.11.004

166. 166.

     Li B, Li L, Li M, Lam SM, Wang G, Wu Y, Zhang H, Niu C, Zhang X, Liu X et al (2019 ) Microbiota depletion impairs thermogenesis of brown adipose tissue and browning of white adipose tissue. Cell Rep 26: 2720–2737 e5

     Not in our library10.1016/j.celrep.2019.02.015

167. 167.

     Trompette A, Gollwitzer ES, Pattaroni C, Lopez‐Mejia IC, Riva E, Pernot J, Ubags N, Fajas L, Nicod LP, Marsland BJ (2018 ) Dietary fiber confers protection against flu by shaping Ly6c(−) patrolling monocyte hematopoiesis and CD8(+) T cell metabolism. Immunity 48: 992–1005 e8

     Not in our library10.1016/j.immuni.2018.04.022

168. 168.

     Zmora N, Suez J, Elinav E (2019 ) You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol 16: 35–56

     Not in our library10.1038/s41575-018-0061-2

169. 169.

     Cani PD, Van Hul M, Lefort C, Depommier C, Rastelli M, Everard A (2019 ) Microbial regulation of organismal energy homeostasis. Nat Metab 1: 34–46

     Not in our library10.1038/s42255-018-0017-4

170. 170.

     Li G, Xie C, Lu S, Nichols RG, Tian Y, Li L, Patel D, Ma Y, Brocker CN, Yan T et al (2017 ) Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab 26: 801

     Not in our library10.1016/j.cmet.2017.10.007

171. 171.

     Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia‐Martin R, Grinspoon SK et al (2017 ) Adipose‐derived circulating miRNAs regulate gene expression in other tissues. Nature 542: 450–455

     Not in our library10.1038/nature21365

172. 172.

     Charman WN, Porter CJ, Mithani S, Dressman JB (1997 ) Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 86: 269–282

     Not in our library10.1021/js960085v

173. 173.

     Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, Amadiume SC, Goncalves MD, Hodakoski C, Lundquist MR et al (2018 ) Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560: 499–503

     Not in our library10.1038/s41586-018-0343-4

174. 174.

     Quail DF, Olson OC, Bhardwaj P, Walsh LA, Akkari L, Quick ML, Chen IC, Wendel N, Ben‐Chetrit N, Walker J et al (2017 ) Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM‐CSF. Nat Cell Biol 19: 974–987

     Not in our library10.1038/ncb3578

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.