The endocrine function of adipose tissues in health and cardiometabolic disease

Article metrics


In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease.

Key points

  • White and brown adipocytes secrete many peptide hormones (adipokines), bioactive lipids (lipokines) and RNA molecules with local (paracrine) and systemic (endocrine) effects on the brain, pancreatic β-cells, the liver, skeletal muscle and the cardiovascular system.

  • Production and secretion of adipokines and lipokines is dependent on the energy status of adipose tissues. Through endocrine action, these factors contribute to systemic energy metabolism by regulating appetite, thermogenesis, glucose metabolism and lipid metabolism.

  • Many peptides that were initially described as adipokines are secreted by endothelial and immune cells located in adipose tissues, as well as by other organs, which means the endocrine contribution of adipocytes can be difficult to ascertain.

  • In healthy states, white and brown adipose tissues secrete endocrine factors that maintain organ functions and metabolic homeostasis.

  • In obesity, hypertrophic adipocytes and adipose tissue-resident immune cells accelerate a chronic, proinflammatory profile with altered secretion of adipokines and lipokines, thereby exacerbating cardiometabolic disease.

  • Preclinical and clinical studies show that activating or inhibiting the signalling of specific adipokines or lipokines could be an approach suitable to treat or prevent the development of cardiometabolic diseases. However, in almost all cases, efficacy and safety in humans needs to be proven.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Endocrine effects of adipocyte-secreted factors.
Fig. 2: Endocrine factors released by healthy and unhealthy adipose tissues.
Fig. 3: Functional relevance of adipokines and lipokines in cardiometabolic diseases.


  1. 1.

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

  2. 2.

    Karastergiou, K. & Mohamed-Ali, V. The autocrine and paracrine roles of adipokines. Mol. Cell Endocrinol. 318, 69–78 (2010).

  3. 3.

    Lehr, S., Hartwig, S. & Sell, H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin. Appl. 6, 91–101 (2012).

  4. 4.

    Ali Khan, A. et al. Comparative secretome analyses of primary murine white and brown adipocytes reveal novel adipokines. Mol. Cell Proteomics 17, 2358–2370 (2018).

  5. 5.

    Seldin, M. M. et al. A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metab. 27, 1138–1155 (2018). This study identified lipocalin 5 as a novel adipokine regulating muscle mitochondria by using an unbiased computational approach based on multiorgan transcriptomics of various mouse strains.

  6. 6.

    Giordano, A., Smorlesi, A., Frontini, A., Barbatelli, G. & Cinti, S. White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ. Eur. J. Endocrinol. 170, R159–R171 (2014).

  7. 7.

    Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013).

  8. 8.

    Scheja, L. & Heeren, J. Metabolic interplay between white, beige, brown adipocytes and the liver. J. Hepatol. 64, 1176–1186 (2016).

  9. 9.

    Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).

  10. 10.

    Crewe, C., An, Y. A. & Scherer, P. E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 127, 74–82 (2017).

  11. 11.

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

  12. 12.

    Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

  13. 13.

    Boucher, J., Kleinridders, A. & Kahn, C. R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 6, a009191 (2014).

  14. 14.

    Xu, X. et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 18, 816–830 (2013).

  15. 15.

    Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).

  16. 16.

    Kloting, N. et al. Insulin-sensitive obesity. Am. J. Physiol. Endocrinol. Metab. 299, E506–E515 (2010).

  17. 17.

    Karpe, F. & Pinnick, K. E. Biology of upper-body and lower-body adipose tissue—link to whole-body phenotypes. Nat. Rev. Endocrinol. 11, 90–100 (2015).

  18. 18.

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

  19. 19.

    Li, Y. et al. Secretin-activated brown fat mediates prandial thermogenesis to induce satiation. Cell 175, 1561–1574 (2018).

  20. 20.

    Heine, M. et al. Lipolysis triggers a systemic insulin response essential for efficient energy replenishment of activated brown adipose tissue in mice. Cell Metab. 28, 644–655 (2018).

  21. 21.

    Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).

  22. 22.

    Villarroya, F., Cereijo, R., Villarroya, J., Gavalda-Navarro, A. & Giralt, M. Toward an understanding of how immune cells control brown and beige adipobiology. Cell Metab. 27, 954–961 (2018).

  23. 23.

    Takeshita, S., Fumoto, T., Naoe, Y. & Ikeda, K. Age-related marrow adipogenesis is linked to increased expression of RANKL. J. Biol. Chem. 289, 16699–16710 (2014).

  24. 24.

    Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).

  25. 25.

    Cawthorn, W. P. et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 20, 368–375 (2014).

  26. 26.

    Costa, R. M., Neves, K. B., Tostes, R. C. & Lobato, N. S. Perivascular adipose tissue as a relevant fat depot for cardiovascular risk in obesity. Front. Physiol. 9, 253 (2018).

  27. 27.

    Xiong, W. et al. Brown adipocyte-specific PPARγ (peroxisome proliferator-activated receptor gamma) deletion impairs perivascular adipose tissue development and enhances atherosclerosis in mice. Arterioscler Thromb. Vasc. Biol. 38, 1738–1747 (2018).

  28. 28.

    Antonopoulos, A. S. et al. Detecting human coronary inflammation by imaging perivascular fat. Sci. Transl Med. 9, eaal2658 (2017).

  29. 29.

    Guglielmi, V. & Sbraccia, P. Epicardial adipose tissue: at the heart of the obesity complications. Acta Diabetol. 54, 805–812 (2017).

  30. 30.

    Bluher, M. & Mantzoros, C. S. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 64, 131–145 (2015).

  31. 31.

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

  32. 32.

    Fischer, A. W., Cannon, B. & Nedergaard, J. Leptin-deficient mice are not hypothermic, they are anapyrexic. Mol. Metab. 6, 173 (2017).

  33. 33.

    Farooqi, I. S. & O’Rahilly, S. 20 years of leptin: human disorders of leptin action. J. Endocrinol. 223, T63–70 (2014).

  34. 34.

    Boden, G., Chen, X., Mozzoli, M. & Ryan, I. Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab. 81, 3419–3423 (1996).

  35. 35.

    Sinha, M. K. et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest. 97, 1344–1347 (1996).

  36. 36.

    Francisco, V. et al. Obesity, fat mass and immune system: role for leptin. Front. Physiol. 9, 640 (2018).

  37. 37.

    Hube, F. et al. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm. Metab. Res. 28, 690–693 (1996).

  38. 38.

    Wrann, C. D. et al. FOSL2 promotes leptin gene expression in human and mouse adipocytes. J. Clin. Invest. 122, 1010–1021 (2012).

  39. 39.

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

  40. 40.

    Mantzoros, C. S. et al. Activation of β3 adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 45, 909–914 (1996).

  41. 41.

    Trayhurn, P., Duncan, J. S., Rayner, D. V. & Hardie, L. J. Rapid inhibition of ob gene expression and circulating leptin levels in lean mice by the beta 3-adrenoceptor agonists BRL 35135A and ZD2079. Biochem. Biophys. Res. Commun. 228, 605–610 (1996).

  42. 42.

    Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).

  43. 43.

    Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).

  44. 44.

    Hayes, M. R. et al. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 11, 77–83 (2010).

  45. 45.

    Scott, M. M., Williams, K. W., Rossi, J., Lee, C. E. & Elmquist, J. K. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J. Clin. Invest. 121, 2413–2421 (2011).

  46. 46.

    Denroche, H. C. et al. Disrupted leptin signaling in the lateral hypothalamus and ventral premammillary nucleus alters insulin and glucagon secretion and protects against diet-induced obesity. Endocrinology 157, 2671–2685 (2016).

  47. 47.

    Xu, J. et al. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509 (2018).

  48. 48.

    Berglund, E. D. et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Invest. 122, 1000–1009 (2012).

  49. 49.

    Hubert, A. et al. Selective deletion of leptin signaling in endothelial cells enhances neointima formation and phenocopies the vascular effects of diet-induced obesity in mice. Arterioscler. Thromb. Vasc. Biol. 37, 1683–1697 (2017). Using endothelial cell-specific Lepr -knockout mice, this study identified leptin signalling in endothelial cells as an important mechanism counteracting obesity-associated neointima formation.

  50. 50.

    Wu, Y., Fortin, D. A., Cochrane, V. A., Chen, P. C. & Shyng, S. L. NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic beta-cells. J. Biol. Chem. 292, 15512–15524 (2017).

  51. 51.

    Dunmore, S. J. & Brown, J. E. The role of adipokines in beta-cell failure of type 2 diabetes. J. Endocrinol. 216, T37–45 (2013).

  52. 52.

    Soedling, H. et al. Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells. Mol. Metab. 4, 619–630 (2015).

  53. 53.

    Fang, H. & Judd, R. L. Adiponectin regulation and function. Compr. Physiol. 8, 1031–1063 (2018).

  54. 54.

    Komai, A. M. et al. White adipocyte adiponectin exocytosis is stimulated via β3-adrenergic signaling and activation of Epac1: catecholamine resistance in obesity and type 2 diabetes. Diabetes 65, 3301–3313 (2016).

  55. 55.

    Kikai, M. et al. Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE−/− mice. Biochem. Biophys. Res. Commun. 497, 1097–1103 (2018).

  56. 56.

    Trayhurn, P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 93, 1–21 (2013).

  57. 57.

    Sulston, R. J. et al. Increased circulating adiponectin in response to thiazolidinediones: investigating the role of bone marrow adipose tissue. Front. Endocrinol. 7, 128 (2016).

  58. 58.

    Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8, 731–737 (2002).

  59. 59.

    Kim, J. Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).

  60. 60.

    Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003).

  61. 61.

    Mao, X. et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat. Cell Biol. 8, 516–523 (2006).

  62. 62.

    Vasiliauskaite-Brooks, I. et al. Structural insights into adiponectin receptors suggest ceramidase activity. Nature 544, 120–123 (2017).

  63. 63.

    Ye, R., Wang, M., Wang, Q. A. & Scherer, P. E. Adiponectin-mediated antilipotoxic effects in regenerating pancreatic islets. Endocrinology 56, 2019–2028 (2015).

  64. 64.

    Mandal, P., Pratt, B. T., Barnes, M., McMullen, M. R. & Nagy, L. E. Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J. Biol. Chem. 286, 13460–13469 (2011).

  65. 65.

    Caligiuri, A. et al. Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology 47, 668–676 (2008).

  66. 66.

    Okamoto, Y. et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106, 2767–2770 (2002).

  67. 67.

    Qiao, L. et al. Adiponectin deficiency impairs maternal metabolic adaptation to pregnancy in mice. Diabetes 66, 1126–1135 (2017).

  68. 68.

    Cheng, L. et al. Adiponectin deficiency leads to female subfertility and ovarian dysfunctions in mice. Endocrinology 157, 4875–4887 (2016).

  69. 69.

    Aye, I. L., Rosario, F. J., Powell, T. L. & Jansson, T. Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc. Natl Acad. Sci. USA 112, 12858–12863 (2015).

  70. 70.

    Hu, X. et al. MitoNEET deficiency alleviates experimental alcoholic steatohepatitis in mice by stimulating endocrine adiponectin-Fgf15 axis. J. Biol. Chem. 291, 22482–22495 (2016).

  71. 71.

    Wang, J. et al. Myeloid cell-specific lipin-1 deficiency stimulates endocrine adiponectin-FGF15 axis and ameliorates ethanol-induced liver injury in mice. Sci. Rep. 6, 34117 (2016).

  72. 72.

    Cook, K. S. et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237, 402–405 (1987).

  73. 73.

    Wu, X. et al. Contribution of adipose-derived factor D/adipsin to complement alternative pathway activation: lessons from lipodystrophy. J. Immunol. 200, 2786–2797 (2018).

  74. 74.

    Hertle, E. et al. The alternative complement pathway is longitudinally associated with adverse cardiovascular outcomes. The CODAM study. Thromb. Haemost. 115, 446–457 (2016).

  75. 75.

    McCullough, R. L. et al. Complement factor D protects mice from ethanol-induced inflammation and liver injury. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G66–G79 (2018).

  76. 76.

    Lo, J. C. et al. Adipsin is an adipokine that improves beta cell function in diabetes. Cell 158, 41–53 (2014).

  77. 77.

    Maslowska, M. et al. Plasma acylation stimulating protein, adipsin and lipids in non-obese and obese populations. Eur. J. Clin. Invest. 29, 679–686 (1999).

  78. 78.

    Hotamisligil, G. S. & Bernlohr, D. A. Metabolic functions of FABPs—mechanisms and therapeutic implications. Nat. Rev. Endocrinol. 11, 592–605 (2015).

  79. 79.

    Villeneuve, J. et al. Unconventional secretion of FABP4 by endosomes and secretory lysosomes. J. Cell Biol. 217, 649–665 (2018).

  80. 80.

    Cao, H. et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 17, 768–778 (2013).

  81. 81.

    Burak, M. F. et al. Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes. Sci. Transl Med. 7, 319ra205 (2015).

  82. 82.

    Girona, J. et al. FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway. PLOS ONE 8, e81914 (2013).

  83. 83.

    Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014). This study discovered that cold exposure triggers the induction of NRG4 expression in BAT of mice and in parallel reduces hepatic DNL through NRG4 receptor (ERBB3/ERBB4) signalling, providing evidence for a novel endocrine BAT–liver axis.

  84. 84.

    Guo, L. et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J. Clin. Invest. 127, 4449–4461 (2017).

  85. 85.

    Nugroho, D. B., Ikeda, K., Kajimoto, K., Hirata, K. I. & Emoto, N. Activation of neuregulin-4 in adipocytes improves metabolic health by enhancing adipose tissue angiogenesis. Biochem. Biophys. Res. Commun. 504, 427–433 (2018).

  86. 86.

    Nugroho, D. B. et al. Neuregulin-4 is an angiogenic factor that is critically involved in the maintenance of adipose tissue vasculature. Biochem. Biophys. Res. Commun. 503, 378–384 (2018).

  87. 87.

    Christian, M. Transcriptional fingerprinting of “browning” white fat identifies NRG4 as a novel adipokine. Adipocyte 4, 50–54 (2015).

  88. 88.

    Chen, Z. et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol. Metab. 6, 863–872 (2017).

  89. 89.

    Montagner, A. et al. Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65, 1202–1214 (2016).

  90. 90.

    Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).

  91. 91.

    Chan, K. L. et al. Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J. Biol. Chem. 290, 16979–16988 (2015).

  92. 92.

    Cimen, I. et al. Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation. Sci. Transl Med. 8, 358ra126 (2016). The study showed that oral supplementation with the lipokine palmitoleate reduces the size of atherosclerotic lesions in apolipoprotein E-deficient mice by relieving cholesterol-induced endoplasmic reticulum stress and inflammatory mechanisms in macrophages.

  93. 93.

    Herman, M. A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012).

  94. 94.

    Yang, Z. H., Miyahara, H. & Hatanaka, A. Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes. Lipids Health Dis. 10, 120 (2011).

  95. 95.

    Guo, X. et al. Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice. PLOS ONE 7, e39286 (2012).

  96. 96.

    Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat. Commun. 4, 1528 (2013).

  97. 97.

    Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014). This study describes the discovery of FAHFAs as a novel class of lipokines that are tightly linked to WAT DNL and systemic insulin sensitivity.

  98. 98.

    Vijayakumar, A. et al. Absence of carbohydrate response element binding protein in adipocytes causes systemic insulin resistance and impairs glucose transport. Cell Rep. 21, 1021–1035 (2017).

  99. 99.

    Hammarstedt, A. et al. Adipose tissue dysfunction is associated with low levels of the novel palmitic acid hydroxystearic acids. Sci. Rep. 8, 15757 (2018).

  100. 100.

    Syed, I. et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 27, 419–427 (2018).

  101. 101.

    Pflimlin, E. et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab. 28, 217–227 (2018).

  102. 102.

    Syed, I. et al. Methodological issues in studying PAHSA biology: masking PAHSA effects. Cell Metab. 28, 543–546 (2018).

  103. 103.

    Kuda, O. On the complexity of PAHSA research. Cell Metab. 28, 541–542 (2018).

  104. 104.

    Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 23, 631–637 (2017).

  105. 105.

    Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120 (2018).

  106. 106.

    Huang-Doran, I., Zhang, C. Y. & Vidal-Puig, A. Extracellular vesicles: novel mediators of cell communication in metabolic disease. Trends Endocrinol. Metab. 28, 3–18 (2017).

  107. 107.

    Chen, Y. et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat. Commun. 7, 11420 (2016).

  108. 108.

    Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).

  109. 109.

    Ying, W. et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171, 372–384 (2017).

  110. 110.

    BonDurant, L. D. & Potthoff, M. J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 38, 173–196 (2018).

  111. 111.

    Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016).

  112. 112.

    Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441–453 (2016).

  113. 113.

    Hansen, J. S. et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol. Metab. 4, 551–560 (2015).

  114. 114.

    Markan, K. R. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63, 4057–4063 (2014). This study identified the liver as the source of circulating FGF21 and its insulin-sensitizing effects in acute refeeding and overfeeding.

  115. 115.

    Liang, Q. et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 63, 4064–4075 (2014).

  116. 116.

    BonDurant, L. D. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 25, 935–944 (2017).

  117. 117.

    Hondares, E. et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 286, 12983–12990 (2011).

  118. 118.

    Fisher, F. M. et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).

  119. 119.

    Huang, Z. et al. The FGF21-CCL11 axis mediates beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab. 26, 493–508 (2017).

  120. 120.

    Keipert, S. et al. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol. Metab. 4, 537–542 (2015).

  121. 121.

    Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).

  122. 122.

    Ruan, C. C. et al. A2A receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab. 28, 476–489 (2018). This study provides evidence that hypertension-induced cardiac hypertrophy and fibrosis is counter-regulated by FGF21 induced in and secreted by BAT in this condition.

  123. 123.

    Hjortebjerg, R. et al. Insulin, IGF-1, and GH receptors are altered in an adipose tissue depot-specific manner in male mice with modified GH action. Endocrinology 158, 1406–1418 (2017).

  124. 124.

    Masternak, M. M. et al. Effects of caloric restriction on insulin pathway gene expression in the skeletal muscle and liver of normal and long-lived GHR-KO mice. Exp. Gerontol. 40, 679–684 (2005).

  125. 125.

    Gunawardana, S. C. & Piston, D. W. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am. J. Physiol. Endocrinol. Metab. 308, E1043–E1055 (2015).

  126. 126.

    Kloting, N. et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 6, 79–87 (2007).

  127. 127.

    Berry, D. C. et al. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin A homeostasis in tissues other than the eye. J. Biol. Chem. 288, 24528–24539 (2013).

  128. 128.

    Moraes-Vieira, P. M. et al. Antigen presentation and T-cell activation are critical for RBP4-induced insulin resistance. Diabetes 65, 1317–1327 (2016).

  129. 129.

    Thompson, S. J. et al. Hepatocytes are the principal source of circulating RBP4 in mice. Diabetes 66, 58–63 (2017).

  130. 130.

    Preitner, F., Mody, N., Graham, T. E., Peroni, O. D. & Kahn, B. B. Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 297, E1420–E1429 (2009).

  131. 131.

    Fedders, R. et al. Liver-secreted RBP4 does not impair glucose homeostasis in mice. J. Biol. Chem. 293, 15269–15276 (2018).

  132. 132.

    Lee, S. A., Yuen, J. J., Jiang, H., Kahn, B. B. & Blaner, W. S. Adipocyte-specific overexpression of retinol-binding protein 4 causes hepatic steatosis in mice. Hepatology 64, 1534–1546 (2016).

  133. 133.

    Lu, J., Chatterjee, M., Schmid, H., Beck, S. & Gawaz, M. CXCL14 as an emerging immune and inflammatory modulator. J. Inflamm. (Lond.) 13, 1 (2016).

  134. 134.

    Cereijo, R. et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab. 28, 750–763 (2018). This study describes the release of CXCL14 by BAT into the circulation in response to cold exposure, resulting in increased WAT browning and BAT activation via M2 macrophage recruitment.

  135. 135.

    Pedersen, B. K. & Febbraio, M. A. Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, (814–816 (2007).

  136. 136.

    Schmidt-Arras, D. & Rose-John, S. IL-6 pathway in the liver: from physiopathology to therapy. J. Hepatol. 64, 1403–1415 (2016).

  137. 137.

    Mohamed-Ali, V. et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 82, 4196–4200 (1997).

  138. 138.

    Zhang, W. et al. Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity. J. Biol. Chem. 289, 32178–32185 (2014).

  139. 139.

    Matsubara, T. et al. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metab. 15, 38–50 (2012).

  140. 140.

    Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

  141. 141.

    Wunderlich, F. T. et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12, 237–249 (2010).

  142. 142.

    Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).

  143. 143.

    Braune, J. et al. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity. J. Immunol. 198, 2927–2934 (2017).

  144. 144.

    Theurich, S. et al. IL-6/Stat3-dependent induction of a distinct, obesity-associated NK cell subpopulation deteriorates energy and glucose homeostasis. Cell Metab. 26, 171–184 (2017).

  145. 145.

    Xu, E. et al. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat. Commun. 8, 14803 (2017).

  146. 146.

    Schwartz, D. R. & Lazar, M. A. Human resistin: found in translation from mouse to man. Trends Endocrinol. Metab. 22, 259–265 (2011).

  147. 147.

    Tan, Y. et al. Antiresistin RNA oligonucleotide ameliorates diet-induced nonalcoholic fatty liver disease in mice through attenuating proinflammatory cytokines. Biomed. Res. Int. 2015, 414860 (2015).

  148. 148.

    Benomar, Y. et al. Central resistin/TLR4 impairs adiponectin signaling, contributing to insulin and FGF21 resistance. Diabetes 65, 913–926 (2016).

  149. 149.

    Savage, D. B. et al. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 50, 2199–2202 (2001).

  150. 150.

    Qatanani, M., Szwergold, N. R., Greaves, D. R., Ahima, R. S. & Lazar, M. A. Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J. Clin. Invest. 119, 531–539 (2009).

  151. 151.

    Corre, J., Hebraud, B. & Bourin, P. Concise review: growth differentiation factor 15 in pathology: a clinical role? Stem Cells Transl Med. 2, 946–952 (2013).

  152. 152.

    Ding, Q. et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology 150, 1688–1696 (2009).

  153. 153.

    Lee, S. E. et al. Growth differentiation factor 15 mediates systemic glucose regulatory action of T-helper type 2 cytokines. Diabetes 66, 2774–2788 (2017).

  154. 154.

    Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).

  155. 155.

    Emmerson, P. J. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 23, 1215–1219 (2017).

  156. 156.

    Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157 (2017).

  157. 157.

    Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl Med. 9, eaan8732 (2017). This study showed that pharmacological administration of a GDF15 analogue reduces body weight and improves metabolism in obese rodents and monkeys.

  158. 158.

    Fukuhara, A. et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307, 426–430 (2005).

  159. 159.

    Carbone, F. et al. Regulation and function of extracellular nicotinamide phosphoribosyltransferase/visfatin. Compr. Physiol. 7, 603–621 (2017).

  160. 160.

    Stromsdorfer, K. L. et al. NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860 (2016).

  161. 161.

    Xia, M. et al. Endothelial NLRP3 inflammasome activation and enhanced neointima formation in mice by adipokine visfatin. Am. J. Pathol. 184, 1617–1628 (2014).

  162. 162.

    Kieswich, J. et al. Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment. Diabetologia 59, 2477–2486 (2016).

  163. 163.

    Wesener, D. A. et al. Recognition of microbial glycans by human intelectin-1. Nat. Struct. Mol. Biol. 22, 603–610 (2015).

  164. 164.

    Yang, R. Z. et al. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am. J. Physiol. Endocrinol. Metab. 290, E1253–E1261 (2006).

  165. 165.

    Watanabe, T., Watanabe-Kominato, K., Takahashi, Y., Kojima, M. & Watanabe, R. Adipose tissue-derived omentin-1 function and regulation. Compr. Physiol. 7, 765–781 (2017).

  166. 166.

    Tan, B. K. et al. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 57, 801–808 (2008).

  167. 167.

    Bluher, M. Vaspin in obesity and diabetes: pathophysiological and clinical significance. Endocrine 41, 176–182 (2012).

  168. 168.

    Kloting, N. et al. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem. Biophys. Res. Commun. 339, 430–436 (2006).

  169. 169.

    Fain, J. N., Buehrer, B., Bahouth, S. W., Tichansky, D. S. & Madan, A. K. Comparison of messenger RNA distribution for 60 proteins in fat cells versus the nonfat cells of human omental adipose tissue. Metabolism 57, 1005–1015 (2008).

  170. 170.

    Zieger, K. et al. Ablation of kallikrein 7 (KLK7) in adipose tissue ameliorates metabolic consequences of high fat diet-induced obesity by counteracting adipose tissue inflammation in vivo. Cell. Mol. Life Sci. 75, 727–742 (2018).

  171. 171.

    Chou, S. H. et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl Acad. Sci. USA 108, 6585–6590 (2011).

  172. 172.

    Petersen, K. F. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109, 1345–1350 (2002).

  173. 173.

    Perry, R. J. et al. Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis. J. Clin. Invest. 127, 657–669 (2017).

  174. 174.

    Oberlin, D. & Buettner, C. How does leptin restore euglycemia in insulin-deficient diabetes? J. Clin. Invest. 127, 450–453 (2017).

  175. 175.

    Cui, H., Lopez, M. & Rahmouni, K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat. Rev. Endocrinol. 13, 338–351 (2017).

  176. 176.

    Levin, B. E. & Lutz, T. A. Amylin and leptin: co-regulators of energy homeostasis and neuronal development. Trends Endocrinol. Metab. 28, 153–164 (2017).

  177. 177.

    Li, Z., Kelly, L., Heiman, M., Greengard, P. & Friedman, J. M. Hypothalamic amylin acts in concert with leptin to regulate food intake. Cell Metab. 22, 1059–1067 (2015).

  178. 178.

    Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).

  179. 179.

    Lee, J. et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat. Med. 22, 1023–1032 (2016). In this study the plant-derived molecule withaferin A was identified as a leptin sensitizer that reduces body weight and improves glucose homeostasis of diet-induced obese mice.

  180. 180.

    Saxena, N. K. & Anania, F. A. Adipocytokines and hepatic fibrosis. Trends Endocrinol. Metab. 26, 153–161 (2015).

  181. 181.

    Kubota, T. et al. Pioglitazone ameliorates smooth muscle cell proliferation in cuff-induced neointimal formation by both adiponectin-dependent and -independent pathways. Sci. Rep. 6, 34707 (2016).

  182. 182.

    Zhou, M. et al. Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice without adiponectin. J. Hepatol. 53, 1108–1116 (2010).

  183. 183.

    Okada-Iwabu, M. et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503, 493–499 (2013).

  184. 184.

    Yamashita, T. et al. An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis. Sci. Rep. 8, 11843 (2018).

  185. 185.

    Menzaghi, C. & Trischitta, V. The adiponectin paradox for all-cause and cardiovascular mortality. Diabetes 67, 12–22 (2018).

  186. 186.

    Aleksandrova, K., Mozaffarian, D. & Pischon, T. Addressing the perfect storm: biomarkers in obesity and pathophysiology of cardiometabolic risk. Clin. Chem. 64, 142–153 (2018).

  187. 187.

    Zoi, I. et al. RANKL signaling and ErbB receptors in breast carcinogenesis. Trends Mol. Med. 22, 839–850 (2016).

  188. 188.

    Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).

  189. 189.

    Sanyal, A. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392, 2705–2717 (2019).

  190. 190.

    Kataoka, Y. et al. Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. J. Am. Coll. Cardiol. 63, 2722–2733 (2014).

  191. 191.

    Matsuo, K. et al. Omentin functions to attenuate cardiac hypertrophic response. J. Mol. Cell Cardiol. 79, 195–202 (2015).

  192. 192.

    Hiramatsu-Ito, M. et al. Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice. Cardiovasc. Res. 110, 107–117 (2016).

  193. 193.

    Yuan, L. et al. Vaspin protects rats against myocardial ischemia/reperfusion injury (MIRI) through the TLR4/NF-kappaB signaling pathway. Eur. J. Pharmacol. 835, 132–139 (2018).

  194. 194.

    Sakamoto, Y. et al. Visceral adipose tissue-derived serine protease inhibitor prevents the development of monocrotaline-induced pulmonary arterial hypertension in rats. Pflugers Arch. 469, 1425–1432 (2017).

  195. 195.

    O’Neill, S. M. et al. Targeting adipose tissue via systemic gene therapy. Gene Ther. 21, 653–661 (2014).

  196. 196.

    Aouadi, M. et al. Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc. Natl Acad. Sci. USA 110, 8278–8283 (2013). This study describes a method to selectively target small interfering RNAs to macrophages in epididymal WAT but not subcutaneous WAT or other organs.

  197. 197.

    Chang, H. R., Kim, H. J., Xu, X. & Ferrante, A. W. Jr. Macrophage and adipocyte IGF1 maintain adipose tissue homeostasis during metabolic stresses. Obesity (Silver Spring) 24, 172–183 (2016).

  198. 198.

    Almuraikhy, S. et al. Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance. Diabetologia 59, 2406–2416 (2016).

  199. 199.

    Weiner, J. et al. Brown adipose tissue (BAT) specific vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation. Mol. Metab. 6, 482–493 (2017).

Download references


The authors acknowledge the support of grants from the Deutsche Forschungsgemeinschaft (SCHE522/4-1), Collaborative Research Center (SFB 1328) and Heisenberg Professorship (HE3645/10-1).

Author information

The authors contributed equally to all aspects of the article.

Correspondence to Joerg Heeren.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks D. Langin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Uncoupling protein 1

(UCP1). A unique proton transporter that shuttles protons back into the mitochondrial matrix and uncouples the electron transfer chain from ATP synthesis, a process that generates heat.

M2 macrophages

Macrophages polarized by type 2 immunity-related cytokines such as IL-4 and IL-13, which maintain tissue homeostasis by counteracting proinflammatory processes and facilitating tissue regeneration.


A genetic or acquired condition that is characterized by lack of adipose tissue, insulin resistance and hyperglycaemia.


Pathological thickening of the subendothelial layer (intima) of arteries due to atherosclerosis or other arterial injuries


Small cytosol-containing membrane vesicles that are released by one cell to be taken up by other cells and release their content, for example microRNA.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading