The effects of growth hormone on adipose tissue: old observations, new mechanisms


The ability of growth hormone (GH) to induce adipose tissue lipolysis has been known for over five decades; however, the molecular mechanisms that mediate this effect and the ability of GH to inhibit insulin-stimulated glucose uptake have scarcely been documented. In this same time frame, our understanding of adipose tissue has evolved to reveal a complex structure with distinct types of adipocyte, depot-specific differences, a biologically significant extracellular matrix and important endocrine properties mediated by adipokines. All these aforementioned features, in turn, can influence lipolysis. In this Review, we provide a historical and current overview of the lipolytic effect of GH in humans, mice and cultured cells. More globally, we explain lipolysis in terms of GH-induced intracellular signalling and its effect on obesity, insulin resistance and lipotoxicity. In this regard, findings that define molecular mechanisms by which GH induces lipolysis are described. Finally, data are presented for the differential effect of GH on specific adipose tissue depots and on distinct classes of metabolically active adipocytes. Together, these cellular, animal and human studies reveal novel cellular phenotypes and molecular pathways regulating the metabolic effects of GH on adipose tissue.

Key points

  • Growth hormone (GH) exposure in humans potently stimulates the release of free fatty acids from adipose tissue into the circulation after a lag phase of 1–2 hours and with a peak effect after 3–4 hours.

  • This GH-induced increase in circulating free fatty acids is causally linked to the antagonistic effects of GH on basal and insulin-stimulated glucose uptake.

  • Overexpression of FSP27 or exposure to a GH receptor antagonist, pegvisomant, can block the diabetogenic effects of GH.

  • GH-induced activation of the MEK–ERK pathway has a key role in PPARγ inactivation and FSP27 downregulation, thus increasing lipolysis and insulin resistance.

  • GH impacts adipose tissue in a depot-specific manner and influences other features of adipose tissue (for example, senescence, adipocyte subpopulations and fibrosis), all of which could influence lipolysis.

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Fig. 1: GH-induced lipolysis and insulin resistance.
Fig. 2: Body composition assessed by CT in adults with GH deficiency.
Fig. 3: Effects of GH in humans on FFA levels and insulin sensitivity.


  1. 1.

    Brockmann, G. A. & Bevova, M. R. Using mouse models to dissect the genetics of obesity. Trends. Genet. 18, 367–376 (2002).

    CAS  PubMed  Google Scholar 

  2. 2.

    Friedman, J. M. A war on obesity, not the obese. Science 299, 856–858 (2003).

    CAS  PubMed  Google Scholar 

  3. 3.

    Moller, N. & Jorgensen, J. O. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr. Rev. 30, 152–177 (2009).

    PubMed  Google Scholar 

  4. 4.

    Luft, R., Ikkos, D., Gemzell, C. A. & Olivecrona, H. Effect of human growth hormone in hypophysectomised diabetic subjects. Lancet 1, 721–722 (1958).

    CAS  PubMed  Google Scholar 

  5. 5.

    Davidson, M. B. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr. Rev. 8, 115–131 (1987). This classic review provides a historical perspective and a thorough understanding of early studies on the role of GH on carbohydrate and lipid metabolism.

    CAS  PubMed  Google Scholar 

  6. 6.

    Rabinowitz, D. & Zierler, K. L. A metabolic regulating device based on the actions of human growth hormone and of insulin, singly and together, on the human forearm. Nature 199, 913–915 (1963).

    CAS  PubMed  Google Scholar 

  7. 7.

    Tunaru, S. et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat. Med. 9, 352–355 (2003).

    CAS  PubMed  Google Scholar 

  8. 8.

    Nielsen, S., Moller, N., Christiansen, J. S. & Jorgensen, J. O. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes 50, 2301–2308 (2001). The lipolytic action of GH is responsible for its reduction of insulin sensitivity in human volunteers.

    CAS  PubMed  Google Scholar 

  9. 9.

    Unger, R. H., Clark, G. O., Scherer, P. E. & Orci, L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim. Biophys. Acta 1801, 209–214 (2010).

    CAS  PubMed  Google Scholar 

  10. 10.

    Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10 (1997).

    CAS  PubMed  Google Scholar 

  11. 11.

    Boden, G., Chen, X., Ruiz, J., White, J. V. & Rossetti, L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J. Clin. Invest. 93, 2438–2446 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Dresner, A. et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103, 253–259 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ferrannini, E., Barrett, E. J., Bevilacqua, S. & DeFronzo, R. A. Effect of fatty acids on glucose production and utilization in man. J. Clin. Invest. 72, 1737–1747 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Rajala, M. W. & Scherer, P. E. Minireview: the adipocyte — at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144, 3765–3773 (2003).

    CAS  PubMed  Google Scholar 

  15. 15.

    Ahmadian, M., Wang, Y. & Sul, H. S. Lipolysis in adipocytes. Int. J. Biochem. Cell Biol. 42, 555–559 (2010).

    CAS  PubMed  Google Scholar 

  16. 16.

    Jenkins, C. M. et al. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 279, 48968–48975 (2004).

    CAS  PubMed  Google Scholar 

  17. 17.

    Villena, J. A., Roy, S., Sarkadi-Nagy, E., Kim, K. H. & Sul, H. S. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J. Biol. Chem. 279, 47066–47075 (2004).

    CAS  PubMed  Google Scholar 

  18. 18.

    Zechner, R. et al. FAT SIGNALS — lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 15, 279–291 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383–1386 (2004).

    CAS  PubMed  Google Scholar 

  20. 20.

    Granneman, J. G., Moore, H. P., Krishnamoorthy, R. & Rathod, M. Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (ABHD5) and adipose triglyceride lipase (ATGL). J. Biol. Chem. 284, 34538–34544 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Lass, A. et al. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman syndrome. Cell Metab. 3, 309–319 (2006).

    CAS  PubMed  Google Scholar 

  22. 22.

    Subramanian, V. et al. Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes. J. Biol. Chem. 279, 42062–42071 (2004).

    CAS  PubMed  Google Scholar 

  23. 23.

    Miyoshi, H. et al. Control of adipose triglyceride lipase action by serine 517 of perilipin A globally regulates protein kinase A-stimulated lipolysis in adipocytes. J. Biol. Chem. 282, 996–1002 (2007).

    CAS  PubMed  Google Scholar 

  24. 24.

    Yang, X. et al. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 11, 194–205 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gong, J. et al. FSP27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites. J. Cell Biol. 195, 953–963 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Keller, P. et al. Fat-specific protein 27 regulates storage of triacylglycerol. J. Biol. Chem. 283, 14355–14365 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kim, J. Y. et al. Assessment of fat-specific protein 27 in the adipocyte lineage suggests a dual role for FSP27 in adipocyte metabolism and cell death. Am. J. Physiol. Endocrinol. Metab. 294, E654–E667 (2008).

    CAS  PubMed  Google Scholar 

  28. 28.

    Puri, V. et al. Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. J. Biol. Chem. 282, 34213–34218 (2007).

    CAS  PubMed  Google Scholar 

  29. 29.

    Nishino, N. et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J. Clin. Invest. 118, 2808–2821 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Grahn, T. H. et al. Fat-specific protein 27 (FSP27) interacts with adipose triglyceride lipase (ATGL) to regulate lipolysis and insulin sensitivity in human adipocytes. J. Biol. Chem. 289, 12029–12039 (2014).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Singh, M. et al. Fat-specific protein 27 inhibits lipolysis by facilitating the inhibitory effect of transcription factor Egr1 on transcription of adipose triglyceride lipase. J. Biol. Chem. 289, 14481–14487 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Raben, M. S. Growth hormone. 1. Physiologic aspects. N. Engl. J. Med. 266, 31–35 (1962).

    CAS  PubMed  Google Scholar 

  33. 33.

    Raben, M. S. & Hollenberg, C. H. Effect of growth hormone on plasma fatty acids. J. Clin. Invest. 38, 484–488 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Glick, S. M., Roth, J., Yalow, R. S. & Berson, S. A. Immunoassay of human growth hormone in plasma. Nature 199, 784–787 (1963).

    CAS  PubMed  Google Scholar 

  35. 35.

    Giustina, A. & Veldhuis, J. D. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr. Rev. 19, 717–797 (1998).

    CAS  PubMed  Google Scholar 

  36. 36.

    Roth, J., Glick, S. M., Yalow, R. S. & Berson, S. A. Hypoglycemia: a potent stimulus to secretion of growth hormone. Science 140, 987–988 (1963).

    CAS  PubMed  Google Scholar 

  37. 37.

    Zierler, K. L. & Rabinowitz, D. Roles of insulin and growth hormone, based on studies of forearm metabolism in man. Medicine 42, 385–402 (1963).

    CAS  PubMed  Google Scholar 

  38. 38.

    Richelsen, B. et al. Growth hormone treatment of obese women for 5 wk: effect on body composition and adipose tissue LPL activity. Am. J. Physiol. 266, E211–E216 (1994).

    CAS  PubMed  Google Scholar 

  39. 39.

    Krag, M. B. et al. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am. J. Physiol. Endocrinol. Metab. 292, E920–E927 (2007).

    CAS  PubMed  Google Scholar 

  40. 40.

    Norrelund, H. et al. Effects of GH on urea, glucose and lipid metabolism, and insulin sensitivity during fasting in GH-deficient patients. Am. J. Physiol. Endocrinol. Metab. 285, E737–E743 (2003).

    CAS  PubMed  Google Scholar 

  41. 41.

    Jorgensen, J. O. et al. Marked effects of sustained low growth hormone (GH) levels on day-to-day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects. J. Clin. Endocrinol. Metab. 77, 1589–1596 (1993).

    CAS  PubMed  Google Scholar 

  42. 42.

    Jorgensen, J. O. et al. Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition. Clin. Endocrinol. 45, 681–688 (1996).

    CAS  Google Scholar 

  43. 43.

    Moller, N. et al. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J. Clin. Endocrinol. Metab. 74, 1012–1019 (1992).

    CAS  PubMed  Google Scholar 

  44. 44.

    Bredella, M. A. et al. Body composition and ectopic lipid changes with biochemical control of acromegaly. J. Clin. Endocrinol. Metab. 102, 4218–4225 (2017).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Krusenstjerna-Hafstrom, T. et al. Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. J. Clin. Endocrinol. Metab. 96, 2548–2557 (2011).

    CAS  PubMed  Google Scholar 

  46. 46.

    Shulman, G. I. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology 19, 183–190 (2004).

    CAS  PubMed  Google Scholar 

  47. 47.

    Nielsen, C. et al. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J. Clin. Endocrinol. Metab. 93, 2842–2850 (2008).

    CAS  PubMed  Google Scholar 

  48. 48.

    Jessen, N. et al. Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. Am. J. Physiol. Endocrinol. Metab. 288, E194–E199 (2005).

    CAS  PubMed  Google Scholar 

  49. 49.

    del Rincon, J. P. et al. Growth hormone regulation of p85α expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes 56, 1638–1646 (2007).

    PubMed  Google Scholar 

  50. 50.

    Dominici, F. P. et al. Influence of the crosstalk between growth hormone and insulin signalling on the modulation of insulin sensitivity. Growth Horm. IGF Res. 15, 324–336 (2005).

    CAS  PubMed  Google Scholar 

  51. 51.

    Nellemann, B. et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol. 210, 392–402 (2014).

    CAS  Google Scholar 

  52. 52.

    Mekala, K. C. & Tritos, N. A. Effects of recombinant human growth hormone therapy in obesity in adults: a meta analysis. J. Clin. Endocrinol. Metab. 94, 130–137 (2009).

    CAS  PubMed  Google Scholar 

  53. 53.

    Thankamony, A. et al. Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes. J. Clin. Endocrinol. Metab. 99, 639–647 (2014).

    CAS  PubMed  Google Scholar 

  54. 54.

    Sharma, R. et al. Growth hormone controls lipolysis by regulation of FSP27 expression. J. Endocrinol. 239, 289–301 (2018). In both mice and cell culture models, GH regulates lipolysis and insulin sensitivity employing ERK-dependent and STAT5-dependent mechanisms to control PPARγ-mediated transcription of FSP27.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Sharma, V. M. et al. Growth hormone acts along the PPARγ-FSP27 axis to stimulate lipolysis in human adipocytes. Am. J. Physiol. Endocrinol. Metab. 316, E34–E42 (2019). In human adipocytes, GH regulates lipolysis through ERK-dependent phosphorylation of PPARγ and transcriptional regulation of FSP27.

    CAS  PubMed  Google Scholar 

  56. 56.

    Troike, K. M. et al. Impact of growth hormone on regulation of adipose tissue. Compr. Physiol. 7, 819–840 (2017).

    PubMed  Google Scholar 

  57. 57.

    Brooks, A. J. & Waters, M. J. The growth hormone receptor: mechanism of activation and clinical implications. Nat. Rev. Endocrinol. 6, 515–525 (2010). This excellent article provides a thorough understanding of the GH–GHR interaction as a function of downstream intracellular signalling.

    CAS  PubMed  Google Scholar 

  58. 58.

    Rowlinson, S. W. et al. An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. Nat. Cell Biol. 10, 740–747 (2008). The GH–GHR interaction can activate both STAT5 and ERK dependent intracellular signalling pathways. In light of findings that GH-lipolysis and insulin resistance are primarily dependent on ERK-dependent signaling, specific and yet to be discovered ERK-dependent GH analogues might have strong therapeutic and clinical significance.

    CAS  PubMed  Google Scholar 

  59. 59.

    Waters, M. J. The growth hormone receptor. Growth. Horm. IGF Res. 28, 6–10 (2016).

    CAS  PubMed  Google Scholar 

  60. 60.

    Lanning, N. J. & Carter-Su, C. Recent advances in growth hormone signaling. Rev. Endocr. Metab. Disord. 7, 225–235 (2006).

    CAS  PubMed  Google Scholar 

  61. 61.

    Herrington, J., Smit, L. S., Schwartz, J. & Carter-Su, C. The role of STAT proteins in growth hormone signaling. Oncogene 19, 2585–2597 (2000).

    CAS  PubMed  Google Scholar 

  62. 62.

    Wang, X., Darus, C. J., Xu, B. C. & Kopchick, J. J. Identification of growth hormone receptor (GHR) tyrosine residues required for GHR phosphorylation and JAK2 and STAT5 activation. Mol. Endocrinol. 10, 1249–1260 (1996).

    CAS  PubMed  Google Scholar 

  63. 63.

    Xu, B. C., Wang, X., Darus, C. J. & Kopchick, J. J. Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J. Biol. Chem. 271, 19768–19773 (1996).

    CAS  PubMed  Google Scholar 

  64. 64.

    Hansen, L. H. et al. Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation. J. Biol. Chem. 271, 12669–12673 (1996).

    CAS  PubMed  Google Scholar 

  65. 65.

    Ram, P. A., Park, S. H., Choi, H. K. & Waxman, D. J. Growth hormone activation of Stat 1, Stat 3, and Stat 5 in rat liver. Differential kinetics of hormone desensitization and growth hormone stimulation of both tyrosine phosphorylation and serine/threonine phosphorylation. J. Biol. Chem. 271, 5929–5940 (1996).

    CAS  PubMed  Google Scholar 

  66. 66.

    Smit, L. S. et al. The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. Mol. Endocrinol. 10, 519–533 (1996).

    CAS  PubMed  Google Scholar 

  67. 67.

    Moriggl, R. et al. Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol. Cell. Biol. 16, 5691–5700 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Davey, H. W., Park, S. H., Grattan, D. R., McLachlan, M. J. & Waxman, D. J. STAT5b-deficient mice are growth hormone pulse-resistant. Role of STAT5b in sex-specific liver p450 expression. J. Biol. Chem. 274, 35331–35336 (1999).

    CAS  PubMed  Google Scholar 

  69. 69.

    Davey, H. W. et al. STAT5b is required for GH-induced liver IGF-I gene expression. Endocrinology 142, 3836–3841 (2001).

    CAS  PubMed  Google Scholar 

  70. 70.

    Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003).

    CAS  PubMed  Google Scholar 

  71. 71.

    Scalco, R. C. et al. Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect. Genet. Mol. Biol. 40, 436–441 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Zhu, T., Ling, L. & Lobie, P. E. Identification of a JAK2-independent pathway regulating growth hormone (GH)-stimulated p44/42 mitogen-activated protein kinase activity. GH activation of Ral and phospholipase D is Src-dependent. J. Biol. Chem. 277, 45592–45603 (2002).

    CAS  PubMed  Google Scholar 

  73. 73.

    Ueki, K. et al. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol. Cell. Biol. 22, 965–977 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Jorgensen, J. O. et al. GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. Am. J. Physiol. Endocrinol. Metab. 291, E899–E905 (2006).

    PubMed  Google Scholar 

  75. 75.

    Krusenstjerna-Hafstrom, T. et al. Insulin and GH signaling in human skeletal muscle in vivo following exogenous GH exposure: impact of an oral glucose load. PLOS ONE 6, e19392 (2011).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Green, H., Morikawa, M. & Nixon, T. A dual effector theory of growth-hormone action. Differentiation 29, 195–198 (1985).

    CAS  PubMed  Google Scholar 

  77. 77.

    Doi, T. et al. Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I. I. Relationship between increased glomerular size and mesangial sclerosis. Am. J. Pathol. 137, 541–552 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Lupu, F., Terwilliger, J. D., Lee, K., Segre, G. V. & Efstratiadis, A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev. Biol. 229, 141–162 (2001). These studies systematically address the specific contribution of IGF1 versus GH on linear growth.

    CAS  PubMed  Google Scholar 

  79. 79.

    Dietz, J. & Schwartz, J. Growth hormone alters lipolysis and hormone-sensitive lipase activity in 3T3-F442A adipocytes. Metabolism 40, 800–806 (1991).

    CAS  PubMed  Google Scholar 

  80. 80.

    Richelsen, B. et al. Regulation of lipoprotein lipase and hormone-sensitive lipase activity and gene expression in adipose and muscle tissue by growth hormone treatment during weight loss in obese patients. Metabolism 49, 906–911 (2000).

    CAS  PubMed  Google Scholar 

  81. 81.

    Doris, R., Vernon, R. G., Houslay, M. D. & Kilgour, E. Growth hormone decreases the response to anti-lipolytic agonists and decreases the levels of Gi2 in rat adipocytes. Biochem. J. 297, 41–45 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Yip, R. G. & Goodman, H. M. Growth hormone and dexamethasone stimulate lipolysis and activate adenylyl cyclase in rat adipocytes by selectively shifting Gi alpha2 to lower density membrane fractions. Endocrinology 140, 1219–1227 (1999).

    CAS  PubMed  Google Scholar 

  83. 83.

    Ottosson, M. et al. Growth hormone inhibits lipoprotein lipase activity in human adipose tissue. J. Clin. Endocrinol. Metab. 80, 936–941 (1995).

    CAS  PubMed  Google Scholar 

  84. 84.

    Zhao, J. T. et al. Identification of novel GH-regulated pathway of lipid metabolism in adipose tissue: a gene expression study in hypopituitary men. J. Clin. Endocrinol. Metab. 96, E1188–E1196 (2011).

    PubMed  Google Scholar 

  85. 85.

    Puri, V. et al. Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc. Natl Acad. Sci. USA 105, 7833–7838 (2008).

    CAS  PubMed  Google Scholar 

  86. 86.

    Nielsen, T. S. et al. Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue. J. Clin. Endocrinol. Metab. 96, E1293–E1297 (2011).

    CAS  PubMed  Google Scholar 

  87. 87.

    Pedersen, M. H. et al. Substrate metabolism and insulin sensitivity during fasting in obese human subjects: impact of GH blockade. J. Clin. Endocrinol. Metab. 102, 1340–1349 (2017).

    PubMed  Google Scholar 

  88. 88.

    Kaltenecker, D. et al. Adipocyte STAT5 deficiency promotes adiposity and impairs lipid mobilisation in mice. Diabetologia 60, 296–305 (2017).

    CAS  PubMed  Google Scholar 

  89. 89.

    Nordstrom, S. M., Tran, J. L., Sos, B. C., Wagner, K. U. & Weiss, E. J. Disruption of JAK2 in adipocytes impairs lipolysis and improves fatty liver in mice with elevated GH. Mol. Endocrinol. 27, 1333–1342 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Shi, S. Y. et al. Adipocyte-specific deficiency of Janus kinase (JAK) 2 in mice impairs lipolysis and increases body weight, and leads to insulin resistance with ageing. Diabetologia 57, 1016–1026 (2014).

    CAS  PubMed  Google Scholar 

  91. 91.

    Slayton, M., Gupta, A., Balakrishnan, B. & Puri, V. CIDE proteins in human health and disease. Cells 8, 238 (2019).

    Google Scholar 

  92. 92.

    Rubio-Cabezas, O. et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol. Med. 1, 280–287 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Tanaka, N. et al. Adipocyte-specific disruption of fat-specific protein 27 causes hepatosteatosis and insulin resistance in high-fat diet-fed mice. J. Biol. Chem. 290, 3092–3105 (2015).

    CAS  PubMed  Google Scholar 

  94. 94.

    Zandbergen, F. et al. The G0/G1 switch gene 2 is a novel PPAR target gene. Biochem. J. 392, 313–324 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Burgermeister, E. et al. Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor γ. Mol. Cell. Biol. 27, 803–817 (2007).

    CAS  PubMed  Google Scholar 

  96. 96.

    Banks, A. S. et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature 517, 391–395 (2015).

    CAS  PubMed  Google Scholar 

  97. 97.

    Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Li, P. et al. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 147, 815–826 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    List, E. O. et al. The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice. Mol. Endocrinol. 27, 524–535 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    List, E. O. et al. Adipocyte-specific GH receptor-null (AdGHRKO) mice have enhanced insulin sensitivity with reduced liver triglycerides. Endocrinology 160, 68–80 (2019).

    PubMed  Google Scholar 

  101. 101.

    List, E. O. et al. Liver-specific GH receptor gene-disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles. Endocrinology 155, 1793–1805 (2014).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Berryman, D. E. et al. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm. IGF. Res. 14, 309–318 (2004).

    CAS  PubMed  Google Scholar 

  103. 103.

    Palmer, A. J. et al. Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology 150, 1353–1360 (2009).

    CAS  PubMed  Google Scholar 

  104. 104.

    Bartke, A. Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel findings. Aging Cell 7, 285–290 (2008).

    CAS  PubMed  Google Scholar 

  105. 105.

    Berryman, D. E. et al. Two-year body composition analyses of long-lived GHR null mice. J. Gerontol. A. Biol. Sci. Med. Sci. 65, 31–40 (2010).

    PubMed  Google Scholar 

  106. 106.

    Heiman, M. L., Tinsley, F. C., Mattison, J. A., Hauck, S. & Bartke, A. Body composition of prolactin-, growth hormone, and thyrotropin-deficient Ames dwarf mice. Endocrine 20, 149–154 (2003).

    CAS  PubMed  Google Scholar 

  107. 107.

    Junnila, R. K. et al. Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology 157, 4502–4513 (2016).

    CAS  PubMed  Google Scholar 

  108. 108.

    Luque, R. M. et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLOS ONE 6, e15767 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Hill, C. M. et al. Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure. Aging Cell 15, 509–521 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Berryman, D. E., Lubbers, E. R., Magon, V., List, E. O. & Kopchick, J. J. A dwarf mouse model with decreased GH/IGF-1 activity that does not experience life-span extension: potential impact of increased adiposity, leptin, and insulin with advancing age. J. Gerontol. A Biol. Sci. Med. Sci. 69, 131–141 (2014).

    CAS  PubMed  Google Scholar 

  111. 111.

    Berryman, D. E. et al. Effect of growth hormone on susceptibility to diet-induced obesity. Endocrinology 147, 2801–2808 (2006).

    CAS  PubMed  Google Scholar 

  112. 112.

    Olsson, B. et al. Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet. Endocrinology 146, 920–930 (2005).

    CAS  PubMed  Google Scholar 

  113. 113.

    Robertson, K., Kopchick, J. J. & Liu, J. L. Growth hormone receptor gene deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice. Am. J. Physiol. Endocrinol. Metab. 291, E491–E498 (2006).

    CAS  PubMed  Google Scholar 

  114. 114.

    Yang, T. et al. Growth hormone receptor antagonist transgenic mice are protected from hyperinsulinemia and glucose intolerance despite obesity when placed on a HF diet. Endocrinology 156, 555–564 (2015).

    PubMed  Google Scholar 

  115. 115.

    Silha, J. V. et al. Perturbations in adiponectin, leptin and resistin levels in acromegaly: lack of correlation with insulin resistance. Clin. Endocrinol. 58, 736–742 (2003).

    CAS  Google Scholar 

  116. 116.

    Ueland, T. et al. Associations between body composition, circulating interleukin-1 receptor antagonist, osteocalcin, and insulin metabolism in active acromegaly. J. Clin. Endocrinol. Metab. 95, 361–368 (2010).

    CAS  PubMed  Google Scholar 

  117. 117.

    Fain, J. N., Ihle, J. H. & Bahouth, S. W. Stimulation of lipolysis but not of leptin release by growth hormone is abolished in adipose tissue from Stat5a and b knockout mice. Biochem. Biophys. Res. Commun. 263, 201–205 (1999).

    CAS  PubMed  Google Scholar 

  118. 118.

    Kanety, H. et al. Total and high molecular weight adiponectin are elevated in patients with Laron syndrome despite marked obesity. Eur. J. Endocrinol. 161, 837–844 (2009).

    CAS  PubMed  Google Scholar 

  119. 119.

    Nilsson, L. et al. Prolactin and growth hormone regulate adiponectin secretion and receptor expression in adipose tissue. Biochem. Biophys. Res. Commun. 331, 1120–1126 (2005).

    CAS  PubMed  Google Scholar 

  120. 120.

    White, U. A., Maier, J., Zhao, P., Richard, A. J. & Stephens, J. M. The modulation of adiponectin by STAT5-activating hormones. Am. J. Physiol. Endocrinol. Metab. 310, E129–E136 (2016).

    PubMed  Google Scholar 

  121. 121.

    Eden Engstrom, B., Burman, P., Holdstock, C. & Karlsson, F. A. Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients. J. Clin. Endocrinol. Metab. 88, 5193–5198 (2003).

    PubMed  Google Scholar 

  122. 122.

    Reyes-Vidal, C. et al. Prospective study of surgical treatment of acromegaly: effects on ghrelin, weight, adiposity, and markers of CV risk. J. Clin. Endocrinol. Metab. 99, 4124–4132 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Ray, H., Pinteur, C., Frering, V., Beylot, M. & Large, V. Depot-specific differences in perilipin and hormone-sensitive lipase expression in lean and obese. Lipids Health Dis. 8, 58 (2009).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Freda, P. U. et al. Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly. J. Clin. Endocrinol. Metab. 93, 2334–2343 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Bengtsson, B. A. et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J. Clin. Endocrinol. Metab. 76, 309–317 (1993).

    CAS  PubMed  Google Scholar 

  126. 126.

    Johannsson, G. et al. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J. Clin. Endocrinol. Metab. 82, 727–734 (1997).

    CAS  PubMed  Google Scholar 

  127. 127.

    Benencia, F. et al. Male bovine GH transgenic mice have decreased adiposity with an adipose depot-specific increase in immune cell populations. Endocrinology 156, 1794–1803 (2015).

    CAS  PubMed  Google Scholar 

  128. 128.

    Stout, M. B. et al. Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. Oncotarget 6, 26702–26715 (2015).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Berryman, D. E. & List, E. O. Growth hormone’s effect on adipose tissue: quality versus quantity. Int. J. Mol. Sci. 18, 1621 (2017).

    PubMed Central  Google Scholar 

  130. 130.

    Flint, D. J., Binart, N., Kopchick, J. & Kelly, P. Effects of growth hormone and prolactin on adipose tissue development and function. Pituitary 6, 97–102 (2003).

    CAS  PubMed  Google Scholar 

  131. 131.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Gude, M. F. et al. PAPP-A, IGFBP-4 and IGF-II are secreted by human adipose tissue cultures in a depot-specific manner. Eur. J. Endocrinol. 175, 509–519 (2016).

    CAS  PubMed  Google Scholar 

  133. 133.

    Hjortebjerg, R. et al. Depot-specific and GH-dependent regulation of IGF binding protein-4, pregnancy-associated plasma protein-A, and stanniocalcin-2 in murine adipose tissue. Growth Horm. IGF Res. 39, 54–61 (2018).

    CAS  PubMed  Google Scholar 

  134. 134.

    Boucher, J. et al. Differential roles of insulin and IGF-1 receptors in adipose tissue development and function. Diabetes 65, 2201–2213 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer 9, 81–94 (2009).

    CAS  PubMed  Google Scholar 

  137. 137.

    McHugh, D. & Gil, J. Senescence and aging: causes, consequences, and therapeutic avenues. J. Cell Biol. 217, 65–77 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Xu, L. et al. Improves the in vitro developmental competence and reprogramming efficiency of cloned bovine embryos by additional complimentary cytoplasm. Cell. Reprogram. 21, 51–60 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Villaret, A. et al. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes 59, 2755–2763 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    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).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Stout, M. B., Justice, J. N., Nicklas, B. J. & Kirkland, J. L. Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology 32, 9–19 (2017).

    CAS  PubMed  Google Scholar 

  142. 142.

    Stout, M. B. et al. Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging 6, 575–586 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Comisford, R. et al. Growth hormone receptor antagonist transgenic mice have increased subcutaneous adipose tissue mass, altered glucose homeostasis and no change in white adipose tissue cellular senescence. Gerontology 62, 163–172 (2016).

    CAS  PubMed  Google Scholar 

  144. 144.

    Bogazzi, F. et al. Growth hormone is necessary for the p53-mediated, obesity-induced insulin resistance in male C57BL/6J x CBA mice. Endocrinology 154, 4226–4236 (2013).

    CAS  PubMed  Google Scholar 

  145. 145.

    Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Palmer, A. K. et al. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64, 2289–2298 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

    CAS  PubMed  Google Scholar 

  148. 148.

    Pasarica, M. et al. Adipose tissue collagen VI in obesity. J. Clin. Endocrinol. Metab. 94, 5155–5162 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Householder, L. A. et al. Increased fibrosis: a novel means by which GH influences white adipose tissue function. Growth Horm. IGF Res. 39, 45–53 (2018).

    CAS  PubMed  Google Scholar 

  150. 150.

    Hagberg, C. E. et al. Flow cytometry of mouse and human adipocytes for the analysis of browning and cellular heterogeneity. Cell Rep. 24, 2746–2756.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Gao, H. et al. CD36 is a marker of human adipocyte progenitors with pronounced adipogenic and triglyceride accumulation potential. Stem Cells 35, 1799–1814 (2017).

    CAS  PubMed  Google Scholar 

  152. 152.

    Varlamov, O., Chu, M., Cornea, A., Sampath, H. & Roberts, C. T. Jr. Cell-autonomous heterogeneity of nutrient uptake in white adipose tissue of rhesus macaques. Endocrinology 156, 80–89 (2015).

    PubMed  Google Scholar 

  153. 153.

    Seydoux, J. et al. Adrenoceptor heterogeneity in human white adipocytes differentiated in culture as assessed by cytosolic free calcium measurements. Cell. Signal. 8, 117–122 (1996).

    CAS  PubMed  Google Scholar 

  154. 154.

    Gliemann, J. & Vinten, J. Lipogenesis and insulin sensitivity of single fat cells. J. Physiol. 236, 499–516 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Salans, L. B. & Dougherty, J. W. The effect of insulin upon glucose metabolism by adipose cells of different size. Influence of cell lipid and protein content, age, and nutritional state. J. Clin. Invest. 50, 1399–1410 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Sanchez-Gurmaches, J. & Guertin, D. A. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat. Commun. 5, 4099 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Chau, Y. Y. et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat. Cell Biol. 16, 367–375 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Bluher, M., Patti, M. E., Gesta, S., Kahn, B. B. & Kahn, C. R. Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. J. Biol. Chem. 279, 31891–31901 (2004).

    PubMed  Google Scholar 

  159. 159.

    Xia, B. et al. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice. PLOS Genet. 13, e1007110 (2017).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Lee, K. Y. et al. Developmental and functional heterogeneity of white adipocytes within a single fat depot. EMBO J. 38, e99291 (2019).

    PubMed  Google Scholar 

  161. 161.

    Min, S. Y. et al. Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells. Proc. Natl Acad. Sci. USA 116, 17970–1797 (2019).

    CAS  PubMed  Google Scholar 

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J.J.K. acknowledges the support of the state of Ohio’s Eminent Scholar Program, which includes a gift from Milton and Lawrence Goll and AMVETS. J.J.K. and D.E.B. acknowledge the support of NIH/NIA AG059779, The Edison Biotechnology Institute and Diabetes Institute at Ohio University. V.P. acknowledges the support of NIH/NIDDK grant DK10171, NIH/NHLBI HL139049 and funds from Osteopathic Heritage Foundation’s Vision 2020 to Heritage College of Osteopathic Medicine at Ohio University. K.Y.L. acknowledges the support of start-up funds from Ohio University Heritage College of Osteopathic Medicine, the Ohio University Diabetes Institute and the American Diabetes Association Junior Faculty Development Award 1–17-JDF-055.

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J.J.K., V.P., D.E.B., K.Y.L. and J.O.L.J. wrote the manuscript. J.J.K., V.P., D.E.B., K.Y.L. and J.O.L.J. surveyed the literature, substantially contributed to related discussions and carried out review and editing of the manuscript before submission.

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Correspondence to John J. Kopchick.

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

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GH deficiency

(GHD). A rare disorder characterized by the inadequate secretion of growth hormone (GH); GHD can be categorized into congenital or acquired, and/or childhood or adult onset.


Also known as hypopituitarism. Inadequate production or absence of anterior pituitary hormones.


A condition caused by hypersecretion of growth hormone from a pituitary tumour that is managed by surgical tumour removal or medical control.


A degenerative process that involves scarring within the renal glomeruli of the kidney.

Laron syndrome

A rare condition of growth hormone resistance characterized by short stature, which is often caused by mutations in the GHR gene and is inherited in an autosomal recessive manner.

Senolytic agents

Small molecules that can selectively target and kill senescent cells.

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Kopchick, J.J., Berryman, D.E., Puri, V. et al. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol 16, 135–146 (2020).

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