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

Abstract

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.

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Acknowledgements

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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Glossary

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.

Panhypopituitarism

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

Acromegaly

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

Glomerulosclerosis

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). https://doi.org/10.1038/s41574-019-0280-9

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