The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals.

Katrine L Høyer,Kevin Y Lee,Nils Erik Magnusson,John J Kopchick,Niels Jessen,Edward O List,Emily Kissinger,Vishwajeet Puri,Rita Sharma,Jens O L Jørgensen,Morten L Høgild

doi:10.14814/phy2.14373

Katrine L Høyer, Kevin Y Lee + Show 9 more

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https://doi.org/10.14814/phy2.14373

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Abstract

AimSince GH stimulates lipolysis in vivo after a 2‐hr lag phase, we studied whether this involves GH signaling and gene expression in adipose tissue (AT).MethodsHuman subjects (n = 9) each underwent intravenous exposure to GH versus saline with measurement of serum FFA, and GH signaling, gene array, and protein in AT biopsies after 30–120 min. Human data were corroborated in adipose‐specific GH receptor knockout (FaGHRKO) mice versus wild‐type mice. Expression of candidate genes identified in the array were investigated in 3T3‐L1 adipocytes.ResultsGH increased serum FFA and AT phosphorylation of STAT5b in human subjects. This was replicated in wild‐type mice, but not in FaGHRKO mice. The array identified 53 GH‐regulated genes, and Ingenuity Pathway analysis showed downregulation of PDE3b, an insulin‐dependent antilipolytic signal, upregulation of PTEN that inhibits insulin‐dependent antilipolysis, and downregulation of G0S2 and RASD1, both encoding antilipolytic proteins. This was confirmed in 3T3‐L1 adipocytes, except for PDE3B, including reciprocal effects of GH and insulin on mRNA expression of PTEN, RASD1, and G0S2. Conclusion (a) GH directly stimulates AT lipolysis in a GHR‐dependent manner, (b) this involves suppression of antilipolytic signals at the level of gene expression, (c) the underlying GH signaling pathways remain to be defined.

Highlights

Triglycerides (TAG) in adipose tissue, which constitute the major energy depot in the body (Large, Peroni, Letexier, Ray, & Beylot, 2004) are hydrolyzed to free fatty acids (FFA) and glycerol during catabolic conditions by a hormonally regulated process called lipolysis (Nielsen, Jessen, Jorgensen, Moller, & Lund, 2014; Wolfe et al, 1987)
The present study demonstrates that acute stimulation of lipolysis and GHR signaling in human adipose tissue (AT) are detectable in vivo after an intravenous bolus of GH
This was documented by a significant increase in circulating FFA levels concomitantly with AT STAT5b phosphorylation, which is the upstream part of the major GH signaling pathway

Summary

Introduction

Triglycerides (TAG) in adipose tissue, which constitute the major energy depot in the body (Large, Peroni, Letexier, Ray, & Beylot, 2004) are hydrolyzed to free fatty acids (FFA) and glycerol during catabolic conditions by a hormonally regulated process called lipolysis (Nielsen, Jessen, Jorgensen, Moller, & Lund, 2014; Wolfe et al, 1987). GH is a recognized regulator of lipolysis (Moller & Jorgensen, 2009; Raben, 1962), and we have shown that an intravenous GH bolus induces a several fold increase in circulating FFA levels peaking after 2–3 hr ( Moller, Jorgensen, Schmitz, et al, 1990) followed by a gradual decline toward baseline after 8 hr (Gravholt et al, 1999) This is accompanied by and causally linked to suppression of insulin-stimulated glucose uptake in skeletal muscle,(Moller, Jorgensen, Alberti, Flyvbjerg, & Schmitz, 1990), which is noteworthy since insulin is a main inhibitor of lipolysis (Jensen & Nielsen, 2007). The regulation of known GH-dependent genes was detected concomitant with an acute increase in circulating FFA levels, but genes associated with lipid mobilization in skeletal muscle were not changed This suggests that the lipolytic effect of GH is due to its direct effects on adipose tissue

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