Temporal patterns of lipolytic regulators in adipose tissue after acute growth hormone exposure in human subjects: A randomized controlled crossover trial

• Published in: Molecular metabolism (Germany) Vol. 29; pp. 65 - 75
• Main Authors: Hjelholt, Astrid Johannesson, Lee, Kevin Y., Arlien-Søborg, Mai Christiansen, Pedersen, Steen Bønløkke, Kopchick, John J., Puri, Vishwajeet, Jessen, Niels, Jørgensen, Jens Otto L.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.11.2019; Elsevier
• Subjects: Adipose Tissue - metabolism; Adipose Tissue - pathology; Adult; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biomarkers - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cross-Over Studies; Down-Regulation - drug effects; Fatty Acids, Nonesterified - blood; FSP27; G0S2; Growth hormone; Human Growth Hormone - administration & dosage; Human Growth Hormone - analogs & derivatives; Human Growth Hormone - pharmacology; Humans; Lipolysis; Male; Mice; Mice, Transgenic; Original; Placebo Effect; PPAR gamma - metabolism; PTEN; Signal Transduction; Young Adult; PTEN; G0S2; FSP27; Growth hormone; Lipolysis
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2019.08.013

Growth hormone (GH) stimulates lipolysis, but the underlying mechanisms remain incompletely understood. We examined the effect of GH on the expression of lipolytic regulators in adipose tissue (AT). In a randomized, placebo-controlled, cross-over study, nine men were examined after injection of 1) a GH bolus and 2) a GH-receptor antagonist (pegvisomant) followed by four AT biopsies. In a second study, eight men were examined in a 2 × 2 factorial design including GH infusion and 36-h fasting with AT biopsies obtained during a basal period and a hyperinsulinemic-euglycemic clamp. Expression of GH-signaling intermediates and lipolytic regulators were studied by PCR and western blotting. In addition, mechanistic experiments in mouse models and 3T3-L1 adipocytes were performed. The GH bolus increased circulating free fatty acids (p < 0.0001) together with phosphorylation of signal transducer and activator of transcription 5 (STAT5) (p < 0.0001) and mRNA expression of the STAT5-dependent genes cytokine-inducible SH2-containing protein (CISH) and IGF-1 in AT. This was accompanied by suppressed mRNA expression of G0/G1 switch gene 2 (G0S2) (p = 0.007) and fat specific protein 27 (FSP27) (p = 0.002) and upregulation of phosphatase and tensin homolog (PTEN) mRNA expression (p = 0.03). Suppression of G0S2 was also observed in humans after GH infusion and fasting, as well as in GH transgene mice, and in vitro studies suggested MEK-PPARγ signaling to be involved. GH-induced lipolysis in human subjects in vivo is linked to downregulation of G0S2 and FSP27 and upregulation of PTEN in AT. Mechanistically, in vitro data suggest that GH acts via MEK to suppress PPARγ-dependent transcription of G0S2. ClinicalTrials.govNCT02782221 and NCT01209429. •Acute GH exposure in human subjects in vivo stimulates lipolysis and release of FFA together with GH signaling in adipose tissue.•GH-induced lipolysis is associated with suppression of G0S2 and FSP27 and upregulation of PTEN in human subjects in vivo.•Inhibition of MEK and activation of PPARγ abrogate GH-induced suppression of G0S2 mRNA expression in vitro.