Growth hormone acts along the PPARγ-FSP27 axis to stimulate lipolysis in human adipocytes

• Published in: American journal of physiology: endocrinology and metabolism 2019-01, Vol.316 (1), p.E34-E42
• Main Authors: Sharma, Vishva M, Vestergaard, Esben Thyssen, Jessen, Niels, Kolind-Thomsen, Peter, Nellemann, Birgitte, Nielsen, Thomas S, Vendelbo, Mikkel Holm, Møller, Niels, Sharma, Rita, Lee, Kevin Y, Kopchick, John J, Jørgensen, Jens Otto Lunde, Puri, Vishwajeet
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipocytes, White - metabolism; Adipose tissue; Apoptosis Regulatory Proteins; Cytosol; Effects; Gene Expression Regulation; Growth hormones; Human Growth Hormone - metabolism; Humans; In Vitro Techniques; Insulin; Insulin resistance; Lipids; Lipolysis; Lipolysis - genetics; Male; MAP Kinase Signaling System; Metabolic pathways; Metabolism; Molecular modelling; Phosphorylation; Physiology; PPAR gamma - metabolism; Proteins; Proteins - genetics; Proteins - metabolism; Signaling; Substrates; Transcription; Translocation; Young Adult
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00129.2018

The lipolytic effects of growth hormone (GH) have been known for half a century and play an important physiological role for substrate metabolism during fasting. In addition, sustained GH-induced lipolysis is causally linked to insulin resistance. However, the underlying molecular mechanisms remain elusive. In the present study, we obtained experimental data in human subjects and used human adipose-derived stromal vascular cells (hADSCs) as a model system to elucidate GH-triggered molecular signaling that stimulates adipose tissue lipolysis and insulin resistance in human adipocytes. We discovered that GH downregulates the expression of fat-specific protein (FSP27), a negative regulator of lipolysis, by impairing the transcriptional ability of the master transcriptional regulator, peroxisome proliferator-activated receptor-γ (PPARγ) via MEK/ERK activation. Ultimately, GH treatment promotes phosphorylation of PPARγ at Ser and causes its translocation from nucleus to the cytosol. Surprisingly, FSP27 overexpression inhibited PPARγ Ser phosphorylation and promoted its nuclear retention. GH antagonist treatment had similar effects. Our study identifies a novel signaling mechanism by which GH transcriptionally induces lipolysis via the MEK/ERK pathway that acts along PPARγ-FSP27 in human adipose tissue.