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

Vishva M. Sharma, Esben Thyssen Vestergaard, Niels Jessen, Peter Kolind-Thomsen, Birgitte Nellemann, Thomas S. Nielsen, Mikkel Holm Vendelbo, Niels Møller, Rita Sharma, Kevin Y. Lee, John J. Kopchick, Jens Otto Lunde Jørgensen, Vishwajeet Puri

American Journal of Physiology-Endocrinology and Metabolism1/1/2019·DOI·Read paper

Abstract

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 Ser273and causes its translocation from nucleus to the cytosol. Surprisingly, FSP27 overexpression inhibited PPARγ Ser273phosphorylation 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.

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