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

Author:

Sharma Vishva M.12,Vestergaard Esben Thyssen34,Jessen Niels356,Kolind-Thomsen Peter356,Nellemann Birgitte3,Nielsen Thomas S.37,Vendelbo Mikkel Holm38,Møller Niels36,Sharma Rita12,Lee Kevin Y.12,Kopchick John J.129,Jørgensen Jens Otto Lunde36,Puri Vishwajeet12

Affiliation:

1. Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio

2. The Diabetes Institute, Ohio University, Athens, Ohio

3. Medical Research Laboratory, Aarhus University, Aarhus, Denmark

4. Department of Pediatrics, Randers Regional Hospital, Randers, Denmark

5. Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark

6. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

7. Faculty of Health and Medical Sciences, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

8. Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark

9. Edison Biotechnology Institute, Ohio University, Athens, Ohio

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 Ser273 and causes its translocation from nucleus to the cytosol. Surprisingly, FSP27 overexpression inhibited PPARγ Ser273 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.

Funder

NIH/NIDDK

Osteopathic Heritage Foundation's Vision 2020

State of Ohio Eminent Scholar Program

MERCK-CCI Award

The Lundbeck Foundation

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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