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Growth hormone acts along the PPAR?-FSP27 axis to stimulate lipolysis in human adipocytes.

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-? (PPAR?) via MEK/ERK activation. Ultimately, GH treatment promotes phosphorylation of PPAR? at Ser273 and causes its translocation from nucleus to the cytosol. Surprisingly, FSP27 overexpression inhibited PPAR? 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 PPAR?-FSP27 in human adipose tissue.

SUBMITTER: Sharma VM

PROVIDER: S-EPMC6417689 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Sharma Vishva M VM Vestergaard Esben Thyssen ET Jessen Niels N Kolind-Thomsen Peter P Nellemann Birgitte B Nielsen Thomas S TS Vendelbo Mikkel Holm MH Møller Niels N Sharma Rita R Lee Kevin Y KY Kopchick John J JJ Jørgensen Jens Otto Lunde JOL Puri Vishwajeet V

American journal of physiology. Endocrinology and metabolism 20181016 1

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 sign ...[more]

PMID: 30325658

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Project description:Nicotinamide adenine dinucleotide (NAD+) -dependent protein deacetylase SIRT1 plays an important role in the regulation of metabolism. Although the administration of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to ameliorate metabolic disorders, such as insulin resistance and glucose intolerance, the direct effect of NMN on the regulation of lipid metabolism in adipocytes remains unclear. We here investigated the effect of NMN on lipid storage in 3T3-L1 differentiated adipocytes. Oil-red O staining showed that NMN treatment reduced lipid accumulation in these cells. NMN was found to enhance lipolysis in adipocytes since the concentration of glycerol in the media was increased by NMN treatment. Western blotting and real-time RT-PCR analysis revealed that adipose triglyceride lipase (ATGL) expression at both protein and mRNA level was increased with NMN treatment in 3T3-L1 adipocytes. Whereas NMN increased SIRT1 expression and AMPK activation, an AMPK inhibitor compound C restored the NMN-dependent upregulation of ATGL expression in these cells, suggesting that NMN upregulates ATGL expression through the SIRT1-AMPK axis. NMN administration significantly decreased subcutaneous fat mass in mice on a high-fat diet. We also found that adipocyte size in subcutaneous fat was decreased with NMN treatment. Consistent with the alteration of fat mass and adipocyte size, the ATGL expression in subcutaneous fat was slightly, albeit significantly, increased with NMN treatment. These results indicate that NMN suppresses subcutaneous fat mass in diet-induced obese mice, potentially in part via the upregulation of ATGL. Unexpectedly, the reduction in fat mass as well as ATGL upregulation with NMN treatment were not observed in epididymal fat, implying that the effects of NMN are site-specific in adipose tissue. Thus, these findings provide important insights into the mechanism of NMN/NAD+ in the regulation of metabolism. Highlights • NMN induces lipolysis by increasing ATGL expression in 3T3-L1 adipocytes.• NMN enhances ATGL expression through SIRT1/AMPK axis in 3T3-L1 adipocytes.• NMN ameliorates diet-induced obesity in mice by suppressing adipocyte hypertrophy.

Dataset Information

Growth hormone acts along the PPAR?-FSP27 axis to stimulate lipolysis in human adipocytes.

Publications

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

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