Identification of novel GH-regulated pathway of lipid metabolism in adipose tissue : a gene expression study in hypopituitary men

Context: Adipose tissue is a major target of GH action. GH stimulates lipolysis and reduces fat mass. The molecular mechanism underlying cellular and metabolic effects of GH in adipose tissue is not well understood. Objective: The aim of this study is to identify GH-responsive genes that regulate lipid metabolism in adipose tissue. Design: Eight men with GH deficiency underwent measurement of plasma free fatty acid (FFA), whole-body lipid oxidation, and fat biopsies before and after 1 month of GH treatment (0.5 mg/d). Gene expression profiling was performed using Agilent 44K G4112F arrays using a two-color design. Differentially expressed genes were identified using an empirical Bayes, moderated t test, with a false discovery rate under 5%. Target genes were validated by quantitative RT-PCR. Results: GH increased circulating IGF-I and FFA and stimulated fat oxidation. A total of 246 genes were differentially expressed, of which 135 were up-regulated and 111 down-regulated. GH enhanced adipose tissue expression of IGF-I and SOCS3. GH increased expression of patatin-like phospholipase domain containing 3 (PNPLA3), a novel triglyceride (TG) hydrolase, but not hormone- sensitive lipase (HSL), a classical TG hydrolase. GH repressed cell death-inducing DFFA-like effector A (CIDEA), a novel lipid droplets-associated protein, promoting TG storage. GH differentially regulated genes promoting diacylglycerol synthesis. GH suppressed hydroxysteroid (11_) dehydrogenase 1, which activates local cortisol production and genes encoding components of extracellular matrix and TGF-_ signaling pathway. Conclusion: GH stimulates the TG/FFA cycle by regulating the expression of novel genes that enhance TG hydrolysis, reduce TG storage, and promote diacylglycerol synthesis. GH represses adipocyte growth, differentiation and inflammation.