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Free Fatty Acids Inhibit Growth Hormone/Signal Transducer and Activator of Transcription-5 Signaling in Human Muscle: A Potential Feedback Mechanism

Medical Department M (Endocrinology and Diabetes) (N.M., L.C.G., S.L., J.O.L.J., N.J.), Aarhus University Hospital, and Department of Pharmacology (O.S.), University of Aarhus, 8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Niels Jessen, M.D., Ph.D., Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, 8000 Aarhus C, Denmark. E-mail: niels.jessen{at}ki.au.dk.

Context: Stimulation of lipolysis, leading to increased blood concentrations of free fatty acids (FFAs), is a primary effect of GH and phosphorylation of intracellular signal transducer and activator of transcription (STAT)-5 is a primary mediator of the effects of GH.

Objective: Based on preliminary results, we intended to test whether FFAs exert a negative feedback inhibition of STAT5 phosphorylation in skeletal muscle.

Design and Participants: Eight healthy young men were investigated for 8 h on four occasions at four different FFA levels in a single blind, randomized manner. Acipimox was used to suppress FFA levels and Intralipid was infused to obtain appropriate FFA concentrations. Somatostatin was infused to control GH levels and GH, insulin, and glucagon were replaced. Muscle biopsies were taken after 8 h and compared with a fifth biopsy taken under normal basal conditions.

Setting: The study was conducted at a university clinical research unit.

Results: GH concentrations remained steady and comparable in all studies and FFA concentrations varied between 0.01 and 1.71 mmol/liter on the four occasions (P < 0.05). We observed a dose-dependent 40% decrease of STAT5 phosphorylation in skeletal muscle with increasing concentrations of FFAs.

Conclusions: Our results strongly suggest the existence of a negative feedback loop, whereby effects of GH may be dampened by FFA inhibition of GH-dependent STAT5 phosphorylation. The mechanisms behind and biological consequences of this finding awaits additional studies.