Free fatty acids inhibit growth hormone/signal transducer and activator of transcription-5 signaling in human muscle: a potential feedback mechanism.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Møller
Niels
N
Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, University of Aarhus, Aarhus C 8000, Denmark.
Gormsen
Lars C
LC
Schmitz
Ole
O
Lund
Sten
S
Jørgensen
Jens Otto L
JO
Jessen
Niels
N
D000328:Adult; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000502:physiology*; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D006801:Humans; D007260:Infusion Pumps; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016037:Single-Blind Method; D055815:Young Adult
D005230:Fatty Acids, Nonesterified; D050799:STAT5 Transcription Factor; D019382:Human Growth Hormone; D011494:Protein Kinases