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Impact of Fasting on Growth Hormone Signaling and Action in Muscle and Fat

Medical Department M (Endocrinology and Diabetes) (L.M., L.D., J.F., N.M., J.O.L.J.), Aarhus University Hospital, Aarhus Sygehus, DK-8000 Aarhus C, Denmark; Department of Internal Medicine (H.N.), Viborg Hospital, DK-8800 Viborg, Denmark; and Department for Translational Diabetology (N.B.), Steno Diabetes Center, DK-2820 Gentofte, Denmark

Address all correspondence and requests for reprints to: Louise Moller, Medical Department M, Aarhus Sygehus, Norrebrogade 44, DK-8000 Aarhus, Denmark. E-mail: louisem{at}dadlnet.dk.

Context: Whether GH promotes IGF-I production or lipolysis depends on nutritional status, but the underlying mechanisms remain unknown.

Objective: To investigate the impact of fasting on GH-mediated changes in substrate metabolism, insulin sensitivity, and signaling pathways.

Design: We conducted a randomized crossover study.

Subjects: Ten healthy men (age 24.3 ± 0.6 yr, body mass index 23.1 ± 0.4 kg/m²) participated.

Intervention: A GH bolus administered 1) postabsorptively and 2) in the fasting state (37.5 h). Skeletal muscle and adipose tissue biopsies were taken, and a hyperinsulinemic-euglycemic clamp was performed on both occasions.

Main Outcome Measures: Metabolic clearance rate (MCR) of GH, substrate metabolism, and insulin sensitivity were measured. Biopsies were subjected to Western blotting for expression of signaling proteins and to RT-PCR for expression of suppressor of cytokine signaling protein 3 and IGF-I mRNA.

Results: Fasting was associated with reduced MCR of GH (P < 0.01), enhanced lipolytic responsiveness to GH, decreased insulin sensitivity (P < 0.01), and reduced IGF-I bioactivity (P = 0.04). After the GH bolus, phosphorylation of signal transducers and activators of transcription protein 5b (pSTAT5b) were observed in both conditions; however, the phospho-STAT5b/STAT5b ratio was significantly decreased in the fasting state (muscle P = 0.02 and fat P = 0.02).

Conclusion: The combination of fasting and GH exposure translates into enhanced lipolysis, reduced IGF-I activity and insulin sensitivity, and blunted activation of the Janus kinase (JAK)/STAT pathway. Whether this change in signaling activity is related to the change in MCR of GH and/or the concomitant shift in the metabolic effects of GH merits future attention.