Impact of fasting on growth hormone signaling and action in muscle and fat.

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/m(2)) 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-ImRNA. 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. (J Clin Endocrinol Metab 94: 965-972, 2009)