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

Abstract

Whether GH promotes IGF-I production or lipolysis depends on nutritional status, but the underlying mechanisms remain unknown. To investigate the impact of fasting on GH-mediated changes in substrate metabolism, insulin sensitivity, and signaling pathways. We conducted a randomized crossover study. Ten healthy men (age 24.3 +/- 0.6 yr, body mass index 23.1 +/- 0.4 kg/m(2)) participated. 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. 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. 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). 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.