GH signaling in human adipose and muscle tissue during ‘feast and famine’: amplification of exercise stimulation following fasting compared to glucose administration

Abstract

Objective: Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original 'feast and famine hypothesis' by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression. Design and methods: Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion ('feast') and ii) after a 36 h fast ('famine'). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise. Results: GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days. Conclusions: This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the 'feast and famine hypothesis'; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization.

Temporal patterns of lipolytic regulators in adipose tissue after acute growth hormone exposure in human subjects: A randomized controlled crossover trial

“…Consistent with previous human studies [6], [7], [8], [9], [10], [11], we recorded STAT5 phosphorylation in AT 60 min after the GH bolus together with upregulated gene expression of IGF-1 and CISH . JAK2-STAT5 signaling is considered the dominant GH signaling pathway [44], and studies in adipocyte-specific STAT5 and JAK2 knockout mice imply that the JAK2-STAT5 pathway also mediates GH-induced lipolysis [12], [45].…”

“…This temporal pattern suggests that the effect involves regulation of gene expression in AT. We have consistently demonstrated that systemic GH acutely activates the STAT5 signaling pathway, which is considered the canonical pathway whereby GH regulates transcription of target genes [5], in human AT in vivo [6], [7], [8], [9], [10], [11]. In support of this, studies in rodents indicate that STAT5 is involved in GH-induced lipolysis [12], [13], [14], [15], but there are also in vitro studies to suggest that GH stimulates lipolysis via activation of the MAPK pathway [16], [17].…”

“…A general shortcoming of previous human in vivo studies is that AT biopsies were obtained shortly after GH exposure, which may not appropriately capture changes in gene and protein expression [8], [11], [23], [25], [26], and several studies have included only a single AT biopsy after GH exposure [8], [10], [23], [25], [26]. Therefore, in the present study, we obtained multiple AT biopsies in nine obese but otherwise healthy, human subjects before and 60, 180, and 300 min following a single GH bolus to encompass the temporal effect of GH on the expression of lipolytic regulators.…”

Targeted sequencing analysis of PPARG identifies a risk variant associated with obstructive sleep apnea in Chinese Han subjects

“…PPARG polymorphisms may be involved in the growth hormone/STAT5B pathway [35], and mice that were deficient in members of this pathway developed craniofacial abnormalities [30]. The growth hormone/STAT5B pathway also plays an important role in regulating energy metabolism in adipose and muscle tissue, suggesting that PPARG may cause craniofacial abnormalities and dysfunction of adipose and muscle tissue metabolism through this pathway [36,37]. In addition, the rs1801282 SNP is located in an exon and is a missense variant that affects the amino acid sequence of the PPARG protein (Pro12Ala).…”

Growth Hormone Replacement Therapy in Patients without Adult Growth Hormone Deficiency: What Answers Do We Have So Far?

“…This hormone plays an important role in the regulation of anabolism and in the preservation of lean mass, and some of these anabolic effects are mediated by stimulation of lipolysis. Studies in humans have shown that GH reduces protein breakdown by about 30% during fasting, and this effect depends on the mobilization of free fatty acids from lipid stores [10].…”