Growth hormone signaling and action in obese versus lean human subjects

Morten Lyng Hogild, Ann Mosegaard Bak, Steen Bonlokke Pedersen, Jorgen Rungby, Jan Frystyk, Niels Moller, Niels Jessen and Jens Otto Lunde Jorgensen

American Journal of Physiology - Endocrinology and Metabolism 2019. 316: E333-E344.


Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (?IGF-I: lean, ?66?±?10 vs. obese, 27?±?16 µg/l; P < 0.01; ?GH: lean, 647?±?280 vs. obese, 544?±?220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

Our Thoughts on This Paper

While it is well established that obesity causes insulin resistance, much less is known about how obesity modifies other hormonal signaling pathways. Several studies have indicated that in addition to the suppression of anabolic actions of insulin, there is a coordinate activation of catabolic pathways in obesity (Ravussin et al. 2014). While growth hormone is not generally thought of as catabolic, it does mobilize fatty acids for growth and energy and is a key counter-regulatory hormone to insulin during fasting. In this work, Hogild et al. evaluate growth hormone signaling in human subjects and ask whether this could be moderated by obesity. They show that GH levels in response to fasting are attenuated in obesity. While GH produced similar increases in lipolysis in the lean and obese subjects, they only observed elevated endogenous glucose production in the obese subjects, potentially suggesting direct hepatic actions, rather than indirect regulation of gluconeogenesis through lipolysis. More importantly, overall insulin sensitivity and glucose disposal rates were reduced equally in lean and obese individuals after a GH bolus. These data compellingly argue that GH signaling is similar in the lean and obese, and that it’s counter-regulatory role during fasting is less prominent in the obese. Thus GH is unlikely to be the missing catabolic factor associated with obesity.

Written by Dave Bridges on March 6, 2019.


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