Ghrelin Induces Abdominal Obesity Via GHS-R-Dependent Lipid Retention

Abstract

Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

“…In another report, a low dose of ghrelin administered peripherally produced an increase in FAS and decreases in CPT‐1α mRNAs expression without affecting food intake. Although some reports have shown an increase in liver adiposity with ghrelin treatment (Davies et al ., 2009), others have shown the opposite effect with ghrelin preventing fat accumulation and improving redox state in the liver of high fat‐fed animals (Barazzoni et al ., 2013) but also under caloric restriction (Stark et al ., 2015). Additional factors may account for the differences in results reported by different groups: mouse age and strain, subchronic vs. chronic ghrelin treatment and via of administration (central vs. peripheral).…”

“…However, its role on hepatic steatosis is not known. Recent publications have suggested that it may increase liver adiposity through p53 signaling (Davies et al ., 2009; Porteiro et al ., 2013), although others have shown the opposite effect with ghrelin preventing fat accumulation and improving redox state in the liver of high fat‐fed animals (Barazzoni et al ., 2013) and also under pair‐feed conditions (Stark et al ., 2015). The goal of this work was to determine whether deletion of ghrelin might prevent the age‐associated NAFLD and to determine whether its effects are mediated through the p300‐C/EBPα/β pathway.…”

Unacylated ghrelin is associated with changes in body composition and body fat distribution during long-term exercise intervention

“…In contrast, Thompson et al (3) observed parallel adipogenic effects of UAG with AG, via a mechanism independent of the GHS-R 1a in rats. Davies et al (24) observed that a chronic infusion of AG induced abdominal obesity, whereas UAG had no effect on adiposity in rats.…”

Clinical application of ghrelin administration for gastric cancer patients undergoing gastrectomy

“…X/A-like cells of the oxyntic glands in the stomach produce the majority of ghrelin, and smaller amounts are secreted by other organs, such as the intestine, pancreas, kidney, and hypothalamus [15,16]. Ghrelin has several physiological functions in addition to the secretion of GH, including the promotion of the appetite signal that antagonizes leptin in the hypothalamus [17], stimulation of gastrointestinal activity (e.g., peristalsis, gastric acid secretion, and pancreatic excretion through the vagal nerves) [18], and regulation of fat metabolism [19] (Table 1). Ghrelin also mitigates proinflammatory cytokine production and attenuates the stress signal [20].…”