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 that hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by growth hormone secretagogue receptor (GHS-R 1a )-mediated lipolysis.Chronic intravenous infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial subcutaneous 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 (ABCG1) mRNA expression and circulating free fatty acids (FFAs) were halved by ghrelin infusion].In contrast, ghrelin treatment did not upregulate biomarkers of adipogenesis [peroxisome proliferator-activated receptor (PPAR)2 or CCAAT/enhancer binding protein (C/EBP)] or substrate uptake (glucose transporter, GLUT4, lipoprotein lipase or CD36) and although ghrelin elevated sterol regulatory element binding protein (SREBP)1c expression, WAT-specific mediators of lipogenesis [liver X receptor (LXR) 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.