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.

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The liver is central to the maintenance of glucose and lipid homeostasis, and liver X receptors (LXRs) are key regulators of expression of the genes involved. So far, effects of activation of LXR in human hepatocytes have not been well characterized. Here we show that treatment of primary human hepatocytes with the synthetic LXR ligand 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride (GW3965) results in reduced output of bile acids and very low density lipoprotein triglycerides and induced expression of adipose differentiation-related protein accompanied by increased lipid storage. Genome wide-expression profiling identified novel human LXR target genes in the glycolytic and lipogenic pathways and indicated that LXR activation reduced hepatic insulin sensitivity. Comparative experiments showed significant differences in the response to GW3965 between human and rat hepatocytes, raising the question as to how well rodent models reflect the human situation. In summary, the risk of hepatic steatosis upon pharmaceutical targeting of LXR may be a particularly serious consequence in humans.When adaptive physiological strategies to cope with surplus energy become exceeded, associated pathogeneses such as glucose intolerance, insulin resistance, and dyslipidemia develop. Members of the nuclear receptor family have emerged as key metabolic sensors regulating the expression of genes involved in intermediary metabolism (Francis et al., 2003;Shulman and Mangelsdorf, 2005) and LXR␣ and LXR␤, acting as cholesterol sensors, are considered to be potential drug targets for the alleviation of symptoms of metabolic diseases (Zelcer and Tontonoz, 2006).In rodents but not in humans, LXR activation enhances hepatic cholesterol catabolism partly through increased expression of cytochrome P450 7A1, the rate-limiting enzyme in the classic conversion of cholesterol to bile acids (Chiang et al., 2001). Moreover, it has been shown that LXR agonists

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