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Effect of Des-acyl Ghrelin on Adiposity and Glucose Metabolism

Department of Surgery (W.Z., B.C., J.-y.L., H.W., M.W.M.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Physiology and Pathophysiology (W.Z.), Peking University Health Science Center, Beijing 100191, People’s Republic of China

Address all correspondence and requests for reprints to: Weizhen Zhang, 1520B MSRBI, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0666. E-mail: weizhenz{at}umich.edu; or Michael W. Mulholland, 2101 Taubman, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0346. E-mail: micham{at}umich.edu.

Ghrelin, a gastric peptide hormone, has been reported to regulate GH secretion and energy homeostasis. Here, we examined the effect of des-acyl ghrelin driven from the fatty acid-binding protein-4 (FABP4) promoter on adiposity and glucose metabolism. A high level of expression of des-acyl ghrelin (692 ± 293 fmol/g fat) in adipose tissue was detected in FABP4-ghrelin transgenic mice, but not in wild-type littermates. Circulating des-acyl ghrelin was significantly higher in FABP4-ghrelin transgenic mice (8409 ± 3390 pM) compared with wild-type mice (513 ± 58 pM). No significant change was observed for plasma acylated ghrelin and obestatin. Epididymal and perirenal fat masses decreased 35 ± 9 and 52 ± 9%, respectively, in FABP4-ghrelin transgenic mice. FABP4-ghrelin transgenic mice are resistant to obesity induced by high-fat diet. Brown fat mass was not affected by overexpression of ghrelin in adipose tissue. Glucose tolerance tests showed glucose levels to be significantly lower in FABP4-ghrelin transgenic mice than in controls after glucose administration. Insulin sensitivity testing showed that FABP4-ghrelin transgenic mice had a 28 ± 5% greater hypoglycemic response to insulin. Our study demonstrates that overexpression of ghrelin from the FABP4 promoter impairs the development of white adipose tissues, and alters glucose tolerance and insulin sensitivity in mice.

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