Original Article
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World J Gastroenterol. Mar 14, 2014; 20(10): 2653-2663
Published online Mar 14, 2014. doi: 10.3748/wjg.v20.i10.2653
Exenatide improves hepatic steatosis by enhancing lipid use in adipose tissue in nondiabetic rats
Kosuke Tanaka, Yuko Masaki, Masatake Tanaka, Masayuki Miyazaki, Munechika Enjoji, Makoto Nakamuta, Masaki Kato, Masatoshi Nomura, Toyoshi Inoguchi, Kazuhiro Kotoh, Ryoichi Takayanagi
Kosuke Tanaka, Yuko Masaki, Masatake Tanaka, Masayuki Miyazaki, Masaki Kato, Masatoshi Nomura, Kazuhiro Kotoh, Ryoichi Takayanagi, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Munechika Enjoji, Department of Clinical Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
Makoto Nakamuta, Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan
Toyoshi Inoguchi, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka 812-8582, Japan
Author contributions: All the authors contributed equally to this manuscript.
Correspondence to: Masaki Kato, MD, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. mkato11@intmed3.med.kyushu-u.ac.jp
Telephone: +81-92-6425282 Fax: +81-92-6425287
Received: September 28, 2013
Revised: November 12, 2013
Accepted: January 14, 2014
Published online: March 14, 2014
Processing time: 165 Days and 3 Hours
Abstract

AIM: To investigate the metabolic changes in skeletal muscle and/or adipose tissue in glucagon-like peptide-1-induced improvement of nonalcoholic fatty liver disease (NAFLD).

METHODS: Male Wistar rats were fed either a control diet (control group) or a high-fat diet (HFD). After 4 wk, the HFD-fed rats were subdivided into two groups; one group was injected with exenatide [HFD-Ex(+) group] and the other with saline [HFD-Ex(-) group] every day for 12 wk. The control group received saline and were fed a control diet. Changes in weight gain, energy intake, and oxygen consumption were analyzed. Glucose tolerance tests were performed after 8 wk of treatment. Histological assessments were performed in liver and adipose tissue. RNA expression levels of lipid metabolism related genes were evaluated in liver, skeletal muscle, and adipose tissue.

RESULTS: Exenatide attenuated weight gain [HFD-Ex(-) vs HFD-Ex(+)] and reduced energy intake, which was accompanied by an increase in oxygen consumption and a decrease in the respiratory exchange ratio [HFD-Ex(-) vs HFD-Ex(+)]. However, exenatide did not affect glucose tolerance. Exenatide reduced lipid content in the liver and adipose tissue. Exenatide did not affect the expression of lipid metabolism-related genes in the liver or skeletal muscle. In adipose tissue, exenatide significantly upregulated lipolytic genes, including hormone-sensitive lipase, carnitine palmitoyltransferase-1, long-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase 1 [HFD-Ex(-) vs HFD-Ex(+)]. Exenatide also upregulated catalase and superoxide dismutase 2 [HFD-Ex(-) vs HFD-Ex(+)].

CONCLUSION: In addition to reducing appetite, enhanced lipid use by exenatide in adipose tissue may reduce hepatic lipid content in NAFLD, most likely by decreasing lipid influx into the liver.

Keywords: Adipose tissue; Energy expenditure; Exenatide; Glucagon-like peptide-1; Hepatic steatosis; Lipolysis; Nonalcoholic fatty liver disease

Core tip: Glucagon-like peptide-1 (GLP-1) is reported to improve nonalcoholic fatty liver disease (NAFLD), mainly via direct action on the liver. However, organs other than the liver may also be involved in regulation of hepatic lipid contents. In this study, we found significant upregulation of lipolytic genes in adipose tissue in exenatide-treated NAFLD rats. Up-regulation of catalase, superoxide dismutase and mitochondrial morphological regulators was observed in adipose tissue. These metabolic changes were accompanied by increased oxygen consumption and decreased respiratory exchange ratio. Taken together, enhanced lipid use by GLP-1 in adipose tissue may play an important role in the improvement of NAFLD.