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Attenuation of Diet-Induced Weight Gain and Adiposity through Increased Energy Expenditure in Mice Lacking Angiotensin II Type 1a Receptor

Departments of Molecular Medicine and Metabolism (R.K., T.S., J.N., M.T., T.T., M.K., T.C., Y.O.) and Clinical and Molecular Endocrinology (R.K., Y.H.), Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone (M.T., T.T., Y.O.), Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062; Department of Medicine, Division of Atherosclerosis and Diabetes, National Cardiovascular Center Hospital (Y.M., Y.Y.), Suita, Osaka 560-0005; Center for Tsukuba Advanced Research Alliance, Aspect of Functional Genomic Biology, Institute of Applied Biochemistry, University of Tsukuba (A.F.), Ten-noudai, Ibaraki 305-8577; and Department of Medical Biochemistry, Ehime University School of Medicine (M.H.), Shitsukawa, Shigenobu, Onsen-gun, Ehime 791-0295, Japan

Address all correspondence and requests for reprints to: Dr. Yoshihiro Ogawa, Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: ogawa.mmm{at}mri.tmd.ac.jp.

Given that angiotensin II (AII) type 1 and 2 receptors (Agtr1 and Agtr2) are expressed in adipose tissue, AII may act directly on adipose tissue. However, regardless of whether AII directly modulates adipose tissue growth and metabolism in vivo and, if so, whether it is mediated via Agtr1 are still matters of debate. To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtr1a (Agtr1a^–/– mice) during a high-fat diet. The Agtr1a^–/– mice exhibited the attenuation of diet-induced body weight gain and adiposity, and insulin resistance relative to wild-type littermates (Agtr1a^+/+ mice). They also showed increased energy expenditure accompanied by sympathetic activation, as revealed by increased rectal temperature and oxygen consumption, increased expression of uncoupling protein-1 mRNA in brown adipose tissue, and increased urinary catecholamine excretion. The heterozygous Agtr1a-deficient mice (Agtr1a^+/– mice) also exhibited metabolic phenotypes similar to those of Agtr1a^–/– mice. Using mouse embryonic fibroblasts derived from Agtr1a^+/+ and Agtr1a^–/– mice, we found no significant difference between genotypes in the ability to differentiate into lipid-laden mature adipocytes. In primary cultures of mouse mature adipocytes, AII increased the expression of mRNAs for some adipocytokines, which was abolished by pharmacological blockade of Agtr1. This study demonstrates that Agtr1a^–/– mice exhibit attenuation of diet-induced weight gain and adiposity through increased energy expenditure. The data also suggest that AII does not affect directly adipocyte differentiation, but can modulate adipocytokine production via Agtr1.

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