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Mechanism of Amelioration of Insulin Resistance by ß₃-Adrenoceptor Agonist AJ-9677 in the KK-A^y/Ta Diabetic Obese Mouse Model

From the Department of Pharmacology III (H.K., M.O., K.K., Y.F.), Discovery Research Laboratories; the Research and Development Coordination (A.N.) and the Department of Toxicology (K.T.), Developmental Research Laboratories, Dainippon Pharmaceutical Co., Osaka; and the Department of Metabolic Diseases (H.K., S.K., T.K.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Address correspondence and reprint requests to Hiroshi Kato, Department of Pharmacology III, Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka 564-0053, Japan. E-mail: hiroshi-kato{at}dainippon-pharm.co.jp .

The mechanism by which the specific ß₃-adrenoceptor agonist AJ-9677 relieves insulin resistance in vivo was investigated by studying its effects in the white and brown adipose tissues of the KK-A^y/Ta diabetic obese mouse model. AJ-9677 reduced the total weight of white adipose tissues by reducing the size of the adipocytes, an effect associated with the normalization of tumor necrosis factor- (TNF-) and leptin expression levels. The levels of uncoupling protein (UCP)-1 mRNA in brown adipose tissue were increased threefold. AJ-9677 caused a marked increase (20- to 80-fold) in the expression of UCP-1 in white adipose tissues. The levels of UCP-2 mRNA were increased in both the white and brown adipose tissues of diabetic obese mice, and AJ-9677 further upregulated UCP-2 mRNA levels in brown adipose tissue, but reduced its levels in white adipose tissue. UCP-3 mRNA levels were not essentially changed by AJ-9677. However, AJ-9677 significantly (two- to four-fold) upregulated the GLUT4 mRNA and protein levels in white and brown adipose tissues and the gastrocnemius. The generation of small adipocytes, presumably mediated by increased expression of UCP-1 in addition to increased lipolysis in response to AJ-9677, was associated with decreased TNF- and free fatty acid production and may be the mechanism of amelioration of insulin resistance in KK-A^y/Ta diabetic obese mice.

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