Mechanism of Amelioration of Insulin Resistance by β3-Adrenoceptor Agonist AJ-9677 in the KK-Ay/Ta Diabetic Obese Mouse Model
- Hiroshi Kato,
- Mayumi Ohue,
- Kaori Kato,
- Akinori Nomura,
- Kaoru Toyosawa,
- Yasuji Furutani,
- Satoshi Kimura and
- Takashi Kadowaki
- 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 .
Abstract
The mechanism by which the specific β3-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-Ay/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-α (TNF-α) 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-α and free fatty acid production and may be the mechanism of amelioration of insulin resistance in KK-Ay/Ta diabetic obese mice.
Footnotes
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ELISA, enzyme-linked immunosorbent assay; FFA, free fatty acid; NEFA, nonesterified fatty acid; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction; PPAR-γ, peroxisome proliferator-activated receptor γ; PVDF, polyvinylidene difluoride; RT, reverse transcription; TNF-α, tumor necrosis factor-α; UCP, uncoupling protein.
- by the American Diabetes Association, Inc.
