Mechanism of amelioration of insulin resistance by beta(3)-adrenoceptor agonist AJ-9677 in the KK-A(y)/Ta diabetic obese mouse model

• Published in: Diabetes (New York, N.Y.) Vol. 50; no. 1; p. 113
• Main Authors: Kato, Hiroshi, Ohue, Mayumi, Kato, Kaori, Nomura, Akinori
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.01.2001
• Subjects: Adipocytes; Adrenergic receptors; Body fat; Diabetes; Fatty acids; Insulin resistance; Obesity; Proteins; Tumor necrosis factor-TNF
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.50.1.113

The mechanism by which the specific beta3-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-alpha (TNF-alpha) 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-alpha and free fatty acid production and may be the mechanism of amelioration of insulin resistance in KK-Ay/Ta diabetic obese mice.