Mechanism of amelioration of insulin resistance by beta3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model.

Abstract

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.

• Authors: H Kato, M Ohue, K Kato, A Nomura, K Toyosawa, Y Furutani, S Kimura, T Kadowaki
• Journal: Diabetes (Diabetes) Vol. 50 Issue 1 Pg. 113-22 (Jan 2001) ISSN: 0012-1797 [Print] United States
• PMID: 11147775 (Publication Type: Journal Article)

Chemical References

• ((3-((2R)-(((2R)-3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yloxy)acetic acid
• Acetates
• Adrenergic beta-Agonists
• Blood Glucose
• Carrier Proteins
• Fatty Acids, Nonesterified
• Glucose Transporter Type 4
• Indoles
• Insulin
• Ion Channels
• Leptin
• Membrane Proteins
• Membrane Transport Proteins
• Mitochondrial Proteins
• Monosaccharide Transport Proteins
• Muscle Proteins
• Proteins
• RNA, Messenger
• Slc2a4 protein, mouse
• Triglycerides
• Tumor Necrosis Factor-alpha
• Ucp1 protein, mouse
• Ucp2 protein, mouse
• Ucp3 protein, mouse
• Uncoupling Protein 1
• Uncoupling Protein 2
• Uncoupling Protein 3

Topics

• Acetates
• Adipose Tissue (drug effects, pathology)
• Adrenergic beta-Agonists (pharmacology)
• Animals
• Blood Glucose (analysis)
• Carrier Proteins (metabolism)
• Diabetes Mellitus (genetics, pathology, physiopathology)
• Fatty Acids, Nonesterified (blood)
• Glucose Transporter Type 4
• Indoles (pharmacology)
• Insulin (blood)
• Insulin Resistance
• Ion Channels
• Leptin (genetics, metabolism)
• Membrane Proteins (metabolism)
• Membrane Transport Proteins
• Mice
• Mitochondrial Proteins
• Monosaccharide Transport Proteins (metabolism)
• Muscle Proteins
• Obesity
• Proteins (metabolism)
• RNA, Messenger (metabolism)
• Triglycerides (blood)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Uncoupling Protein 1
• Uncoupling Protein 2
• Uncoupling Protein 3