Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat.
The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.
Umekawa
T
T
First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan.
Yoshida
T
T
Sakane
N
N
Saito
M
M
Kumamoto
K
K
Kondo
M
M
D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000737:chemistry / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D051275:Glucose Transporter Type 4; D006153:Guanosine Diphosphate / Q000032:analysis / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins; D009765:Obesity; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3; D000071256:Uncoupling Protein 1; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D004149:Dioxoles; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C495694:Slc2a4 protein, rat; D000071256:Uncoupling Protein 1; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D006153:Guanosine Diphosphate