guanosine-diphosphate and Diabetes-Mellitus

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.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic beta-Agonists; Analysis of Variance; Animals; Blotting, Northern; Blotting, Western; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dioxoles; Eating; Glucose Transporter Type 4; Guanosine Diphosphate; Hypoglycemic Agents; Immunohistochemistry; Ion Channels; Male; Membrane Proteins; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; RNA, Messenger; Uncoupling Protein 1; Weight Gain

The anti-obesity and anti-diabetic actions of BRL 26830A, beta 3-adrenoceptor agonist, (2 mg/kg administered intramuscularly daily for 2 weeks) were evaluated in obese diabetic Yellow KK mice and C57B1 control mice. The following parameters were compared in the treated vs. control animals: brown adipose tissue (BAT) thermogenesis, resting metabolic rate (RMR), insulin receptors in adipocytes, and blood glucose and serum insulin levels during a glucose overloading test. BRL 26830A significantly increased BAT thermogenesis and RMR but it decreased the amount of white adipose tissue without affecting food intake. Those actions contributed to the mitigation of obesity in Yellow KK mice. BRL 26830A also increased the concentration of insulin receptors and decreased the levels of serum insulin and blood glucose during the glucose overloading test in Yellow KK mice. In the glucose overloading test performed one hour after BRL 26830A injection, insulin secretion was significantly increased and the blood glucose level was markedly decreased in both groups. These observations suggest that BRL 26830A possesses anti-obesity and anti-diabetic actions and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus with obesity.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Ethanolamines; Guanosine Diphosphate; Insulin; Male; Mice; Mice, Inbred Strains; Mitochondria; Obesity; Organ Size; Oxygen Consumption; Proteins

Thermogenesis of brown adipose tissue (BAT) of genetically obese mice, KKAY mice, was examined by measuring the BAT mitochondrial guanosine diphosphate (GDP) binding as an index of thermogenesis and comparing it with that of normal C57BL mice. No great difference in GDP binding was observed in KKAY and C57BL mice fed a stock diet. However, when they were given a sucrose solution, the increase in BAT mitochondrial GDP binding of KKAY mice (+22%) was much lower than that of C57BL mice (+106%). A high fat diet increased BAT mitochondrial GDP binding in KKAY mice to the same extent (+82%) as in C57BL mice. When the mice were fasted for 48 h, BAT mitochondrial GDP binding of C57BL mice decreased by 70%, while that of KKAY mice showed no change. Both acute exposure to cold and norepinephrine injections increased GDP binding in KKAY mice by 90% and 131%, respectively. These results indicate that low BAT thermogenesis in response to sucrose intake may be a cause of obesity in KKAY mice, and this may be brought about by defects in the central nervous system.

Topics: Adipose Tissue, Brown; Aging; Animals; Body Temperature Regulation; Body Weight; Diabetes Mellitus; Fasting; Female; Guanosine Diphosphate; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria; Sucrose

GDP binding to brown-adipose-tissue mitochondria from adult diabetic--obese (db/db) mice was significantly less than with lean siblings. Binding was also decreased in the mutant mice before obesity had begun to develop. Decreased GDP binding was found to result from a decrease in the number of binding sites.

Topics: Adipose Tissue, Brown; Animals; Binding Sites; Diabetes Mellitus; Guanine Nucleotides; Guanosine Diphosphate; In Vitro Techniques; Kinetics; Mice; Mice, Obese; Mitochondria; Obesity