Anti-obesity and anti-diabetic effects of mazindol in yellow KK mice: its activating effect on brown adipose tissue thermogenesis.

1. The anti-obesity and anti-diabetic effects of mazindol were evaluated in obese diabetic yellow KK mice and C57Bl control mice. 2. The study compound was fed through a gastric tube at a rate of 1 or 2 mg/kg per day (0.01 mol/L HCl as control) for 2 weeks. The following parameters were compared in treated and control animals: bodyweight, food intake, white adipose tissue (WAT) weight, brown adipose tissue (BAT) weight and its thermogenesis, noradrenaline (NA) turnover, blood glucose and serum insulin levels and glucose transporter 4 (GLUT4). 3. Furthermore, bodyweight loss of mice pair-fed the same amount of food as the mazindol-treated mice for 2 weeks was measured. 4. Mazindol significantly decreased food intake and significantly increased guanosine-5'-diphosphate-binding in BAT mitochondria and NA turnover in BAT in both yellow KK and C57Bl groups. The amounts of WAT in subcutaneous, mesenteric and retroperitoneal regions and bodyweights were significantly decreased in both groups. Bodyweight loss in mice pair fed with the mazindol-treated groups was approximately 70% compared with that in the mazindol-treated groups. Furthermore, mazindol decreased the levels of blood glucose and serum insulin during the glucose overloading test in yellow KK mice, but it did not influence the GLUT4 protein concentration in WAT and muscle. 5. These observations suggest that mazindol possesses both an anti-obesity action, due to the inhibition of appetite as well as the activation of BAT thermogenesis via increased NA turnover in BAT, and an anti-diabetic action. Consequently, mazindol may be useful for the treatment of obesity as well as non-insulin-dependent diabetes mellitus in obese persons.