Biochemical mechanisms responsible for the attenuation of diabetic and obese conditions in ob/ob mice treated with dopaminergic agonists

OBJECTIVE: We previously reported that a two week treatment with SKF 38393 (SKF, a dopamine D-1 receptor agonist), plus bromocriptine (BC, a dopamine D-2 receptor agonist) acted synergistically to normalize hyperphagia, body fat, hyperglycaemia and hyperlipidaemia in ob/ob mice. The present study fu rther investigates the biochemical mechanisms triggered by this drug treatm ent. DESIGN: Six week old female C57BL/6J ob/ob mice were divided into three gro ups and treated for two weeks with either BC and SKF, vehicle (control), or vehicle and pair fed to match the drug-treated group's daily food intake. RESULTS: BC/SKF treatment reduced food consumption by 55%, and treated mice weighed less than either pair fed or adlibitum fed controls after two week s of treatment. Moreover, oxygen consumption was increased by 2.4-fold and the respiratory quotient (RO) decreased from 1.23 to 0.96 (indicating a red uction in de novo lipogenesis) by drug treatment relative to adlibitum fed controls, but these parameters were unaffected by pair feeding control mice . The treatment also reduced blood glucose and free fatty acids (FFA) relat ive to pair fed and adlibitum fed controls. BC/SKF treatment (but not pair feeding) concurrently reduced lipolysis, lipogenic enzyme activities and he patic gluconeogenic enzyme activities. Treatment also increased hepatic con centrations of glycogen and xylulose-5-phosphate (X-5-P), a key stimulator of glycolysis. Finally, BC/SKF, but not pair feeding, reduced the circulati ng concentrations of thyroxine and corticosterone, two hormones known to in crease lipolysis, lipogenesis and hyperglycaemia. Drug treatment also incre ased serum dehydroepiandrosterone (DHEA) sulfate concentrations, an inhibit or of body fat store accumulation. CONCLUSION: These findings demonstrate that BC/SKF treatment not only norma lizes hyperphagia of ob/ob mice, but also redirects several metabolic and e ndocrine activities, independent of its effects on feeding to improve the o bese-diabetic syndrome in ob/ob mice.