It has been postulated that dopaminergic activities comprise a major functional component of a central regulatory system for metabolism which can be manipulated by dopamine modulating drugs. The present study is aimed at delineating the role and importance of pharmacological dopaminergic activation in the regulation of metabolism during obesity and diabetes. We treated C57BL/6J ob/ob mice for 2 weeks with bromocriptine (dopamine D2 agonist), SKF38393 (dopamine D1 agonist), both drugs combined or vehicle and monitored the effects of such treatment on body composition, food consumption, and serum metabolites. Bromocriptine and SKF38393 individually produced moderate improvements in obesity, hyperglycemia, and hyperinsulinemia. However, a combination of bromocriptine plus SKF38393 resulted in major reductions in body weight (7.5 g), body fat (40%), food consumption (42%), and serum concentrations of glucose (59%), triglyceride (37%), free fatty acid (45%) and insulin (49%) while increasing protein mass (8%). These results indicate that regulatory components of metabolism in the ob/ob mouse are modulated by and/or are comprised of dopaminergic activities. Importantly, dopaminergic D1/D2 receptor coactivation maximizes this dopaminergic response (i.e., improvement of metabolic abnormalities) in these mice.