In-vitro studies have implicated the A(1) adenosine receptor (A(1)AR) of adipocytes in inhibition of lipolysis, stimulation of lipogenesis and enhancement of the action of insulin on glucose metabolism. To determine whether any of these activities were physiologically relevant in an intact animal, A(1)AR was overexpressed in adipose tissue of transgenic mice. Lower plasma free fatty acid (FFA) levels were observed in the transgenic mice relative to the litter-matched controls, supporting a significant physiological role for adipocyte A(1)AR in the control of lipolysis. However, no differences were observed in body weights or body composition. On a high fat diet, both the transgenic mice and the litter matched controls, male and female, became equally obese. Unlike the control mice, however, the transgenic mice did not develop insulin resistance, as demonstrated by serum glucose and insulin levels and glucose and insulin tolerance tests. These findings demonstrate that adipocyte A(1)AR plays an important physiological role in the control of insulin sensitivity in an intact animal and therefore should be considered to be a potential therapeutic target for the treatment of obesity-related insulin resistance and type 2 diabetes.