OBJECTIVE: Based on results of in vitro studies, it has been hypothesized that blockade of the renin-angiotensin system (RAS) promotes the recruitment and differentiation of pre-adipocytes and that increased formation of small insulin-sensitive adipocytes counteracts ectopic deposition of lipids, thereby improving insulin sensitivity. We investigated the effect of RAS blockade on insulin sensitivity, adipocyte size, and intramuscular lipid content in fructose-fed rats (FFR) as a model of insulin-resistant hypertension. DESIGN AND METHODS: Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (control) and those fed a fructose-rich chow for 6 weeks. FFR were treated with a vehicle or with 1 mg/kg per day of temocapril, an angiotensin-converting enzyme inhibitor, or 0.1 mg/kg per day of olmesartan, an angiotensin II type 1 receptor blocker, for the last 2 weeks. Insulin sensitivity (M value: mg/kg per min) was estimated by the euglycemic hyperinsulinemic glucose clamp method. Sizes of adipocytes derived from epididymal fat and triglyceride content in the soleus muscle were determined. RESULTS: FFR had lower M value, higher blood pressure, larger adipocyte size, higher ratio of epididymal fat pads over body weight (%fat pads), and higher intramuscular triglyceride than did the control rats. Both temocapril and olmesartan significantly improved the M value and decreased blood pressure and adipocyte size without change in %fat pads in FFR. Adipocyte size was negatively correlated with the M value. Treatment for 2 weeks decreased, but not significantly, intramuscular triglyceride. CONCLUSIONS: RAS blockade decreases adipocyte size without change in epididymal %fat pads accompanied by improvement in insulin sensitivity.