We have previously reported that an adenylyl cyclase type 5 (AC5) deficient mouse model (AC5 knock out, KO) lives one-third longer than wild type (WT) mice. Despite greater daily food intake the AC5KO mice weigh less than WT mice and are protected against cardiac stress. In addition, the AC5KO mice have the same molecular signature of caloric restriction, the most common effective intervention to increase healthy longevity.. Since caloric restriction improves metabolic profiles and protects against insulin resistance, obesity and diabetes, we placed 6-8 week old male AC5KO mice and their corresponding wild type littermates (WTL) controls on a 35.5% high fat diet (HFD) for 100 days. At sacrifice, fat deposits were reduced 36% in AC5KO and cholesterol levels were reduced from 131±9.9 mg/dl to 105±3.1 mg/dl, p<0.05. Indirect calorimetry demonstrated that the AC5KO mice had a 16.7% increase in oxygen consumption during the light cycle (p<0.01) and 29.2% increase during the dark cycle (p<0.01) compared to WTL on HFD, suggesting enhanced metabolic rate as the mechanism for decreased adiposity and body weight. AC5KO mice also displayed improved glucose tolerance with a 32% reduction in area under the curve concomitant with a 111% increase in whole body insulin sensitivity (insulin tolerance test). In parallel, conscious non-stressed euglycemic-hyperinsulinemic clamp studies confirmed the marked enhancement of glucose homeostasis and insulin sensitivity in the AC5KO mice. Moreover, WTL developed reduced cardiac function consistent with diabetic cardiomyopathy following high fat diet feeding (e.g., left ventricular (LV) ejection fraction fell from 71±2% to 53±2%) whereas AC5 KO mice had better preserved LV ejection fraction (61±3%). In addition, AC5 KO mice showed 33% decrease in cardiac fibrosis and 40% decrease in apoptosis compared to WTL on HFD. Thus, reduction of AC5 protects against obesity, diabetes and diabetic cardiomyopathy, suggesting that AC5 is a potential novel therapeutic target for the treatment of obesity, diabetes and associated cardiomyopathy.