Adenylyl cyclase type 5 knockout (AC5KO) mice have increased longevity and share a similar phenotype with calorie-restricted wild-type (WT) mice. To determine the in vivo metabolic properties of AC5 deficiency, we compared the effects of standard diet (SD) and high-fat diet (HFD) on obesity, energy balance, glucose regulation, and insulin sensitivity. AC5KO mice on SD had reduced body weight and adiposity compared with WT mice. Blood cholesterol and triglyceride levels were also significantly reduced in AC5KO mice. Indirect calorimetry demonstrated increased oxygen consumption, respiratory exchange ratio, and energy expenditure in AC5KO compared with WT mice on both SD and HFD. AC5KO mice also displayed improved glucose tolerance and increased whole-body insulin sensitivity, accompanied by decreased liver glycogen stores. Euglycemic-hyperinsulinemic clamp studies confirmed the marked improvement of glucose homeostasis and insulin sensitivity in AC5KO mice primarily through increased insulin sensitivity in skeletal muscle. Moreover, the genes involved in mitochondrial biogenesis and function were significantly increased in AC5KO skeletal muscle. These data demonstrate that deficiency of AC5 protects against obesity, glucose intolerance, and insulin resistance, supporting AC5 as a potential novel therapeutic target for treatment of obesity and diabetes.
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