Background: A recent study of obesity in Swedish men found that polymorphisms in the type 3 adenylyl cyclase (AC3) are associated with obesity, suggesting the interesting possibility that AC3 may play a role in weight control. Therefore, we examined the weight of AC3 mice over an extended period of time. Methodology/Principal Findings: We discovered that AC3-/- mice become obese as they age. Adult male AC3-/- mice are about 40% heavier than wild type male mice while female AC3-/- are 70% heavier. The additional weight of AC3-/- mice is due to increased fat mass and larger adipocytes. Before the onset of obesity, young AC3-/- mice exhibit reduced physical activity, increased food consumption, and leptin insensitivity. Surprisingly, the obesity of AC3-/- mice is not due to a loss of AC3 from white adipose and a decrease in lipolysis. Conclusions/Significance: We conclude that mice lacking AC3 exhibit obesity that is apparently caused by low locomotor activity, hyperphagia, and leptin insensitivity. The presence of AC3 in primary cilia of neurons of the hypothalamus suggests that cAMP signals generated by AC3 in the hypothalamus may play a critical role in regulation of body weight.
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