Impairment of AgRP neurons influences body weight, lifespan, and behavior in calorie-restricted mice

Hypothalamic agouti-related peptide (AgRP)-expressing neurons are exclusively located in the arcuate nucleus of the hypothalamus and form the basis of the melanocortin system, a set of CNS circuits regulating energy homeostasis. Besides an important role in driving food intake, AgRP neurons are also involved in modulating complex, non-feeding behaviors. However, it is unknown how AgRP-dependent feeding influences general exploratory behavior. Using the AgRPDTR mouse model with impaired AgRP neuronal functions, we show here that perturbation of AgRP neuronal function leads to sex-dependent body weight changes, lifespan, and altered behavioral responses. Interestingly, neonatal loss of AgRP neurons led to significant sex-specific differences in body weight under AL diet. In addition, reduced AgRP function also reduces the overall activity of animals of both sexes, revealing that AgRP neurons might regulate bodyweight and food intake through different mechanisms in males and females. Our findings highlight the pivotal role of the AgRP neurons, which likely play a fundamental, sex-dependent role in determining longevity, in the regulation of complex behaviors and show that AgRP neurons are critical for complex behavioral adaptations.