Chronic G signaling in AgRP neurons does not cause obesity.

Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate G signaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic G signaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic G signaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic G signaling in AgRP neurons are distinct from the previously reported effects of acute G signaling and also of leptin insensitivity.