High-fat diet enhances food-seeking behavior via sensitizing hunger-sensing neurons in Drosophila I

The function of the central nervous system to regulate food intake can be disrupted by sustained metabolic challenges such as high-fat diet (HFD), which may contribute to the development of various metabolic disorders. In the present study, we found that HFD specifically enhanced food-seeking behavior in fruit flies without altering flies’ baseline metabolism and food consumption. Mechanistically, HFD increased the excitability of a small group of octopaminergic (OA) neurons to a hunger hormone named adipokinetic hormone (AKH), via increasing the accumulation of AKH receptor (AKHR) in these neurons. Upon HFD, excess dietary lipids are transported by a lipoprotein LTP to enter these OA+AKHR+ neurons via the cognate receptor LpR1, which in turn activated AMPK-TOR signaling and suppressed autophagy-dependent degradation of AKHR. Taken together, we uncovered a mechanism that linked HFD, AMPK-TOR signaling, neuronal autophagy, and food-seeking behavior, providing insight in the reshaping of neural circuitry under metabolic challenges and the progression of metabolic diseases.