High-fat diet enhances starvation-induced hyperactivity via sensitizing hunger-sensing neurons in Drosophila

Abstract

Proper regulation of food intake can be disrupted by sustained metabolic challenges such as high-fat diet (HFD), which may result in various metabolic disorders. Previously, we showed that starvation induced sustained hyperactivity, an exploratory component of food-seeking behavior, via a specific group of octopamingeric (OA) neurons (Yu et al., 2016). In the present study, we found that HFD greatly enhanced starvation-induced hyperactivity. HFD increased the excitability of these 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 were transported by a lipoprotein LTP to enter these OA neurons via the cognate receptor LpR1, which activated AMPK-TOR signaling and suppressed autophagy-dependent degradation of AKHR. Taken together, we uncovered a mechanism that linked HFD and starvation-induced hyperactivity, providing insight in the reshaping of neural circuitry under metabolic challenges and the progression of metabolic diseases.