Ghrelin's control of food reward and body weight in the lateral hypothalamic area is sexually dimorphic

Abstract Ghrelin is a stomach-produced hormone that stimulates ingestive behavior and increases motivated behavior to obtain palatable foods. Ghrelin receptors (growth hormone secretagogue receptors; Ghsr) are expressed in the lateral hypothalamic area (LHA), and LHA-targeted ghrelin application increases ingestive behavior in male rodents. However, the effects of LHA ghrelin signaling in females are unexplored. Here we investigated whether LHA ghrelin signaling is necessary and sufficient for control of ingestive and motivated behavior for food in male and female rats. Ghrelin delivered to the LHA increased food intake and motivated behavior for sucrose in both male and female rats, whereas increased food-seeking behavior and body weight were only observed in females. Females had slightly higher Ghsr levels in the LHA compared to males, and importantly, acute blockade of the Ghsr in the LHA significantly reduced food intake, body weight, and motivated behavior for sucrose in female but not male rats. Chronic LHA Ghsr reduction in female rats achieved by RNA inference-mediated Ghsr knockdown, resulting in a 25% reduction in LHA Ghsr mRNA, abolished the reward-driven behavioral effects of LHA-targeted ghrelin, but was not sufficient to affect baseline food intake or food reward responding. Collectively we show that ghrelin acts in the LHA to alter ingestive and motivated behaviors in a sex-specific manner.