A cortico-hypothalamic circuit regulates metabolism and stress resilience in a sex-specific manner

The neural mechanisms controlling food intake and body weight have traditionally been ascribed to neuroendocrine feedback acting within the hypothalamus. However, recent studies highlight that integration of external sensory stimuli within cortical regions also regulates energy metabolism, raising the possibility that sensory input can override homeostatic control of feeding behaviour. In this study, we examined whether a pathway from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH), which responds to acute stressors and suppresses food intake, also produces long-term effects on metabolism and stress-induced behaviour. Manipulation of this pathway was achieved through caspase-mediated chronic ablation or NaChBac-mediated chronic activation in mice. Chronic mPFC-LH ablation increased body weight gain and lean mass in chow-fed males, but not females, and improved glucose clearance in males and insulin sensitivity in females. In contrast, chronic mPFC-LH activation with NaChBac reduced body weight gain and improved glucose handling specifically in high fat diet (HFD)-fed females. Behaviourally, mPFC-LH ablation reduced exploration following acute stress, increased freezing during stress, and decreased hedonic processing in chow-fed males. Conversely, chronic mPFC-LH activation increased exploration after stress and lowered plasma corticosterone levels in males, and increased hedonic responses in chow-fed females, suggesting enhanced behavioural resilience. Collectively, these findings demonstrate that chronic manipulation of the mPFC-LH pathway produces reciprocal, sex- and diet-specific effects on body weight and glucose metabolism, as well as regulating behavioural resilience to acute stress. This novel top-down, cortico-hypothalamic pathway may play an important role in the sex-specific pathogenesis of metabolic and stress-related neuropsychiatric disorders.