Brain-wide Activity Mapping Reveals the Somatosensory Cortex as a Sex-Specific Regulator of High-Fat Diet Intake.

High-fat diet (HFD) consumption engages reward circuitry and promotes neuroadaptations that contribute to overeating and obesity. While mesolimbic dopamine pathways are central to hedonic feeding models, the contribution of sensory cortical systems remains poorly understood. Here, we performed whole-brain activity mapping using Targeted Recombination in Active Populations (TRAP) and network analysis to define the distributed neural consequences of short-term HFD exposure in male and female mice. HFD increased caloric intake in both sexes, with females consuming significantly more than males. Brain-wide analysis revealed striking sex-specific adaptations: HFD selectively increased isocortical activity in males, with the somatosensory cortex (SS) emerging as the most prominently modulated region. SS activity negatively correlated with HFD intake, primarily in males. Network analysis using the SMARTTR pipeline demonstrated that HFD reorganized network activity in a sex-dependent manner, biasing male networks toward associative cortical-thalamic hubs, whereas female networks preferentially recruited subcortical and brainstem structures. To determine causality, we bidirectionally manipulated SS pyramidal neurons using chemogenetics during limited-access HFD exposure. Inhibition of the SS increased HFD intake in males, whereas activation reduced cumulative intake in females, without affecting locomotion. These findings establish the SS as a sex-specific regulator of palatable food consumption and demonstrate that similar behavioral outcomes emerge from distinct circuit architectures across sexes. Collectively, this study expands prevailing reward-centric models of hedonic feeding by identifying sensory cortical control as a critical component of diet-induced neuroadaptations, with important implications for sex-specific therapeutic strategies targeting overeating and obesity.