Distinct Impact of Inflammatory Versus Psychophysiological Stress on Brain‐Wide Activation of Melanocortin Receptor 4–Expressing Neurons

Central melanocortin signaling plays a critical role in maintaining energy homeostasis by regulating energy intake and expenditure, with impairment of this system closely related to metabolic diseases such as obesity. Among melanocortin receptor subtypes, melanocortin receptor 4 (MC4R) is the primary mediator of these effects within the central nervous system. Accumulating evidence suggests that MC4R contributes to stress-induced disruptions in feeding behavior and energy homeostasis. However, the precise neural mechanisms by which stress alters MC4R activity remain incompletely understood. In this study, we compared brain-wide c-Fos expression patterns induced by two distinct stress paradigms: lipopolysaccharide (LPS)-induced inflammatory stress and restraint stress in male mice, and further examined the involvement of MC4R-expressing (MC4R⁺) neurons in these stress conditions. We found that both stressors elicited c-Fos activation in brain areas associated with stress responses as well as feeding regulation. Notably, LPS-induced stress, but not restraint stress, selectively activated MC4R⁺ neurons in the central amygdala (CeA) and oval nucleus of the bed nucleus of stria terminalis (ovBNST). These results highlight the distinct recruitment of MC4R⁺ neurons during acute inflammatory stress in male mice, offering novel insights into the role of MC4R in the stress-induced imbalance of energy homeostasis depending on stressor types.