Neuroendocrine circuits underlying stress integration and systemic fuel homeostasis are substantially intertwined. Accordingly, metabolic diseases such as obesity and diabetes have a high incidence of co-morbidity with stress-associated psychological disorders like anxiety and depression. Importantly, there is a strong female bias in both metabolic and stress-related disorders, making the understanding of sex-specific functions of these pathways critical for treatment. The hypothalamic melanocortin system is a principal regulator of energy balance and also modulates HPA responses to acute stress. Mutations in the melanocortin-4 receptor (MC4R) is the most common monogenic cause of obesity in humans and has been associated with sex-dependent effects, such as more women than men exhibiting ‘emotional’ eating, a behavior that is thought to be stress-induced. Thus, we hypothesized that MC4R deficiency may cause sexually dimorphic metabolic and stress responses. We subjected male and female rats with a MC4R loss-of-function mutation to either chronic variable stress (CVS) or no stress for 31 days. Mid-study, all rats underwent an acute restraint stress challenge. Consistent with previous reports, male and female rats with MC4R deficiency had increased food intake and body weight, which were both decreased by CVS. Contrary to expectation, MC4R genotype did not affect HPA axis or metabolic responses to chronic stress. But importantly, we observed a significant interaction between MC4R genotype and sex in HPA axis tone and acute stress reactivity, such that MC4R deficiency blunted both endpoints in males but exaggerated them in females. Females showed a dramatic 259% and 419% increase in basal corticosterone and HPA reactivity, respectively, compared to males. The heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females.


A.T.B. Chaffin: None. Y. Fang: None. K.R. Larson: None. J. Mul: None. K.K. Ryan: None.


National Institutes of Health (R00HL111319)

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