Sex-specific role of body weight in mediating stress susceptibility through MeA Tac2-Nk3R signaling

Weight fluctuations, such as weight loss or gain, are hallmark features of major depression. However, the potential bidirectional relationship between body weight and depressive-like behaviors remains poorly understood. While the prevalence of major depression is approximately twice as high in women compared to men, the role of body weight in mediating sex differences in depression susceptibility has yet to be fully explored. In the current study, we reported that exposure to two weeks of social isolation during adolescence induced depressive-like behaviors in female mice, while male mice exhibited resilience and did not develop these behavioral abnormalities. Interestingly, female mice displayed slower weight gain during social isolation compared to control mice and isolated male mice. Furthermore, 20% calorie restriction, which suppressed weight gain, mimicked social isolation-induced depressive-like behaviors in both male and female mice. Conversely, a high-fat diet that compensated for the slowed weight gain rescued the depressive-like behaviors in socially isolated female mice. We also found that social isolation led to an increase in the peptide tachykinin 2 (Tac2) within the medial amygdala (MeA) region, which contributed to both the slowed weight gain and the development of depressive-like behaviors. Pharmacological blockade or genetic knockout of the Nk3 receptor (Nk3R), the receptor for Tac2, reversed both the weight gain deficits and the associated behavioral abnormalities. Our findings highlight a sex-specific vulnerability to stress during adolescent social isolation and suggest that slowed weight gain, mediated by MeA Tac2-Nk3R signaling, plays a crucial role in this process. These insights open new avenues for potential therapeutic interventions for depression.