<p>Weight fluctuations, such as weight loss or gain, are hallmark features of major depression. 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. We found that two-week social isolation during adolescence induced depressive-like behaviors in the sucrose preference test (SPT), forced swimming test (FST) and social interaction test (SI), and anxiety-like behaviors in the elevated plus maze (EPM), novelty suppressed feeding test (NSF) and open field test (OFT) in female but not male mice. Interestingly, female mice displayed slower weight gain during social isolation compared to control mice and isolated male mice. Furthermore, 20% but not 10% calorie restriction, which suppressed weight gain, led to depressive-like behaviors in both male and female mice, whereas 40% CR exerted an antidepressant effect. 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 increased peptide tachykinin 2 (Tac2) within the medial amygdala (MeA) mediated slowed weight gain and depressive-like behaviors in isolated mice. Pharmacological blockade or genetic knockout of the Nk3 receptor (Nk3R), the receptor for Tac2, reversed both the weight gain deficits and depressive-like behaviors. Our findings highlight a sex-specific vulnerability to social isolation mediated by MeA Tac2-Nk3R signaling, which open new avenues for potential therapeutic interventions for depression.</p>