Sex-Stratified Characterization of Behavioral, Hippocampal, and Microglial Androgen Responses to Adolescent High-Fat Diet Consumption in Mice

Background: Adolescence is a vulnerable developmental period during which dietary exposure and psychosocial stressors may have lasting effects on higher-order brain functions. Depression often emerges during adolescence, at which time a female preponderance in prevalence becomes apparent. Consumption of a high-fat diet (HFD) is common during adolescence and has been associated with adverse emotional and neurobiological outcomes; however, its consequences have not been systematically characterized in both sexes. Methods: Male and female mice were fed a HFD from postnatal days 28 to 56 (spanning most of adolescence), with chronic unpredictable mild stress (CUMS) used as a challenge to assess stress responsiveness. Results: Sex-stratified analyses revealed that HFD consumption induced anhedonia-like behavior in both sexes, whereas additional behavioral impairments were detected in females. Additionally, HFD consumption amplified the behavioral response to CUMS in females. HFD feeding altered the ventral hippocampal neurostructure and microglial status in both sexes; however, dendritic and spine deficits and microglial activation-like changes were detected across more ventral hippocampal subregions in females, together with increased synaptic engulfment in the vDG. HFD consumption increased circulating leptin and estradiol levels in both sexes, and higher free fatty acid levels were detected in nonstressed HFD-fed mice of both sexes. In females, HFD consumption increased circulating testosterone levels, which was accompanied by increased androgen receptor (AR) nuclear localization and TNF-α expression in hippocampal microglia. Serum from HFD-fed females significantly increased AR nuclear localization (p = 0.0008) and phagocytic activity (p = 0.0038) in primary female microglia. Enzalutamide abolished the serum-induced increase in AR nuclear localization (p < 0.0001), reduced the corresponding increase in phagocytic activity (p = 0.0335), and attenuated the associated induction of TNF-α at both the protein (p = 0.0057) and mRNA (p = 0.0003) levels. Conclusions: These findings characterize sex-stratified behavioral and hippocampal neurobiological consequences of adolescent HFD consumption and suggest a previously underrecognized association between androgen-responsive microglial signaling and the broader hippocampal alterations observed in females. Although the causal contribution of this signaling pathway to the in vivo phenotypes remains to be established, this work provides a framework for further investigating sex-related differences in the neurobiological consequences of adolescent HFD consumption and the potential contribution of endocrine–microglial signaling.