Sex differences in central endozepine expression and regulation of appetite

Glia display inherent sexual dimorphism in their anatomy and physiology and as key regulators of systemic energy homeostasis, may contribute to sex differences in appetite and body weight control. Endozepines are glial produced signaling molecules consisting of the parent protein diazepam binding inhibitor (DBI) which is cleaved to the anorexigenic peptide octadecaneuropeptide (ODN). DBI expression is particularly high in the dorsal vagal complex (DVC) of the hindbrain and hypothalamus, yet whether females and males exhibit differences in endozepine signaling which may contribute to the sex-specific roles of glia in energy balance regulation has not been directly investigated. We determined that female rats were more sensitive to the anorexic effects of central ODN administration when maintained on either chow or high-fat diet. In both sexes and on either diet, the hypophagic response to ODN was dramatically blunted after an overnight fast. We next examined differences in endogenous DBI expression and found that females had higher levels of DBI immunofluorescent protein staining throughout the DVC and around the 3rd ventricle border of the hypothalamus. While 17β-Estradiol injection in males upregulated DVC DBI expression, female DVC DBI expression was not different across estrous cycle phases nor affected by ovariectomy, suggesting there is sex-specific regulation of central DBI transcripts. These data support that female rats have higher endogenous DBI protein expression and are more sensitive to exogenous ODN and thus may have a higher baseline endozepine tone. Further work will determine the physiological relevance of sex-differences in endozepine signaling in glial-mediated responses to dietary challenges.