SUN-468 Sex Differences in Obesity-Mediated Impairment of Reproductive Function

Abstract

Increasing prevalence in obesity has become a significant public concern. C57BL/6J mice are prone to diet-induced obesity (DIO) when fed high-fat diet (HFD), and develop chronic inflammation and metabolic syndrome, making them a good model to analyze mechanisms whereby obesity elicits pathologies. DIO mice demonstrated profound sex differences in response to HFD with respect to inflammation and hypothalamic function. First, we determined that males are prone to DIO, while females are resistant. Ovariectomized females, on the other hand, are susceptible to DIO, implying protection by ovarian hormones. Males, but not females, exhibit changes in gonadotropin hormone concentration and hypothalamic neuropeptide expression. Surprisingly, ovariectomized females remain resistant to neuroendocrine changes, showing that ovarian hormones are not necessary for protection. Second, obese mice exhibit sex differences in DIO-induced inflammation. Proinflammatory cytokines are increased specifically in males, while anti-inflammatory cytokines are increased in the hypothalami of females but not males, which may provide protection to female mice. Again, females are protected from the increase in inflammatory cytokines regardless of the presence of ovarian hormones. Third, males and females deposit fat differentially in subcutaneous and visceral depots. Obese males exhibit reduced synapses in GnRH neurons and diminished GnRH gene expression, which may stem from obesity-mediated activation of immune cells or from direct effect of proinflammatory cytokines on GnRH gene expression, respectively. Proinflammatory cytokines directly repress GnRH gene expression in GT1-7 cells model, while in vivo, obese males show activation of a cytokine-induced transcription factor in GnRH neurons. Our studies suggest that inflammation-induced hypothalamic changes are potentially responsible for diminished levels of gonadotropin hormones, testosterone, and sperm numbers, which corresponds to the observations in obese humans. Taken together, we propose a potential mechanism of obesity-induced impairment of hypothalamic function, and our data implicate neuro-immune mechanisms underlying sex-specific differences in obesity-induced impairment of the hypothalamic function with potential consequences for reproduction and fertility.