RF01 | PMON44 Absence of Kisspeptin in KNDy Neurons of Mice Causes Sexually Dimorphic Metabolic Dysfunction on a High-Fat Diet

Kisspeptin neurons in the arcuate nucleus (ARC) of the hypothalamus are considered as the gonadotropin-releasing hormone (GnRH) pulse generator to control the cascade of hormone secretions that constitute the reproductive axis. These neurons typically co-express Neurokinin B and Dynorphin and are thus dubbed KNDy neurons. In addition, KNDy neuron kisspeptin is hypothesized to be a major sensor and regulator of metabolic homeostasis while relaying energy status to the hypothalamic-pituitary-gonad (HPG) axis. However, the direct metabolic impact of KNDy neuron kisspeptin has not been well-characterized. To explore this role, we examined the metabolic profile of our previously established KNDy neuron-specific kisspeptin knock-out mouse model (Pdyn-Cre/Kissfl/fl, or KO). To do so, we performed glucose tolerance tests, EchoMRI body composition analysis, and measured body weight in wild type (WT) control or KO mice fed with either regular chow or a high-fat diet (HFD, 60% kcal fat, Research Diets, New Brunswick, NJ) for 12 weeks post-weaning. At 4 weeks on the HFD, KO females weighed significantly more than HFD WT females, which continued through the remaining 8 weeks. Additionally, we found significantly decreased glucose tolerance and increased fat mass in HFD KO females compared to HFD WT females. However, KO males exhibited no significant differences in body weight, body composition, or glucose tolerance between the genotypes on either diet. This data suggests that KNDy neuron kisspeptin is critical for metabolic homeostasis and preventing metabolic dysfunction when challenged with a high-fat diet. Our findings further suggest a sexual dimorphism whereby KNDy neuron kisspeptin performs this action predominantly in females. Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.