FRI276 KNDy-Neuron Kisspeptin Is Dispensable For Feeding Behavior, But Critical For Energy Expenditure Leading To Metabolic Dysfunction In Female Mice

Abstract Disclosure: N. Nandankar: None. H. Ganesh: None. A.L. Negron: None. S. Al-Samerria: None. J.E. Levine: None. S. Radovick: None. Hypothalamic kisspeptin (Kiss1) is a critical master regulator of the hypothalamic-pituitary-gonadal axis responsible for reproductive development and function. Kiss1, originating from KNDy neurons in the arcuate nucleus (ARC) of the hypothalamus, is implicated in having a dual role in both reproductive and metabolic functions. Using KNDy neuron-specific Kiss1 KO mice (Pdyn-Cre/Kissfl/fl or KO), we explored the role of Kiss1 from KNDy neurons in peripheral metabolism without dietary intervention. Here, we report that KO females have significantly greater body weight, fat mass, and glucose intolerance vs. control females. Interestingly, these parameters did not differ between KO male mice and controls. To determine whether this phenotype was due to dysregulated feeding behavior (i.e., hyperphagia) in KO mice, we tracked daily food consumption in adult mice for 3 weeks. We found no significant differences in food intake between genotypes of either sex. We used the Comprehensive Laboratory Animal Monitoring System (CLAMS, Columbus Instruments) to analyze energy expenditure in our mouse model. Data from the CLAMS experiments revealed reduced energy expenditure in KO females vs. control females, whereas there was no difference in energy expenditure between KO males and control males. Specifically, the respiratory exchange ratio (RER) was not significantly different in KO females vs. control females, indicating that both groups utilize both carbohydrates and fats as their primary energy source. However, heat expenditure was significantly lower in KO females (20.27 ± 2.29 kcal/kg/hr vs. 14.02 ± 1.18 kcal/kg/hr, WT vs. KO, p < 0.0001, 2-way ANOVA, n = 6-7) during the active dark phase, suggesting a decreased energy expenditure. This data suggests that the obesity and impaired glucose tolerance in females lacking Kiss1 from KNDy neurons is likely due to lower energy expenditure (with the expended energy derived from both carbohydrates and fats), rather than hyperphagic behavior. Presentation: Friday, June 16, 2023