12502 Bdnf Production by Kiss1 Neurons Acts in a Sexually Dependent Way to Control Sexual Development and Energy Balance in Female and Male Mice

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Abstract Disclosure: A.M. Zanesco: None. D. Cabral: None. J. Ferreira: None. F. Valdivieso-Rivera: None. A.L. Carvalho: None. N. Mendes: None. C. Sponton: None. R. Frazao: None. L.A. Velloso: None. The hypothalamus is a key region in the central nervous system that controls different functions such as energy balance, thermogenesis, and reproduction. Kiss1 neurons integrate two distinct neuronal pathways, reproduction, and energy balance, both essential to species survival and maintenance. Recent studies, identify that the Brain-derived neurotrophic factor, BDNF produced by neurons and astrocytes in the hypothalamus is essential to control homeostatic and hedonic feeding by acting in specific groups of hypothalamic neurons. No studies showed the action of BDNF produced in the arcuate nucleus (ARC) of the hypothalamus. Using single-cell RNA sequencing analysis of data obtained from mice hypothalamus reveals that Kiss1 neurons express BDNF and we confirmed this result by immunofluorescence assay. Curiously, there is more expression of BDNF in the female hypothalamus compared with the male hypothalamus. But, when we selected specifically the BDNF produced by KISS1 neurons, this difference disappears. Based on that, we used a Cre-loxP approach to selectively knockout BDNF in Kiss1 neurons and identify the changes in sexual development and energy balance in female and male mice. All experiments were approved by the Animal Use Ethics Committee of UNICAMP (CEUA: 5591-1/2020 and CIBio 04/2021). All female and male mice were evaluated daily to identify their sexual development. We identified no changes in metabolic parameters, such as body weight and adiposity in male and female mice fed on a chow diet. Additionally, BDNF ablation in Kiss1 neurons (BDNF-KO) leaded to a premature vaginal opening, a decreased in uterus and ovary weight, and compromises the regular cyclicity of the estrus cycle in females. No difference was found in the sexual development of male mice, indicating that this effect is sexually dependent. Based on the fact that BDNF produced in VMH and DMH acts as anorexigenic effects, and Kiss1 neurons integrate the neuronal pathway responsible for energy balance, we decided to investigate the effects of BDNF ablation in Kiss1 neurons in female and male mice fed on high-fat diet. Interestingly, male mice without BDNF production in Kiss neurons were protected from obesity development compared with wild-type mice, both fed on a high-fat diet. When they were fed on a chow diet, male BDNF-KO mice, exhibited hyperphagia compared to control mice, showing a disruption in control of food intake and body weight maintenance. No differences were identified in body weight gain, food intake, and adiposity in BDNF-KO female mice. Based on that, we conclude that BDNF produced by Kiss1 exerts different functions in male and female mice. In females, it is more related to sexual development, and males in control of energy balance. This is the first research showing the BDNF production by Kiss1 neurons and its dimorphism effects on male and female mice. Presentation: 6/2/2024