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Description
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The hypothalamus is a region of the central nervous system composed of distinct neuronal populations that regulate fundamental physiological functions, ensuring survival and evolutionary success. Among these functions are: (i) maintenance of energy homeostasis, (ii) regulation of reproductive behavior, and (iii) control of the circadian cycle. Within the hypothalamus, the arcuate nucleus contains Kiss1 neurons, which regulate reproduction through the release of kisspeptin an essential neuropeptide that stimulates GnRH neurons. Additionally, Kiss1 neurons function as interneurons, modulating POMC/CART and AgRP/NPY neurons and thereby influencing energy balance. The maintenance of adequate energy reserves is crucial for normal development and reproductive function, which underscores the interaction between neuronal circuits that regulate energy homeostasis and those that control reproduction. Brain-derived neurotrophic factor (BDNF), a peptide produced in the cells of the central nervous system, plays a key role in neuronal plasticity and survival. Through bioinformatics analysis and RNAscope, we identified that Kiss1 neurons express BDNF. Notably, this expression is both transient and sex-dependent. To investigate the physiological role of BDNF in these neurons, we generated genetically modified mice with a specific deletion of Bdnf in Kiss1 neurons (Kiss1∆BDNF). We assessed sexual development in both sexes and found that female Kiss1∆BDNF mice exhibited precocious puberty, disrupted estrous cycles, and reduced uterine and ovarian size. In contrast, male mice showed no significant differences in sexual development compared to controls. Given the known involvement of Kiss1 neurons and BDNF in energy homeostasis, we fed these mice with a high-fat diet (HFD) for eight weeks. Interestingly, male Kiss1∆BDNF mice displayed resistance to obesity relative to control (Ctl) mice on the same diet. When maintained on a standard diet, these males exhibited increased caloric intake without corresponding weight gain. In females, however, no significant metabolic alterations were observed. In summary, our findings demonstrate that BDNF production by Kiss1 neurons is critical for proper sexual maturation in females and contributes to the regulation of energy balance in males, revealing a clear sexual dimorphism in BDNF function within these neurons. To our knowledge, this is the first evidence of BDNF production by Kiss1 neurons in the arcuate nucleus and its dual role in reproductive and metabolic regulation.
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