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Hypothalamic Kiss1 neurons control gonadotropin-releasing hormone release through the secretion of kisspeptin. Kiss1 neurons serve as a nodal center that conveys essential regulatory cues for the attainment and maintenance of reproductive function. Despite this critical role, the mechanisms that control kisspeptin synthesis and release remain largely unknown. Using Drop-Seq data from the arcuate nucleus of adult mice and in situ hybridization, we identified Nescient Helix-Loop-Helix 2 ( Nhlh2 ), a transcription factor of the basic helix-loop-helix family, to be enriched in Kiss1 neurons. JASPAR analysis revealed several binding sites for NHLH2 in the  Kiss1  and  Tac2  (neurokinin B) 5′ regulatory regions. In vitro luciferase assays evidenced a robust stimulatory action of NHLH2 on human  KISS1  and  TAC3  promoters. The recruitment of NHLH2 to the  KISS1  and  TAC3  promoters was further confirmed through chromatin immunoprecipitation. In vivo conditional ablation of  Nhlh2  from Kiss1 neurons using  Kiss1  Cre : Nhlh2  fl/fl  mice induced a male-specific delay in puberty onset, in line with a decrease in arcuate  Kiss1  expression. Females retained normal reproductive function albeit with irregular estrous cycles. Further analysis of male  Kiss1 Cre :Nhlh2 fl/fl   mice revealed higher susceptibility to metabolic challenges in the release of luteinizing hormone and impaired response to leptin. Overall, in Kiss1 neurons, Nhlh2 contributes to the metabolic regulation of kisspeptin and NKB synthesis and release, with implications for the timing of puberty onset and regulation of fertility in male mice.

Sex-specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2