Sex-specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2.
Leon. Silvia S; Talbi. Rajae R; McCarthy. Elizabeth A EA; Ferrari. Kaitlin K; Fergani. Chrysanthi C; Naule. Lydie L; Choi. Ji Hae JH; Carroll. Rona S RS; Kaiser. Ursula B UB; Aylwin. Carlos F CF; Lomniczi. Alejandro A; Navarro. Víctor M VM
Key Findings
- NHLH2 is highly expressed in Kiss1 neurons and directly stimulates the KISS1 and TAC3 gene promoters.
- Male mice lacking NHLH2 in Kiss1 neurons show delayed puberty and reduced Kiss1 expression.
- These male mice also have impaired luteinizing hormone release and weaker responses to leptin, indicating a metabolic link.
Practical Outcomes
- The study suggests that metabolic health (e.g., leptin levels) can influence kisspeptin signaling, which may affect puberty timing and fertility, especially in males. For biohackers, it highlights the importance of supporting metabolic balance when experimenting with kisspeptin-related interventions, but it does not provide specific dosing or protocol guidance.
Summary
Researchers found that a protein called NHLH2 helps turn on the kisspeptin gene in brain cells that control puberty and fertility. Removing NHLH2 from these cells in male mice delayed puberty and made them more sensitive to metabolic stress, while females were less affected. This shows that kisspeptin production is linked to both reproductive timing and metabolic signals like leptin.
Abstract
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 (<i>Nhlh2</i>), 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 <i>Kiss1</i> and <i>Tac2</i> (neurokinin B) 5' regulatory regions. In vitro luciferase assays evidenced a robust stimulatory action of NHLH2 on human <i>KISS1</i> and <i>TAC3</i> promoters. The recruitment of NHLH2 to the <i>KISS1</i> and <i>TAC3</i> promoters was further confirmed through chromatin immunoprecipitation. In vivo conditional ablation of <i>Nhlh2</i> from Kiss1 neurons using <i>Kiss1</i><sup>Cre</sup>:<i>Nhlh2</i><sup>fl/fl</sup> mice induced a male-specific delay in puberty onset, in line with a decrease in arcuate <i>Kiss1</i> expression. Females retained normal reproductive function albeit with irregular estrous cycles. Further analysis of male <i>Kiss1<sup>Cre</sup>:Nhlh2<sup>fl/fl</sup></i> 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.
Study Information
pubmed
2021
2021-09-08T00:00:00.000Z
10.7554/elife.69765