ESPE Yearbook of Paediatric Endocrinology

Elife. 2021 Sep 8;10:e69765. doi: 10.7554/eLife.69765. PMID: 34494548. https://elifesciences.org/articles/69765

Brief Summary: Using a database for arcuate nucleus transcripts, this study identifies Nhlhl2 as a key regulator of the Kiss1 gene in male mice.

The timing of puberty onset is influenced by the metabolic state. The population of kisspeptin neurons in the arcuate nucleus (ARC) plays a key role in the transmission of metabolic signals, such as leptin or insulin, to GnRH neurons [1]. Many potential binding sites for transcriptional factors (TFs) have been described in the Kiss1 promotor [2], but their role in the transmission of metabolic information has not been investigated.

These authors used a previously described database of ARC transcripts [3] and identified that Nhlh2, a transcriptional factor, is highly enriched in ARC kisspeptin neurons. Based on bioinformatic tools and in vitro assays, it appeared that Kiss1 and TAC3 (coding for Neurokinin b) genes possess a binding site for Nhlh2 and can be activated by this TF. To determine whether Nhlhl2 has a physiological role in kisspeptin neurons, the authors generated a Kiss1-specific Nhlh2 knock-out (KO) mouse. Interestingly, KO males presented a more severe phenotype than KO females: their puberty was delayed and their LH response to fasting and leptin was impaired. Nhlh2 had previously been identified as affecting GnRH network development with a sexual dimorphism: Whole-body Nhlh2 KO male mice are infertile while whole-body Nhlh2 KO female mice are hypogonadal with irregular cycles but still fertile [4].

Overall, this study sheds lights on regulatory mechanisms at the level of Kiss1 promotor, especially in response to nutritional status, and highlights once again the importance to study both sexes.

References: 1. Navarro VM. (2020) “Metabolic regulation of kisspeptin - the link between energy balance and reproduction.” Nat Rev Endocrinol.; 16(8):407–420. 2. Goto T, Tomikawa J, Ikegami K, Minabe S, Abe H, Fukanuma T, Imamura T, Takase K, Sanbo M, Tomita K, Hirabayashi M, Maeda K, Tsukamura H, Uenoyama Y. (2015) “Identification of hypothalamic arcuate nucleus-specific enhancer region of Kiss1 gene in mice.” Mol Endocrinol; 29:121–129. 3. Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A, Tenen D, Goldman M, Verstegen AM, ReschJM, McCarroll SA, Rosen ED, Lowell BB, Tsai LT. (2017) “A molecular census of arcuate hypothalamus and median eminence cell types.” Nat Neurosci; 20:484–496. 4. Cogliati T, Delgado-Romero P, Norwitz ER, Guduric-Fuchs J, Kaiser UB, Wray S, Kirsch IR. (2007) “Pubertal impairment in Nhlh2 null mice is associated with hypothalamic and pituitary deficiencies.” Mol Endocrinol; 21:3013–3027.