NHLH2: at the intersection of obesity and fertility

•Nhlh2 interacts with bHLH, Stat3, and LIM proteins to regulate diverse gene targets.•Nhlh2 knockout mice are sexually dimorphic in reproductive and body-weight phenotypes.•Nhlh2 acts as a molecular sensor to coordinate energy balance and fertility control.

Nescient helix–loop–helix 2 (NHLH2/NSCL2) is a neuronal transcription factor originally thought to be involved in neuronal development and childhood neuroblastomas. Accumulating evidence has since identified roles for NHLH2 in adult phenotypes of obesity and fertility. We summarize these findings here and attempt to link genotype with phenotype in mouse models and humans. In particular, NHLH2 (Nhlh2 in mice) is one of only two genes that are genetically linked to physical activity levels. Nhlh2 also controls obesity and fertility, with strong sexual dimorphism for both phenotypes in Nhlh2 mutant animals. We propose that Nhlh2 might function as a molecular sensor in different adult hypothalamic neurons to regulate energy balance, leading to normal body weight and reproduction.