Dietary Availability Acutely Governs Puberty Onset via Hypothalamic Neural Circuit

Summary Reproduction poses a substantial burden, especially for mammalian females. Puberty onset serves as a vital checkpoint, regulated based on the body’s energy state, to prevent inappropriate reproductive activity under malnutrition. However, the neural basis of this puberty checkpoint remains poorly understood. Here, we demonstrate that peripubertal malnutrition in female mice reduces the synchronous activity episodes of arcuate kisspeptin neurons (SEs kiss ), which are critical regulators of the gonadotropin axis. Improved dietary availability boosts SEs kiss frequency, facilitating puberty onset. Using a viral-genetic approach, we show that the activating agouti-related protein neurons in the arcuate nucleus (ARC Agrp neurons), a hunger center, suppresses SEs kiss , even with enough food. Conversely, loss-of-function of ARC Agrp neurons enhances SEs kiss during malnutrition, partly promoting irregular sexual maturation. Collectively, a neural circuit connecting feeding to reproductive centers is responsible for disinhibiting SEs kiss frequency based on dietary availability, which sheds light on the neural basis of puberty checkpoint. Highlights The pulsatile activity of arcuate kisspeptin neurons emerges and grows before vaginal opening. Pubertal impairment resulting from malnutrition is associated with a reduction in the pulsatile activity of kisspeptin neurons. Pubertal recovery by food availability follows the elevated pulsatile activity of kisspeptin neurons during catch-up growth. The arcuate Agrp neurons suppress the frequency of pulsatile activity of kisspeptin neurons under negative energy balance.