Olivia K. Egan, Megan A. Inglis, Greg M. Anderson

The hormone leptin indirectly communicates metabolic information to brain neurons that control reproduction, using GABAergic circuitry. Agouti-related peptide (AgRP) neurons in the arcuate nucleus are GABAergic, express leptin receptors (LepR) and are known to influence reproduction. This study tested whether leptin actions on AgRP neurons are required and sufficient for puberty onset and subsequent fertility. Firstly, Agrp-Cre and Lepr-flox mice were used to target deletion of LepR to AgRP neurons. AgRP-LepR knockout female mice exhibited mild obesity and adiposity as previously described, as well as a significant delay in the pubertal onset of estrous cycles compared to control animals. No significant differences in male puberty onset or adult fecundity in either sex were observed. Next, mice with a floxed polyadenylation signal causing premature transcriptional termination of the Lepr gene were crossed with AgRP-Cre mice to generate mice with AgRP neuron-specific rescue of LepR. Lepr-null control males and females were morbidly obese, and exhibited delayed puberty onset, no evidence of estrous cycles and minimal fecundity. Remarkably, AgRP-LepR rescue partially or fully restored all of these reproductive attributes to levels similar to those of Lepr-intact controls despite minimal rescue of metabolic function. These results indicate that leptin signalling in AgRP neurons is sufficient for puberty onset and normal adult fecundity in both sexes when leptin signalling is absent in all other cells, and in females absence of AgRP neuron leptin signalling delays puberty. These actions appear to be independent of leptin's metabolic effects.SIGNIFICANCE STATEMENTSexual maturation and fertility are dispensable at the individual level but critical for species survival. Conditions such as nutritional imbalance may therefore suppress puberty onset and fertility in an individual. In societies characterised by widespread obesity, the sensitivity of reproduction to metabolic imbalance has significant public health implications. Deficient leptin signalling due to diet-induced leptin resistance is associated with infertility in humans and rodents, and treatments for human infertility show a decreased success rate with increasing body mass index. Here we show that the transmission of metabolic information to the hypothalamo-pituitary-gonadal axis is mediated by leptin receptors on AgRP neurons. These results provide conclusive new insights into the mechanisms that cause of infertility due to malnourishment.