Rescue of obesity-induced infertility in female mice by silencing AgRP neurons

Obesity impacts multiple sites of the hypothalamus-pituitary gland-ovary axis (HPO axis) and has become a leading cause of female infertility. However, the critical hypothalamic neurons that participate in the development of obesity-induced infertility have not been well defined yet. Previous studies suggested that metabolic-sensing agouti-related peptide-expressing (AgRP) neurons in the arcuate nucleus (ARC) are hyperactive in diet-induced obesity (DIO) mice. We hypothesize that these neurons may convey metabolic dysfunction onto the HPO axis and contribute to obesity-induced infertility's pathophysiological process. To determine if AgRP neurons in obesity play a necessary role in the development of reproductive impairment in obesity, we used the chemogenetic method to normalize the neuronal activity of AgRP neurons in DIO female mice and test if their fertility can be restored. Our results indicated that chemogenetic inhibition of AgRP neurons could fully rescue the reproductive performance of DIO female mice, as manifested by recovered sex hormonal levels, ovulation, and fecundity. Moreover, we assayed serum AgRP levels in normal-weight and obese women and found elevated AgRP levels in obese subjects, suggesting the correlation between obesity and AgRP neuronal hyperactivity. Our results indicated that AgRP neurons constitute a central node connecting metabolism and reproduction, and dysfunctions of these neurons play a crucial role in reproductive impairment induced by metabolic abnormalities.