In obese female mice, a new nanodrug called P‑G3 reduced body fat, improved ovarian health, and boosted the brain‑pituitary signals that control reproduction, leading to more regular cycles and quicker pregnancies. The work was done in mice and used advanced brain‑mapping tools, not in humans.

The dual pathology of obesity-induced infertility, which encompasses both peripheral (ovarian) and central (hypothalamic-pituitary) mechanisms, is well documented. However, existing therapeutic approaches do not target these two pathways concurrently within the context of obesity-related reproductive dysfunction. This study aims to evaluate the effectiveness of P-G3, a novel therapeutic agent that targets both local (ovarian) and systemic (hypothalamic-pituitary axis) levels, in treating obesity-related subfertility in female mice. We adopted a diet-induced obese (DIO) female mouse model to investigate the effect of P-G3. Its effectiveness was evaluated through assessments of metabolic parameters, adipose tissue morphology, estrous cyclicity, and fertility outcomes. To elucidate mechanisms, we analysed pituitary LH secretion and employed advanced neurogenetic tools. Specifically, we applied cFos-TetO lineage tracing coupled with RNA sequencing to profile activated hypothalamic neurons and in vivo multichannel electrophysiology to firstly monitor GnRH neuronal electrical activity within this context. P-G3 significantly reduced overall obesity (by 7.32 g in 8 weeks), especially in the abdominal and peri-ovarian regions, and improved metabolic issues. At the ovary, P-G3 reduced inflammation and enhanced follicular development. At the pituitary, P-G3 enhanced the responsiveness to kisspeptin-54, increasing LH pulse frequency and mean LH level by over 60 % at the proestrus stage. At the hypothalamus, transcriptomics revealed major changes in pathways for energy metabolism and GnRH signalling. Additionally, P-G3 significantly enhanced GnRH neuronal firing, with the pulse-like discharge frequency and amplitude increasing by 91 % and 70 %, respectively. Finally, P-G3 alleviated estrous cycle disorders, increasing cycle regularity by 70 % and reducing mating to birth latency by 4.5 days. P-G3 nanomedicine provides a pioneering dual-scale therapeutic strategy for treating obesity-induced infertility by concurrently alleviating local ovarian adipocyte pathologies and inflammatory and restoring systemic central reproductive axis function, i.e., hypothalamic GnRH activity and pituitary responsiveness, thus comprehensively rescuing folliculogenesis and fertility.