Hypothalamic mechanisms of obesity-associated disturbance of hypothalamic–pituitary–ovarian axis

Ovulatory disorders are the most common clinical feature exhibited among obese women. Initiation of ovulation physiologically requires a surge of gonadotropin-releasing hormone (GnRH) released from GnRH neurons located in the hypothalamus. These GnRH neurons receive metabolic signals from circulation and vicinal neurons to regulate GnRH release. Leptin acts indirectly on GnRH via adjacent leptin receptor (LEPR)-expressing neurons such as proopiomelanocortin (POMC), neuropeptide Y (NPY)/agouti-related peptide (AgRP), and neuronal nitric oxide (NO) synthase (nNOS) neurons to affect GnRH neuronal activities. Additionally, hypothalamic inflammation also affects ovulation independent of obesity. Therefore, this review focuses on hypothalamic mechanisms that underlie the disturbance of hypothalamic–pituitary–ovarian (HPO) axis during obesity with an attempt to promote future studies and/or novel therapeutic strategies for ovulatory disorders in obesity. Obese female mice models demonstrate that obesity-causing ovulatory disorders are mainly for neuroendocrine dysfunction of hypothalamic–pituitary–ovarian (HPO) axis. Hypothalamus is the center of energy homeostasis and reproduction. The proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) and agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons in arcuate nucleus (ARC) regulating energy metabolism interplay with gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus.Kisspeptin neurons act as a mediator between energy metabolism and the reproductive system. Leptin acts on kisspeptin neurons indirectly through POMC/CART and AgRP/NPY neurons to affect energy metabolism and GnRH release.The nitric oxide (NO) signaling pathway is involved in reproduction and energy balance. The kisspeptin–receptor of kisspeptin (Kiss1r) pathway activated by estradiol stimulates the phosphorylation of neuronal NO synthase (nNOS) protein and switches surge-mode release of GnRH and promotes ovulation.Leptin resistance in hypothalamus caused by diet-induced obesity (DIO) hampers the treatment of obesity with leptin. Hypothalamic inflammation induced by high-fat diet (HFD) is regarded as a potential pathophysiological mechanism of obesity and dysfunction of the HPO axis.