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

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. 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. 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. separates cerebrospinal fluid in the central nervous system from circulating blood, prevents the harmful substance to invade brain, and maintains the normal function of the nervous system. It is formed by microvascular endothelial cells, astrocyte end-feet, and pericytes. is a condition in which energy intake exceeds energy expenditure. The high-energy diets include high-fat, high-sucrose, and high-calorie diet. is a plant compound with antioxidant, anti-inflammatory, and antiallergenic properties. is an area located in the central lower part of the brain, adjacent to the third ventricle. It consists of interconnecting neurons controlling caloric intake, energy expenditure, and reproduction. Thus, it is the center of controlling energy homeostasis and reproductive function. is a complete and coordinated neuroendocrine system controlling female reproduction. The HPO axis includes hypothalamic gonadotropin-releasing hormone neurons, pituitary gland, ovaries, and their secreting hormones. is a master switch of innate immunity and inflammation. IKKβ is a kinase that inhibits nuclear factor kappa B and can be activated by inflammatory factors and growth factors. NF-κB is a protein compound. Phosphorylated IKKβ leads to NF-κB activated from an inhibited state, which controls the expression of immune and inflammatory genes. Moreover, IKKβ/NF-κB mediates overnutrition and the dysfunctions of hypothalamic signaling, leading to obesity. is the reproductive cycle of primates and humans. a condition in which the ovary is unable to ovulate during the estrous cycle, mostly due to dysfunction of the hypothalamus or pituitary. as a site in the hypothalamus, is the leak part of the BBB, which is located in the supraoptic recess of the third ventricle wall place. It is highly permeable to macromolecular substances. Harmful molecules in the circulation can enter the brain from OVLT.