Polycystic ovary syndrome (PCOS) is the predominant cause of subfertility in reproductive-aged women; however, its pathophysiology remains unknown. Neurotensin (NTS) is a member of the gut-brain peptide family and is involved in ovulation; its relationship with PCOS is unclear. Here, we found that NTS expression in ovarian granulosa cells and follicular fluids was markedly decreased in patients with PCOS. In the in vitro culture of cumulus-oocyte complexes, the neurotensin receptor 1 (NTSR1) antagonist SR48692 blocked cumulus expansion and oocyte meiotic maturation by inhibiting metabolic cooperation and damaging the mitochondrial structure in oocytes and surrounding cumulus cells. Furthermore, the ERK1/2-early growth response 1 pathway was found to be a key downstream mediator of NTS/NTSR1 in the ovulatory process. Animal studies showed that in vivo injection of SR48692 in mice reduced ovulation efficiency and contributed to irregular estrus cycles and polycystic ovary morphology. By contrast, NTS partially ameliorated the ovarian abnormalities in mice with dehydroepiandrosterone-induced PCOS. Our findings highlighted the critical role of NTS reduction and consequent abnormal NTSR1 signaling in the ovulatory dysfunction of PCOS, suggesting a potential strategy for PCOS treatment.
Polycystic Ovary Syndrome/physiopathology* ; Female ; Animals ; Neurotensin/metabolism* ; Receptors, Neurotensin/antagonists & inhibitors* ; Mice ; Ovulation/drug effects* ; Humans ; Granulosa Cells/metabolism* ; Adult ; Oocytes/metabolism* ; MAP Kinase Signaling System ; Signal Transduction ; Follicular Fluid/metabolism* ; Disease Models, Animal ; Gonadotropin-Releasing Hormone/analogs & derivatives*

A complex set of brain based systems modulate feeding to maintain constant body weight. The adipose derived-hormone, leptin, plays a crucial role in this control by acting on diverse leptin receptor (LepRb)-expressing neurons in the hypothalamus and brainstem to modify behavior and metabolism. In addition to controlling energy expenditure and satiety, leptin controls motivation and the reward value of food by regulating two interconnected systems: hypocretin (HCRT) neurons and the mesolimbic dopamine (MLDA) system. Modest/acute decreases in leptin levels, as associated with mild caloric restriction, increase MLDA activity and overall food-seeking behavior; in contrast, severe starvation or complete leptin deficiency blunt MLDA activity, along with motivation and associated behaviors. Lateral hypothalamic (LHA) LepRb neurons project to dopamine (DA) neurons in the ventral tegmental area, where neurotensin (NT) release augments MLDA function; these LepRb(NT) cells also innervate HCRT neurons to control Hcrt expression and inhibit HCRT neurons. Ablation of LepRb in these cells abrogates the control of HCRT cells by leptin and decreases activity and MLDA function. We propose that this neural pathway regulates the MLDA, activity, and motivation in response to leptin and nutritional status.
Body Weight ; Brain ; Brain Stem ; Caloric Restriction ; Dopamine ; Energy Metabolism ; Hypothalamus ; Leptin ; Metabolism ; Motivation ; Neural Pathways ; Neurons ; Neurotensin ; Nutritional Status ; Obesity ; Orexins ; Receptors, Leptin ; Reward ; Starvation ; Ventral Tegmental Area

Neurotensin receptor-1 (NTR1), which can stimulate the intracellular cascade signal pathway, belongs to the large superfamily of G-protein coupled receptors. NTR1 is related to the occurrence and development of several kinds of diseases. In order to screen the inhibitors for the cancers associated with NTR1 protein, we established a CHO (Chinese hamster ovary) cell line in which human neurotensin receptor-1 was highly expressed. The method is to construct the recombinant plasmid which was lysed with the hNTR1 gene and transfect it into CHO cells. After selected with G418, the cell line was evaluated by Western blotting analysis and calcium flux assays. Through the calcium flux assays on FlexStation 3, we got the EC50 value of neurotensin peptide which is the natural NTR1 agonist, and the IC 50 value of SR48692 which is the known NTR1 antagonist. The established human CHO/NTR1 cell line can be used to study the profile of NTR1 biological activity and further screen of NTR1 antagonists and agonists.
Animals ; CHO Cells ; Calcium Signaling ; Cricetinae ; Cricetulus ; Humans ; Pyrazoles ; pharmacology ; Quinolines ; pharmacology ; Receptors, Neurotensin ; antagonists & inhibitors ; genetics ; metabolism ; Transfection

Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Heat Stress Disorders ; drug therapy ; metabolism ; Hypothalamus ; metabolism ; Male ; Neurotensin ; metabolism ; Phytotherapy ; Rats ; Rats, Wistar ; Tablets