Neurokinin 3 receptor antagonist-induced adipocyte activation improves obesity and metabolism in PCOS-like mice

Neurokinin-B (NKB)-Neurokinin-3-receptor (NK3R) pathway is remarkably sensitive to energy equilibrium; however, its role in metabolic regulation remains unexplored in polycystic ovary syndrome (PCOS). Therefore, this work aimed to investigate the role of NK3R antagonists (NK3Ra) on metabolic dysfunction and obesity in in vitro and in vivo PCOS models. First, an observational study using serum samples collected from 19 PCOS patients was performed. Second, prospective case-control experimental studies where NK3Ra (SB222200) was used to treat PCOS-like mice (BALB/c mice), ovariectomized+estrogen implanted obese mice (C57BL/6J mice) and 3T3-L1 murine preadipocytes were carried out to investigate its effect on metabolism in vivo and in vitro. The fat volumes, serum biochemical indexes, adipokines and inflammatory cytokines, metabolism-related gene expression and the concentrations of ATP, NAD+, NADPH…etc. were studied. We found a positive correlation between serum NKB and lipid metabolism indicators in PCOS women. Using the mouse models, we demonstrated that administration of NK3Ra regulates serum adipokines, inhibits weight gain with a marked decrease in fat volume, adipocyte size, and inflammatory cytokines, and promotes oxidative metabolism and energy consumption. NK3Ra reduces lipid accumulation in mature murine adipocytes by inhibiting the expression of peroxisome proliferator- activated receptor gamma (PPAR-γ) and fatty acid binding protein 4 (FABP4) genes. NK3Ras also enhances oxidative metabolism and energy consumption by maintaining intracellular redox homeostasis. This study backs the use of NK3Ras as a potential therapeutic for PCOS since it ameliorates both reproductive and metabolic aberrations.