Biological Function And Mechanism Of Gpr54 On Lipid Metabolism

Obesity, caused by excessive accumulation of fat is a chronic disease that most likely to be ignored. WHO states that it is a metabolic disorder with sharp rising morbidity at present. Disorder of lipid metabolism is a direct result of obesity, and the most important tissues and organs involved are liver and adipose. Various anti-obesity small molecule compounds are investigated and developed for target therapy in global market, and G-protein-coupled receptor, as star drug target, has drawn a lot of attentions. This study aims to explore the function of Gpr54 (=Kiss1 receptor, Kiss1r), the member of rhodopsin family, on lipid metabolism and obesity. It was found that Gpr54 could accelerate the development of obesity by promoting adipocyte differentiation independent of hormone.The phenotype on the body weight of mice was first explored in castrated Gpr54 KO mice and it was found that the weight increase of KO mice fed by high-fat diet was slower than WT littermates.Then the specific effects of Gpr54 were observed from the change of adipose tissue and liver tissue respectively. It was found in adipose that the tissue coefficient was lower, adipocyte was smaller and inflammation caused by obesity was not as drastic as WT mice. On the other hand, It was found that triglyceride after high-fat diet inducing in liver of KO mice was reduced, which led to decreased level of liver fat. In addition, oil drop formation was accelerated in liver when LO2 were stimulated by Kp-10,the ligand of Gpr54. It suggested that Gpr54 plays a role in lipid metabolism in adipose tissue and liver.Further, we explored the mechanism of Gpr54’s regulation effect on adipose. On cell level we verified that Gpr54 could affect the development of obesity by promoting the differentiation of adipocyte and accumulation of triglyceride. The study on mesenchymal stem cell showed that primary cell of KO mice was less likely to differentiate into adipocyte. Meanwhile, Kp-10 was found to promote adipocyte differentiation and triglyceride synthesis in 3T3-L1 adipocyte differentiation system. To further explore the function and mechanism of Gpr54, genes related to lipid metabolism was screened, and it was found that PPARy, ACC1, ADIPO and FAS, which participate in lipid synthesis, had changed significantly, especially PPARy,which also participates in adipocyte differentiation. Therefore, a follow-up study was carried out by Western Blotting which found that phosphorylation of ERK and p-38 decreased significantly in Gpr54 KO mice. It suggested that Gpr54 promotes lipid synthesis and development of obesity by activating MAPK signaling pathway.In conclusion, Gpr54 directly promotes fat accumulation and adipocyte differentiation, and regulates energy metabolism in the obesity development. This study not only provide basis for further investigation of physiological function of Gpr54 on metabolism, but also provide new ideas to explore the drug target of obesity.