YAP Methylation Promotes Obesity Via Regulating Fatty Acid Synthesis And Oxidation

Research BackgroundObesity is a chronic disease characterized by excess body fat.There is a significant increase in the prevalence of obesity worldwide.At the same time,obesity will increase the risk of coronary heart disease,stroke,hypertension and diabetes,seriously affecting human health and quality of life.Therefore,the indepth study of the pathogenesis of obesity will contribute to the treatment and prevention of obesity.Hippo-YAP/TAZ signaling pathway is a classical tumor suppressive signaling pathway in response to mechanical forces.Hippo-YAP/TAZ signaling pathway activity is not only regulated by glucose,growth factors and other metabolic pathways such as fatty acids.At the same time,Hippo-YAP/TAZ can also directly or indirectly regulate the metabolic homeostasis of the body,affecting obesity,tumor and other major diseases.At present,it has been reported that obesity affects the YAP protein level by affecting the activities of SIRT1 and AMPK,and promotes the development of gastrointestinal tumors.In addition,YAP/TAZ can antagonize the apoptosis of white adipocytes and promote obesity by regulating the JNK signaling pathway.Although YAP transgenic mice showed obvious obesity phenotype,further studies on the molecular mechanism showed that YAP did not promote adipose stem cells to differentiate into adipose tissue,instead,it may activate PPAR activity,an important transcription factor of adipose stem cells,by down-regulating TAZ.However,the functional regulation of Hippo-YAP/TAZ signaling pathway in the formation of obesity is still not very clear.Fatty acids are an important component of adipose tissue,and it is not clear whether Hippo-YAP signaling pathway regulates the occurrence of obesity by affecting the fatty acid synthesis pathway.Our group previously reported that methylation promoted YAP nuclear localization,and transgenic mice with YAP methylation mimics mutants showed enhanced tumorigenic phenotypes.Further studies on transgenic mice with YAP methylation showed that YAP methylation led to obesity in mice by promoting fatty acid synthesis and inhibiting fatty acid oxidation,inhibiting glucose and growth factor tolerance.These studies suggest that YAP methylation may be a potential marker for the clinical diagnosis of obese patients,which has important clinical guiding significance.Purpose of ResearchTo explore the mechanism of YAP methylation regulating fatty acid synthesis and oxidation promoting obesity and its clinical significance.Research MethodThe relationship between YAP methylation and obesity phenotype was demonstrated using Yap K327M(monomethylated modification of lysine in YAP 327 site)transgenic mice.The effect of YAP methylation on the expression levels of key genes during fatty acid synthesis and oxidation was analyzed by qRT-PCR.In vivo glucose and growth factor tolerance test was used to analyze the effects of YapK327M transgenic obese mice on glucose and growth factor tolerance.The levels of YAP methylation in adipose tissue of obese patients were analyzed by immunohistochemistry.Research ResultsYAP methylation promotes obesity via regulating fatty acid synthesis and oxidation,inhibiting glucose and growth factor tolerance.YAP methylation is increased in adipose tissue in obese patientsConclusionYAP methylation induced decreased tolerance to glucose and growth factors in mice,which was consistent with the phenotype of clinical obese patients,suggesting that YAP methylation may be a potential marker for the clinical diagnosis of obese patients,which has important clinical guiding significance.