VEGFA And VEGFB Play Balancing Roles In Adipose Differentiation,Gene Expression And Function

Obesity affects millions of people regardless ages and genders.Excessive fat accumulation is often associated with various health problems including insulin-resistant type II diabetes,cardiovascular disease,non-alcoholic fatty liver,gallbladder disease and cancer.Lipid metabolism happens actively in adipose tissues that are classified as white adipose tissues(WAT)and Brown adipose tissues(BAT).WAT is a major tissue for energy storage in the form of triglycerides and tissue for hormonal secretion such as Leptin and growth factors like VEGFA.BAT,however,is a tissue that generates heat by consuming chemical energy.New evidence suggests that BAT plays important roles in human adults in controlling body temperature as well as body weight.Another type of adipose is discovered recently that is brown-like in morphology and induced in WAT in response to various conditions.In this report,inducible VEGFA repression and VEGFB deletion mouse models were used to study adipose differentiation and function.VEGFA is down regulated using tetracycline regulated gene expression system.In this study,CRISPR-Cas9 system was used to inactivate VEGFB gene,a 22 bp,a 477 bp and a 3bp segments in the coding region were removed.Deletion also created a frame-shift in coding region and could lead to complete loss of VEGFB function as well.We have demonstrated VEGFB knockout causes whitening of brown adipose,further expansion of white adipose,reduced energy consumption,increased expression of white adipose associated genes and decrease of brown adipose-associated genes.VEGFA repression,in contrary,induces development of brown adipocytes in white adipose,deep browning of brown adipose,increase of energy expenditure and upregulation of brown adipose-associated genes while white-adipose associated genes decrease.When two models are crossed together,VEGFA can efficiently reverse the roles of VEGFB on adipose tissues.These balancing roles are demonstrated by morphologic,functional changes along with altered gene expression.Adipose structures and functions are controlled by VEGFA and VEGFB through a large numbers of genes including growth factors,transcription factors,adhesion molecules and metabolic enzymes.Our results suggest that knockout of VEGFB caused functional abnormality including increased TG(Triacylglycerol),lower metabolic activity,glucose intolerance and low insulin sensitivity.By crossing VEGFA repressed mice,these can be significant reversed.Adipose structures and functions are controlled by VEGFA and VEGFB through a large numbers of genes including growth factors,transcription factors,adhesion molecules and metabolic enzymes.Understanding these regulatory network may help to identify new drug targets for prevention and treatment of obesity and diabetes.