Regulatory Roles Of VEGFB₁₆₇ In Adipose Tissue Development And Metabolism

Obesity is caused by excessive lipids accumulation in the body and it is associated with many diseases.There are many causes that can lead to obesity but one of the major causes is the imbalanced development of white and brown adipose tissues.Adipose tissues are classified into white adipose tissue（WAT）that is responsible for lipid storage and brown adipose tissue（BAT）that converts chemical fat to heat.VEGFB is one of the vascular endothelial growth factors（VEGFs）family members and include two isoforms,VEGFB167and VEGFB₁₈₆.Study found that deletion of VEGFB leads to increased body fat accumulation.But which isoform plays major role in controlling adipose development and energy metabolism is still not clear.This study used adipose-specific VEGFB₁₆₇67 expression mouse model(aP2-Vegfb₁₆₇^tg/+)and VEGFB universal knockout mice(Vegfb^-/-)to investigate the roles of VEGFB₁₆₇67 in adipose development and energy metabolism under VEGFB knockout background(Vegfb^-/-/aP2-Vegfb₁₆₇^tg/+).First,we used transgenic mice that specifically overexpressed VEGFB₁₆₇67 in adipose tissue to mate with VEGFB knockout mice(Vegfb^-/-)to establish VEGFB₁₆₇67 adipose tissue-specific mice(Vegfb^-/-/aP2-Vegfb₁₆₇^tg/+).Adipose tissue development analysis found that when VEGFB₁₆₇67 was specifically overexpressed in the fat of VEGFB double-deleted mice,the body fat rate and weight of male and female mice would decrease and were similar to those of wild type（WT）.H&E staining analysis found that the adipocytes showed obvious browning phenomenon,the size of WAT significantly reduced,the decrease of lipid droplets in BAT became smaller,the number of two adipocytes per unit area increased significantly,and the shape of WT adipocytes was almost the same.Gene Expression analysis found that overexpression of the male and female VEGFB₁₆₇67 genes significantly increased the expression of BAT-specific marker regulatory factors Ucp-1,Bmp-7 and Prdm16,while the expression of WAT-specific marker regulatory factor Leptin decreased significantly,and some of them were expressed close to WT,VEGFB₁₆₇67 affected the changes of these factors to regulate the development of adipose tissue,so that gWAT and BAT had a browning trend,that was,less accumulation of adipose tissue,increased energy consumption and changed the body fat rate of mice weight loss.For energy metabolism,when VEGFB₁₆₇67 was specifically overexpressed in the fat of VEGFB double-deleted mice,it would affect the expression of fatty acid transporters in the adipose tissue of male and female mice,thereby reducing the accumulation of fatty acids into white fat,and affecting the differentiation of BAT and gWAT toward browning to strengthen energy metabolism.Body temperature measurement found that the body temperature of Vegfb^-/-/aP2-Vegfb₁₆₇^tg/+male and female mice increased and was close to WT.The metabolic indexes of mice,blood triglycerides and cholesterol,glucose tolerance,for female mice Vegfb^-/-/aP2-Vegfb₁₆₇^tg/+and Vegfb^-/-no difference,but for male mice,when VEGFB₁₆₇67 was overexpressed in VEGFB-deficient mice,it could improve the effect caused by VEGFB deletion,restored it to almost no difference from WT.The results showed that under the background of VEGFB knockout,adipose tissue specifically overexpressed VEGFB167,and the expression of genes related to the development of brown adipose tissue in male and female mice was significantly enhanced,which promoted the development of adipose tissue to brown adipose tissue.At the same time,the energy metabolism of male and female mice was significantly improved,energy consumption was significantly increased,fat accumulation was significantly reduced,and body weight was significantly reduced.VEGFB₁₆₇67 was a potential anti-obesity gene.