FGF9 Inhibits Obesity And Insulin Resistance Induced By A High-fat Diet

Research ObjectivesObesity is a chronic inflammatory disease caused by a chronic imbalance between caloric intake and energy expenditure,which can lead to metabolic dysfunction and insulin resistance.It is closely associated with a variety of diseases,such as nonalcoholic fatty liver disease,hypertension and type 2 diabetes,etc.Studies have shown that many members of the fibroblast growth factor family play an important role in metabolic functions.As a member of the FGF family,FGF9 regulates the development and function of stem cells in a variety of tissues,but whether it affects the body’s metabolism is unknown.We found that the levels of FGF9 in subcutaneous fat was up-regulated under high-fat diet（HFD）conditions,but not in visceral fat.Thus,the purpose of this study is to explore the effect of FGF9 on obesity and insulin resistance caused by HFD,and to provide new strategies for the clinical treatment of obesity and related diseases.Methods and ResultsIn order to explore the effect of FGF9 on fat,we examined the metabolic phenotypes of fat-specific FGF9 overexpressed mice(Ad-FGF9^tgmice)under chow diet.The result showed that the body weight of Ad-FGF9^tgmice decreased because of the reduction of Fat Mass,while the weight loss of Lean Mass was not significantly changed by MRI analysis.In addition,Ad-FGF9^tg mice can increased glucose tolerance and insulin sensitivity.Next,H&E staining result found that cells volume in both subcutaneous adipose tissue and epididymal adipose tissue decreased significantly in Ad-FGF9^tgmice,and Perilipin staining found there are many small lipid droplets in adipocytes of Ad-FGF9^tgmice.It showed that Ad-FGF9^tgmice had stronger lipid metabolism in adipocytes than control.To investigate whether FGF9 promotes adipocyte regeneration,we first isolated subcutaneous fat and epididymal fat tissue,and compared cell numbers by detecting DNA content of two adipose tissues.The results confirmed that the DNA content of two adipose tissues in Ad-FGF9^tgmice was significantly higher than that of control mice,which proved that FGF9 could promote the regeneration of adipose tissue cells indirectly.Subsequently,Brd U was used to label newborn fat cells,and immunofluorescence assay and flow cytometry were used to verify that the newborn adipocytes in Ad-FGF9^tgmice were partly differentiated from the newly generated preadipocytes.In order to investigate whether FGF9 can resist obesity and improve insulin sensitivity,Ad-FGF9^tgmice and control mice were fed on a high-fat diet for three months and sacrificed to analyze their metabolic phenotypes.The results showed that Ad-FGF9^tgmice had a lower weight,fat content and significantly higher insulin sensitivity than control.In addition,we found that the volume of white adipocytes in Ad-FGF9^tgmice decreased significantly.Compared with Ad-FGF9^tg mice,the control mice had more severe fibrosis and inflammation in epididymal adipose tissue induced by HFD,suggesting FGF9 can improve the inflammatory response of epididymal white adipose tissue induced by HFD,thus improving insulin resistance induced by obesity.In general,we conclude that FGF9 can promote the regeneration of adipocytes in two white adipose tissues,reduce the inflammation in epididymal adipose tissue induced by high-fat diet,and thus improve the insulin sensitivity.However,future research is needed to clarify the role of FGF9 in metabolic mechanism,then to evaluate theoretical support for the treatment of obesity diseases.