AMPK Activation By Metformin Suppresses Abnormal Adipose Tissue Extracellular Matrix Remodeling And Ameliorates Insulin Resistance In Obesity

Objectives: To study the mechanisms of adipose tissue fibrosis and whether if Metformin inhibits adipose tissue fibrosis which is related to insulin resistance.Methods:(1) Collect omental adipose tissue from obese and non-obese subjects to confirm the correlationship between obesity and adipose tissue fibrosis and look for the possible mechanisms;(2)Metformin was given to ob/ob mice and HFHS-diet induced obese mice, observe whether metformin could inhibit adipose tissue fibrosis in obesity and find the mechanisms underlying;(3) SVF cells in epididymal adipose tissue were isolated, treated with TGF-β1 that induced fibrogenesis and AMPK activators in the same time to determine whether metformin inhibits adipose tissue fibrosis through AMPK activation;(4) 3T3-L1 cells were differentiated into mature adipocytes to explore the relationship between adipose tissue fibrosis inhibited by metformin and insulin resistance reversed by metformin.Results:(1) Adipose tissue interstitial fibrosis was observed in obese subjects, and the expressions of TGF-β1, α-SMA and TIMP-1 were upregulated, AMPK phosphorylation in adipose tissue was inhibited in the same time;(2) Metformin not only decreased mouse body weight and reversed systemic insulin resistance, but also inhibited adipose tissue fibrosis significantly;(3)Metformin improved AMPK activity and inhibited TGF-β1 signaling pathway in adipose tissue of obese mice;(4) Chemical activators of AMPK, such as Metformin and AICAR, decreased the abnormal upregulation of fibrogenesis and ECM degradation-related proteins induced by TGF-β1;(5)Ad-CA-AMPK was transduced into SVF cells that upregulated AMPK activity, which inhibited TGF-β1-induced fibrosis;(6) With the transduction of Ad-DN-AMPK into SVF cells thatdownregulated AMPK activiry, metformin and AICAR were not able to inhibite TGF-β1-induced fibrosis;(7) In 3T3-L1 adipocytes, metformin and AICAR could inhibit TGF-β1-induced fibrosis and insulin resistance in the same time.Conclusions: Metformin could inhibit adipose tissue fibrosis in obesity, at least partially through AMPK activation, which is related to the improvement of insulin resistance.