Caffeine Promotes Adipocyte Autophagy Through the AMPK/SIRT1 Signaling Pathway and Improves High‐Fat Diet–Induced Obesity and Leptin Resistance

Purpose: Caffeine has been widely studied for its lipid‐lowering and blood‐glucose–lowering effects. This study aimed to investigate whether caffeine can regulate adipocyte autophagy through the AMPK/SIRT1 signaling pathway, both in vivo and in vitro , thereby exerting a hypoglycemic effect. Method: Western blot analysis was conducted to assess changes in the expression levels of FASN, ACC, pACC, SIRT1, LC3II/I, and pAMPKα in 3T3‐L1 cells following caffeine treatment. The size of the lipid droplets was evaluated using Oil Red O staining. Mito Tracker Red and qRT‐PCR were employed to quantify the number of mitochondria in the cells. Six‐week‐old C57BL/6J mice were divided into three groups: control, high‐fat diet (HFD), and HFD + caffeine. After 11 weeks of feeding, insulin resistance was assessed using insulin tolerance and glucose tolerance tests. The expression levels of AMPK α , SIRT1, PPAR γ , P62, and LC3II/I in the adipose tissue of each group were measured using Western Blotting. Serum levels of triglycerides (TG), total cholesterol (TC), and leptin were determined by Elisa. Finally, hematoxylin and eosin (HE) staining was performed to observe the size of adipocytes in visceral adipose tissue. Results: Caffeine significantly inhibits the expression of proteins associated with fat synthesis and reduces lipid droplet size in 3T3‐L1 cells. In addition, caffeine robustly activates the AMPK/SIRT1 signaling pathway in 3T3‐L1 cells, promoting autophagy and enhancing mitochondrial biogenesis. In animal models, caffeine effectively attenuates weight gain and insulin resistance induced by a HFD while reducing serum TG and TC levels. Furthermore, caffeine suppresses leptin resistance and mitigates the increased food intake associated with a HFD. Notably, caffeine enhances AMPK α phosphorylation levels and SIRT1 expression in visceral fat, facilitating adipocyte autophagy and reducing lipid accumulation. At the cellular level, caffeine significantly promotes mitochondrial biogenesis . Conclusion: Caffeine enhances autophagy in adipocytes by activating the AMPK/SIRT1 signaling pathway of adipocytes, contributing to antiobesity effects and improving insulin resistance.