High-Fat-Diet-Induced Extracellular Matrix Deposition Regulates Integrin-FAK Signals in Adipose Tissue to Promote Obesity

Scope High-fat-diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown. Methods and Results This study uses three models-HFD-fed mice, human with obesity, and 3T3-L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin alpha 2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) - focal adhesion kinase (FAK) - c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM - integrin - FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p-JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins - FAK - JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p-JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect. Conclusion HFD-induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK - JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.

Automated summary

This study discovers that high-fat-diet-induced extracellular matrix (ECM) deposition promotes adipogenesis by transmitting signals to adipocytes. Glucose and lipid metabolic disorders and upregulation of ECM-related signaling pathways are observed in obese mice and humans. Furthermore, the study finds that these signaling pathways are stronger in subcutaneous adipose tissue than in visceral adipose tissue in mice, but the opposite is observed in humans.