Saligenin restores insulin responsiveness in lipotoxic myotubes through L-cell-derived GLP-1 via ER stress-autophagy modulation

Saligenin, also known as 2-hydroxybenzyl alcohol (2-HA), has been reported to have anti-inflammatory and antioxidative effects; however, its role in GLP-1 secretion and ER stress regulation remains unclear. In this study, palmitate-induced lipid stress was induced in GLUTag intestinal L-cells, followed by 2-HA treatment. GLP-1 secretion was measured by ELISA, ER stress and Autophagy markers were analyzed by Western blotting, and autophagosome formation was assessed using MDC staining. Conditioned media from treated GLUTag cells were applied to palmitate-induced insulin-resistant C2C12 myotubes to evaluate Insulin signaling. 2-HA increased GLP-1 secretion in lipid-stressed GLUTag cells. This effect was associated with the activation of PPARα, the induction of Autophagy, and the suppression of ER stress, as indicated by reduced eIF2α phosphorylation and CHOP expression. 2-HA also attenuated palmitate-induced Apoptosis. Silencing of PPARα or inhibition of Autophagy abolished these effects. Furthermore, conditioned media from 2-HA-treated GLUTag cells restored IRS-1 and Akt phosphorylation and enhanced glucose uptake in C2C12 myotubes. These improvements were negated by GLP-1 Receptor knockdown, confirming a GLP-1-dependent mechanism. In summary, 2-HA activates the PPARα-autophagy axis to alleviate ER stress and restore GLP-1 secretion in lipotoxic L-cells, thereby supporting GLP-1-associated insulin-responsive signaling in skeletal muscle cells under lipotoxic conditions.