Interaction between Hormone-Sensitive Lipase and ChREBP in Fat Cells Controls Insulin Sensitivity

International audienceImpaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and itstarget, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results inenhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifiesplasma membrane fluidity and enhances insulin signalling. HSL deficiency–mediated effects are suppressed by gene silencingof ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoformwith high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL–ChREBPinteraction may allow therapeutic strategies for the restoration of insulin sensitivit