Insulin resistance is a feature frequently associated to obesity and an early defect in the development of type 2 diabetes. Improvement of fat cell insulin signaling may favor recovery of whole body systemic insulin sensitivity in pre-diabetic and diabetic states. In this context, inhibition of hormone-sensitive lipase (HSL) in adipocytes (an enzyme responsible for fatty acid release by adipose tissue) was demonstrated to be protective against insulin resistance. However, the mechanisms remained unclear. Consequently, my PhD work aimed at understanding the mechanisms linking HSL inhibition and improvement of insulin sensitivity. In human adipocytes, HSL gene silencing increased glucose transport, de novo lipogenesis and insulin signaling. Among de novo lipogenesis enzymes, ELOVL6 was preferentially induced in vitro and in vivo during HSL partial deficiency, resulting in enrichment of phospholipids and triglycerides in oleic acid. ELOVL6 gene silencing in human adipocytes provided the direct demonstration of the role of the enzyme in the beneficial effect of HSL inhibition. Fat cell insulin signaling was also impaired in adipose tissue of Elovl6 null mice. In clinical studies, ELOVL6 expression was blunted in insulin resistant states and restored after bariatric surgery. ELOVL6-mediated oleic acid enrichment of phospholipids was responsible for the positive effect of HSL inhibition on insulin signaling. FRAP studies revealed an increase in plasma membrane fluidity and insulin signaling in adipocytes overexpressing ELOVL6. In the liver, ELOVL6 is a target of ChREBP. Adipose ChREBP, notably the constitutively active isoform ChREBPß, recently emerged as a major determinant of systemic insulin action on glucose metabolism. In humans, we observed in several in vitro models and in vivo studies a strong positive association between adipose ChREBPß and ELOVL6. Dual HSL-ChREBP inhibition blunted adipose ELOVL6 expression in vivo and in vitro and mirrored ELOVL6 gene silencing on fatty acid profile and insulin signaling. Importantly, we found that physical interaction between HSL and ChREBP impairs ChREBP translocation into the nucleus and its transcriptional activity. A naturally short form of HSL devoid of catalytic activity retained the capacity to bind ChREBP. We also demonstrated that ChREBP-HSL interaction was specific of the lipase and restricted to adipocyte. To conclude, our work identifies a novel pathway critical for optimal insulin signaling in fat cells which links the neutral lipase HSL to the glucose-responsive transcription factor ChREBP and its target gene, the fatty acid elongase, ELOVL6. ELOVL6-mediated oleate enrichment in phospholipids increases membrane fluidity and improves insulin signaling. Inhibition of HSL/ChREBP interaction in adipose tissue may be beneficial in the treatment of obesity-associated insulin resistance.