Mice with an intestine-specific <i>Acsl5</i> knockout are protected from high-fat diet (HFD)-induced obesity, insulin resistance, glucose intolerance and hepatic steatosis, and show increased GLP-1 levels, delayed gastric emptying (GE), and decreased food consumption (FC). This evidence concerns the gene ACSL5 and obesity due to melanocortin 4 receptor deficiency.