Acyl-CoA Synthetase 5 Knockout and Inhibitors Protect Against Diet-Induced Obesity in Mice by Activating the Ileal Brake

Genes regulating body fat are shared by mice and humans, and mouse knockout phenotypes for known drug targets correlate well with drug efficacy, suggesting that mouse knockout phenotyping can identify anti-obesity drug targets. 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). Here we provide data on these and further outcomes in mice with a global <i>Acsl5</i> knockout and in mice receiving ACSL5 inhibitors (ACSL5i). We generated <i>Acsl5</i> knockout mice by homologous recombination and identified potent ACSL5i by compound library screening, iterative medicinal chemistry optimization, and by testing whether compounds inhibit oral triglyceride absorption. We found that both genetic and pharmacologic ACSL5 inhibition reproduce the intestine-specific knockout metabolic phenotype. Importantly, the ACSL5i LP-856866 lowered FC in wild-type but not <i>Acsl5</i> knockout mice, indicating targeted ACSL5 inhibition. <i>Acsl5</i> knockout mice had increased fecal free fatty acids but not triglycerides, and adding the lipase inhibitor orlistat to an oral triglyceride load reversed the delayed GE associated with genetic and pharmacologic ACSL5 inhibition; these findings, and the marked GLP-1 release after mice with genetic and pharmacologic ACSL5 inhibition received an oral triglyceride load, suggest ileal brake activation. We conclude that HFD-fed <i>Acsl5</i> knockout mice exhibit a favorable metabolic phenotype, driven by ileal brake activation, which is phenocopied by orally available small molecule ACSL5i.