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Acyl-CoA Synthetase 5 Knockout and Inhibitors Protect Against Diet-Induced Obesity in Mice by Activating the Ileal
David R Powell1, Isaac Van Sligtenhorst1, Alan Main1
1Lexicon Pharmaceuticals, The Woodlands, TX 77381, USA.
Abstract:
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 Acsl5 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 Acsl5 knockout and in mice receiving ACSL5 inhibitors (ACSL5i). We generated Acsl5 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 Acsl5 knockout mice, indicating targeted ACSL5 inhibition. Acsl5 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 Acsl5 knockout mice exhibit a favorable metabolic phenotype, driven by ileal brake activation, which is phenocopied by orally available small molecule ACSL5i.
Insights
Inhibiting ACSL5 in mice combats obesity and metabolic dysfunction by activating the ileal brake, a mechanism also mimicked by small molecule ACSL5 inhibitors, suggesting new anti-obesity drug targets.
Area of Science:
- Metabolic disease research
- Pharmacology
- Genetics
Background:
- Mouse models are valuable for identifying anti-obesity drug targets due to shared fat-regulating genes with humans.
- Intestine-specific Acsl5 knockout mice show protection against high-fat diet-induced obesity and related metabolic issues.
- Acsl5 knockout mice exhibit increased GLP-1, delayed gastric emptying, and reduced food consumption.
Purpose of the Study:
- To investigate the metabolic effects of global Acsl5 knockout and ACSL5 inhibitors (ACSL5i) in mice.
- To determine if genetic and pharmacologic ACSL5 inhibition replicate the intestine-specific knockout phenotype.
- To elucidate the mechanism behind the observed metabolic improvements, specifically ileal brake activation.
Main Methods:
- Generated global Acsl5 knockout mice using homologous recombination.
- Screened compound libraries and optimized medicinal chemistry to identify potent ACSL5 inhibitors.
- Administered ACSL5 inhibitors and assessed metabolic outcomes including food consumption, gastric emptying, GLP-1 levels, and fecal fatty acid content.
Main Results:
- Both global Acsl5 knockout and ACSL5 inhibition mimicked the intestine-specific knockout metabolic phenotype.
- The ACSL5 inhibitor LP-856866 reduced food consumption in wild-type but not Acsl5 knockout mice, confirming targeted inhibition.
- Ileal brake activation, evidenced by GLP-1 release and reversed delayed gastric emptying upon triglyceride load, was observed in Acsl5 knockout and ACSL5 inhibitor-treated mice.
Conclusions:
- Global Acsl5 knockout and pharmacologic ACSL5 inhibition confer a favorable metabolic phenotype in mice fed a high-fat diet.
- The metabolic benefits are driven by ileal brake activation, similar to findings in intestine-specific knockout models.
- Orally available small molecule ACSL5 inhibitors effectively phenocopy the protective metabolic effects of Acsl5 genetic deletion.
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