Intestinal stearoyl-CoA desaturase-inhibition improves obesity-associated metabolic disorders

Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors have been tested in treating metabolic disorders both in preclinical and clinic studies, the tissue-specific role of SCD1 in modulating obesity-associated metabolic disorders remains unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, a SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 (MT1) in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders. Examination of gene expression change in intestine of intestine-specific SCD1 knockout mice fed an obesity-promoting 60% high fat diet using RNASeq.