Intestinal stearoyl-CoA desaturase-2 is highly expressed and nutritionally regulated but dispensable for energy balance

The stearoyl-CoA desaturase (SCD) enzymes convert saturated fatty acids to monounsaturated fatty acids (MUFAs). Deletion of intestinal SCD1 confers metabolic benefits upon high-fat diet (HFD) feeding. We report here that mice express a second SCD isoform in the intestine. SCD2 is expressed at much greater levels than SCD1 along the small intestine and colon. SCD2 displays spatial enrichment in the distal small intestine and in the colon and nutritional regulation by dietary fat and sucrose. Deletion of intestinal SCD2 (in 2iKO mice) reduces colonic, hepatic, and plasma triglycerides. However, MUFA levels and desaturation ratios are largely unimpacted in 2iKO intestines. SCD2 deletion is accompanied by upregulation of SCD1 and the fatty acid transporter, CD36, which together may help retain MUFA balance in the gut. Consistent with a lack of impact on MUFA levels, deletion of SCD2 does not protect mice from HFD-induced metabolic dysfunction. However, upon sucrose refeeding, SCD2 deletion blunts hepatic lipogenesis and triglyceride accumulation, suggesting that intestinal SCD2 modulates interorgan communication under conditions of carbohydrate overfeeding. While SCD1 and CD36 likely help retain MUFA balance in 2iKO mice intestines, primary organoids cultured ex vivo indicate significant reductions in overall desaturase activity in 2iKO organoids, despite increases in Scd1 expression. 2iKO organoids do not, however, induce Cd36 expression, and this is accompanied by a significant induction of ER stress in 2iKO organoids. Together, these data reveal a novel role for intestinal SCD2 in maintaining cellular MUFA balance to modulate responses to nutrient overload and to prevent ER stress. • Scd2 increases in expression along the intestines and is much higher than Scd1 . • Dietary fat and sucrose upregulate intestinal Scd2 expression. • SCD2 and CD36 coordinate to maintain intestinal MUFA balance and mitigate ER stress. • Intestinal SCD1 compensates for loss of SCD2 on high-fat diet. • Intestinal SCD2 modulates hepatic lipogenesis on high-carbohydrate diets.