Abstract 2351 Role of intestinal stearoyl-CoA desaturase-1 in modulating systemic bile acid and energy metabolism

Stearoyl-CoA desaturase-1 converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid esterification and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance. To interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analysis of bile acid content and composition, metabolic phenotyping including body composition, indirect calorimetry and glucose tolerance analyses, and assessment of bile acid signaling pathways. For all in vivo procedures, every effort was made to minimize discomfort and suffering, in accordance with the protocols approved by the Animal Care and Use Committee of Rutgers University, New Brunswick, New Jersey under protocol No. 201900077. iKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt. These increases were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and plasma GLP-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice. Our results indicate that deletion of intestinal SCD1 has significant impacts on bile acid metabolism and whole-body energy balance, likely via activation of TGR5. American Heart Association grant 20CDA35310305 and NIH grant R01DK126963.