The Lipid Handling Capacity of Subcutaneous Fat Requires mTORC2 during Development

Abstract

Overweight and obesity are associated with Type 2 Diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictorexpress mature adipocyte markers but develop a striking lipid storage defect. In vivo,this results in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARgand ChREBP. These include genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, the gene encoding its substrate and insulin effector. Finally, we reveal a potential novel mTORC2 target, ACSS2, which might control intracellular acetyl-CoA availability and regulate metabolic gene expression by altering histone modification in white adipocytes. Exploring this pathway may uncover strategies to promote safe lipid storage and improve insulin sensitivity.