The lipid handling capacity of subcutaneous fat is programmed by mTORC2 during development

Obesity causes type 2 diabetes, cardiovascular diseases, NAFLD, and cancer, but all fat is not equal as subcutaneous white adipose tissue (SWAT) is more metabolically favorable than visceral fat. Here, we investigate mTORC2 function in SWAT growth by deleting its essential subunit Rictor in SWAT precursor cells and examining its effect on adipocyte differentiation and tissue development. We found that Rictor/mTORC2 is not required for SWAT preadipocyte differentiation per se; however, SWAT preadipocytes differentiating without Rictor cannot fully induce the lipid storage transcriptional program. In vivo, this results in smaller adipocytes, reduced SWAT size, lipid re-distribution to visceral and brown fat, and gender-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes PPARg activity towards specific lipid metabolism genes independently of ChREBP, but in coordination, to set the lipid handling capacity of SWAT. Further exploring this pathway may uncover new strategies to stimulate lipid storage in more metabolically favorable SWAT. Overall design: We isolated primary preadipocytes from subcutaneous adipose tissue harboring UBC-CreERT2;Rictorfloxed, which we can induce Rictor deletion by supplementing the cells with Tamoxifen, and compare the transcriptome change between Control and Rictor-KO cells at different days of adipocyte differentiation.