The Lipid Handling Capacity of Subcutaneous Fat Is Programmed by mTORC2 during Development

Abstract

SUMMARY 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 Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting 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 PPARγ and ChREBP, including genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2 , which encodes a major mTORC2 substrate and insulin effector. Further exploring this pathway may uncover new strategies to improve insulin sensitivity.

Adipose mTORC2 is essential for arborization of sensory neurons in white adipose tissue and whole-body energy homeostasis

“…Indeed, leptin and species of free fatty acids have been identified as potential sensory stimuli acting in WAT [15, 16]. Our data provide additional evidence for this hypothesis since arborization of sensory neurons is lost upon ablation of adipose mTORC2, a critical regulator of energy uptake and storage in WAT [23, 25]. In addition, the observed reduction of sensory innervation in WAT lacking mTORC2 coincides with hyperinsulinemia and insulin resistance.…”

“…It is composed of four core components including the kinase subunit mTOR and the mTORC2-specific subunit rapamycin-insensitive companion of mTOR (RICTOR) [17][18][19]. Studies of adipose-specific Rictor knockout mice revealed that loss of adipose mTORC2 causes reduced glucose uptake and impaired lipid handling in adipocytes [20][21][22][23][24][25]. Furthermore, loss of adipose mTORC2 non-cell-autonomously causes hyperinsulinemia and systemic insulin resistance [20,21,23].…”

Integrated Metagenomics and Metabolomics to Reveal the Effects of Policosanol on Modulating the Gut Microbiota and Lipid Metabolism in Hyperlipidemic C57BL/6 Mice

“…In this study, Bacteroidetes , Firmicutes in phylum and Parasutterell and Canaidatus_Saccharimonas in genus level showed high correlation with iWAT and BAT weight and metabolites contents correlated with TCA cycle. Fat in scWAT is more easily metabolized than visceral WAT, which including eWAT and the adipose tissue around liver and heart ( 40 ). Compared with visceral WAT, scWAT is more likely to be mobilized, browned, hydrolyzed, oxidized and thermogenerated ( 41 ).…”

Adipose mTORC2 is essential for sensory innervation in white adipose tissue and whole-body energy homeostasis

“…It has been proposed that sensory neurons may directly communicate the metabolic state of WAT to CNS [ [13] , [14] , [15] ]. Our data provide evidence that this communication is disrupted upon ablation of adipose mTORC2, a critical regulator of energy uptake and storage in WAT [ 23 , 25 ]. We found that reduction of sensory innervation in WAT coincides with systemic insulin resistance.…”

“…It is composed of four core components including the kinase subunit mTOR and the mTORC2-specific subunit rapamycin-insensitive companion of mTOR (RICTOR) [ [16] , [17] , [18] , [19] ]. Studies in adipose-specific Rictor knockout mice revealed that loss of adipose mTORC2 causes reduced glucose uptake and impaired lipid handling in adipocytes [ [20] , [21] , [22] , [23] , [24] , [25] ]. Furthermore, loss of adipose mTORC2 non-cell-autonomously causes hyperinsulinemia and systemic insulin resistance [ 20 , 21 , 23 ].…”