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

Wen-Yu Hsiao; Su Myung Jung; Yuefeng Tang; John A Haley; Rui Li; Huawei Li; Camila Martinez Calejman; Joan Sanchez-Gurmaches; Chien-Min Hung; Amelia K Luciano; Victoria DeMambro; Kathryn E Wellen; Clifford J Rosen; Lihua Julie Zhu; David A Guertin

doi:10.1016/j.celrep.2020.108223

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

Cell Rep. 2020 Oct 6;33(1):108223. doi: 10.1016/j.celrep.2020.108223.

Authors

Affiliations

¹ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
² Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
³ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Division of Endocrinology, Developmental Biology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
⁴ Center for Clinical and Translational Research, Maine Medical Center, Scarborough, MN 04074, USA.
⁵ Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁷ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: david.guertin@umassmed.edu.

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 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.

Keywords: AKT; ChREBP; PPAR-gamma; adipocyte; adipose tissue; lipid metabolism; mTORC2; obesity; type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, White / physiopathology*
Animals
Humans
Lipid Metabolism / physiology*
Mechanistic Target of Rapamycin Complex 2 / metabolism*
Mice
Obesity / physiopathology*
Subcutaneous Fat / physiopathology*

Substances

Mechanistic Target of Rapamycin Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding