Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism.
Adipose tissue de novo lipogenesis (DNL) positively influences insulin sensitivity, is reduced in obesity, and predicts insulin resistance. Therefore, elucidating mechanisms controlling adipose tissue DNL could lead to therapies for type 2 diabetes. Here, we report that mechanistic target of rapamycin complex 2 (mTORC2) functions in white adipose tissue (WAT) to control expression of the lipogenic transcription factor ChREBPβ. Conditionally deleting the essential mTORC2 subunit Rictor in mature adipocytes decreases ChREBPβ expression, which reduces DNL in WAT, and impairs hepatic insulin sensitivity. Mechanistically, Rictor/mTORC2 promotes ChREBPβ expression in part by controlling glucose uptake, but without impairing pan-AKT signalling. High-fat diet also rapidly decreases adipose tissue ChREBPβ expression and insulin sensitivity in wild-type mice, and does not further exacerbate insulin resistance in adipose tissue Rictor knockout mice, implicating adipose tissue DNL as an early target in diet-induced insulin resistance. These data suggest mTORC2 functions in WAT as part of an extra-hepatic nutrient-sensing mechanism to control glucose homeostasis.
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Yuefeng
Y
Tang
Department of Engineering, University of California, San Diego, La Jolla, California 92093, USA.
Martina
M
Wallace
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Joan
J
Sanchez-Gurmaches
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Wen-Yu
WY
Hsiao
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Huawei
H
Li
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Peter L
PL
Lee
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Santiago
S
Vernia
Department of Engineering, University of California, San Diego, La Jolla, California 92093, USA.
Christian M
CM
Metallo
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
David A
DA
Guertin
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000235:genetics; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C506001:Mlxipl protein, mouse; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D021122:Protein Subunits; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors; C525637:rictor protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose