[HTML][HTML] Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism

Y Tang, M Wallace, J Sanchez-Gurmaches… - Nature …, 2016 - nature.com
Y Tang, M Wallace, J Sanchez-Gurmaches, WY Hsiao, H Li, PL Lee, S Vernia, CM Metallo
Nature communications, 2016nature.com
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 …
Abstract
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.
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