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

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.

Insulin resistance causes inflammation in adipose tissue

“…As previously reported (32)(33)(34), HFD-fed AdRiKO mice had an increased body size with no change in adiposity (Supplemental Figure 1, A-C; supplemental material available online with this article; https://doi.org/10.1172/JCI96139DS1). Furthermore, we confirmed that RICTOR expression, AKT (Ser473) phosphorylation, and PKC expression, readouts for mTORC2 signaling, were decreased, while S6K (Thr389) phosphorylation, a readout for mTORC1 signaling, was not affected in eWAT ( Figure 1B; see complete unedited blots in the supplemental material).…”

“…AdRiKO exacerbates systemic insulin resistance upon obesity, as evidenced by impaired glucose clearance in response to insulin treatment ( Figure 1A and refs. [32][33][34]. Thus, the AdRiKO mouse is a good model to investigate the causal relationship between insulin resistance and inflammation upon obesity.…”

“…Insulin resistance-induced inflammation is specific to visceral WAT. Adipose-specific loss of mTORC2 signaling directly causes insulin resistance in all WAT depots and indirectly leads to systemic insulin resistance (32)(33)(34). To test whether AdRiKO causes inflammation in liver or in fat depots other than eWAT (see above), we examined macrophage numbers in peri-renal WAT (prWAT), subcutaneous WAT (sWAT), and liver of HFD-fed AdRiKO and control mice.…”

“…In mammals, mTORC2 consists of mTOR, rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinaseinteracting protein 1 (mSIN1), and mammalian lethal with SEC thirteen 8 (mLST8) (26)(27)(28)(29)(30)(31). Insulin stimulates mTORC2 to promote glucose uptake in adipose tissue (32)(33)(34), liver (35)(36)(37), and skeletal muscle (38,39). Previously, we and others have shown that adipose-specific Rictor knockout (AdRiKO) exacerbates obesity-related complications in mice, such as systemic insulin resistance and hepatic steatosis (32)(33)(34).…”

“…Insulin stimulates mTORC2 to promote glucose uptake in adipose tissue (32)(33)(34), liver (35)(36)(37), and skeletal muscle (38,39). Previously, we and others have shown that adipose-specific Rictor knockout (AdRiKO) exacerbates obesity-related complications in mice, such as systemic insulin resistance and hepatic steatosis (32)(33)(34).…”