Episode 15 - how do mTORC2 and ChREBP-β keep the fat cycle going?

by Break Nutrition | Podcast

Show notes:

Study 1: “Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism” (2013 Tang et al.)
This study looked at the activity of mTORC2 in the adipose tissue of miceFloxed-KO mice missing Rictor, a key element in the mTORC2 complex, were used in this study
In the liver, de novo lipogenesis (DNL) correlates with insulin resistance (IR) but in white adipose tissue (WAT) it correlated with insulin sensitivity (IS)
The activity of Carbohydrate-response Element Binding Protein (ChREBP) seems important for good glycemic control
Well-known mTORC1 drives lipid and protein anabolism
Less known mTORC2 is activated by growth factors
- mTORC2 in WAT takes up glucose independently of the classic AKT-AS160 pathway
The KO-Rictor mice were severely IR (steady-state rate of glucose infusion of 46% vs controls)
- One explanation is that the “activating phosphorylation of the insulin receptor (pIRY1150/1151) is higher in the KO fat (Fig. 3a) possibly suggesting loss of an inhibitory feedback mechanism”
The result of which is the KO-Rictor mice have IR specifically in their adipose tissue
Furthermore, the data collected by the authors suggest losing Rictor “in fat most negatively affects hepatic function”
mTORC2 in fat tissue looks like a key upstream regulator of ChREBP-β driven DNL
KO-Rictor mice on high-fat diets (HFDs) have nearly identical lipid profiles as control eating normal mouse chow
- KO-Rictor mice eating a HFD resist weight gain, due to fat tissue that fails to expand normaly
The role of Rictor seems crucial for allowing fat tissue expansion the more carbs are eaten
A zero-fat diet (ZFD) the mice were also fed improves IS, possibly by forcing more glucose into adipocytes, but the lipogenic genes still aren’t upregulated
An insulin sensitizing signal is expressed in these mice by mTORC2 regulating lipogenic gene expression
In these mice, “Glut4 mRNA and protein fail to induce normally during differentiation (Fig. 9g)”
Glut4 translocation may be impaired
Glyceroneogenesis functions may also be lacking in the adipocytes of KO-Rictor mice
When fat cells inappropriately release fat, this can lead to IR when Rictor/mTORC2 is absent in fat, but this isn’t a primary effect of Rictor loss
ChREBP-β and DNL actvitiy is controlled by adipocyte mTORC2, to some degree by managing glucose flux
- This mTORC2 function seems to happen independently of AKT, the canonical mTORC2 substrate
According to these mechanistic insight, drugs that can selectively activate mTORC2 may become anti-diabetic drugs

Study 2: “De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health” (Eisseing et al. 2013)
The take-away is that DNL in human fat and liver is linked to ChREBP-β and metabolic health
This study recruited +130 subjects that were “gender-matched subgroups including non-obese non-diabetic subjects (controls), obese non-diabetic subjects (obese) and obese subjects with T2D (obese-diabetic) were selected from the total cohort.”
DNL in WAT produces insulin-sensitizing palmitoleate and DNL in the liver causes metabolic disease
Obesity associates with less WAT DNL
GLUT4 is the rate-limiting shuttle for the substrate glucose into WAT DNL
Visceral-WAT (vWAT) DNL is linked to ChREBP-β (the short-form isoform of to ChREBP-α) and Metabolic Syndrom risk factors
Visceral-adipose tissue (VAT) Glut4, Fatty Acid Synthase (FASN) and ChREBP-β mRNA correlated inversely with HOMA–IR
Different WAT depots may incur different DNL activity
vWAT has less stearic acid (C18:0) but the same levels of Palmitoleate (C16:1n7)
Subcutaneous-WAT (sWAT) DNL is restored after bariatric surgery
ChREBP-β and FASN mRNA correlate positively with HOMA–IR and how much the degree of liver steatosis
Glut4 seems to promote insulin sensitivity and may serve as a marker of adipocyte DNL
Interestingly the authors note how their “data indicate a higher capacity of obese humans versus mice to adapt to an unhealthy excess of C18:0 and other saturated fatty acids through D⁹-desaturation“
This may have to do with humans needing to desaturate more fat because of their higher fat diets (when compared to mice)