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