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 HOMAIR
  • 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 HOMAIR 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 [palmitoleate] 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)

 

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