FIG. 8.

TAK1^−/− mice are protected against HFD-induced insulin resistance and glucose intolerance. A: Blood insulin levels were analyzed in 5-month-old mice (WT, n = 5; TAK1^−/−, n = 4), 1-year-old mice (WT, n = 8; TAK1^−/−, n = 9), and mice fed a HFD (WT, n = 10; TAK1^−/−, n = 7). B, C: Glucose tolerance test (GTT) and insulin tolerance test (ITT) analyses in WT(HFD) and TAK1^−/−(HFD) mice (WT, n = 5; TAK1^−/−, n = 4). Blood samples were drawn and glucose levels analyzed every 20 min for up to 2–2.5 h. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. D: Schematic view of the potential role of TAK1/TR4 in lipid homeostasis and hepatic steatosis. Elevated levels of fatty acids during aging and HFD may promote the activation of TAK1 leading to increased transcription of TAK1-responsive genes, such as CD36, Cidec, Cidea, and Mogat1. The induction of these proteins then lead to increased fatty acid uptake and triglyceride synthesis and storage, and promote hepatic steatosis. Induced expression of other transcription factors, such as PPARγ, by TAK1 can also lead to the activation of CD36, Cidec, or other lipogenic genes and may provide an alternative way to further enhance hepatic triglyceride accumulation. (A high-quality color representation of this figure is available in the online issue.)