Exercise ameliorates insulin resistance via regulating TGFβ‐activated kinase 1 (TAK1)‐mediated insulin signaling in liver of high‐fat diet‐induced obese rats

Oct 28, 2018Journal of cellular physiology

Exercise reduces insulin resistance by improving insulin signals controlled by TAK1 in the liver of obese rats on a high-fat diet

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Abstract

Exercise improved insulin sensitivity in high-fat diet-induced obese rats.

High-fat diet feeding resulted in increased body weight, visceral fat mass, and serum free fatty acids, while decreasing hepatic glycogen content and insulin sensitivity.
Obesity was associated with increased levels of TRAF3 and TRIM8 proteins, and decreased levels of USP4, USP18, and DUSP14 proteins, leading to enhanced TAK1 phosphorylation and impaired insulin signaling.
Both chronic and acute exercise training ameliorated insulin resistance in obese rats.
Exercise training reduced phosphorylation of TAK1, JNK1, and IRS1, which led to enhanced Akt phosphorylation in the liver.
Exercise increased protein levels of USP4 and DUSP14 while decreasing TRIM8 levels in the liver of obese rats.

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Exercise is an effective therapy for insulin resistance. However, the underlying mechanism remains to be elucidated. Previous research demonstrated that TGFβ-activated kinase 1 (TAK1)-dependent signaling plays a crucial character in hepatic insulin resistance. Hepatic ubiquitin specific protease 4 (USP4), USP18, and dual-specificity phosphatases 14 (DUSP14) can suppress TAK1 phosphorylation, besides tumor necrosis factor receptor-associated factor 3 (TRAF3) and tripartite motif 8 (TRIM8) promote its phosphorylation. In this study, we tried to verify our hypothesis that exercise improves insulin resistance in high-fat diet (HFD)-induced obese (DIO) rats via regulating the TAK1 dependent signaling and TAK1 regulators in liver. Forty male Sprague-Dawley rats were randomized into four groups (n = 10): standard diet and sedentary as normal control; fed on HFD and DIO-sedentary; fed on HFD and DIO-chronic exercise; and fed on HFD and DIO-acute exercise. HFD feeding resulted in increased body weight, visceral fat mass, serum FFAs and hepatic lipid deposition, but decreased hepatic glycogen content and insulin sensitivity. Moreover, hepatic TRAF3 and TRIM8 protein levels increased, whereas USP4, USP18, and DUSP14 protein levels were decreased under obese status, which resulted in enhanced TAK1 phosphorylation and impaired insulin signaling. Exercise training, containing chronic and acute mode, both ameliorated insulin resistance. Meanwhile, decreased TAK1, c-Jun N-terminal kinase 1 (JNK1), and insulin receptor substrate 1 (IRS1) phosphorylation enhanced Akt phosphorylation in liver. Moreover, exercise enhanced USP4 and DUSP14 protein levels, whereas decreased TRIM8 protein levels in obese rats' liver. These results showed that exercise triggered a crucial modulation in TAK1-dependent signaling and its regulators in obese rats' liver, and distinct improvement in insulin sensitivity, which provide new insights into the mechanism by which physical exercise improves insulin resistance.

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Exercise ameliorates insulin resistance via regulating TGFβ‐activated kinase 1 (TAK1)‐mediated insulin signaling in liver of high‐fat diet‐induced obese rats

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