| First Author | Sato S | Year | 2015 |
| Journal | FASEB J | Volume | 29 |
| Issue | 3 | Pages | 988-1002 |
| PubMed ID | 25466899 | Mgi Jnum | J:219637 |
| Mgi Id | MGI:5629442 | Doi | 10.1096/fj.14-260703 |
| Citation | Sato S, et al. (2015) Elevated levels of TWEAK in skeletal muscle promote visceral obesity, insulin resistance, and metabolic dysfunction. FASEB J 29(3):988-1002 |
| abstractText | Skeletal muscle is responsible for the majority of glucose disposal in body. Impairment in skeletal muscle glucose handling capacity leads to the state of insulin resistance. The TNF-like weak inducer of apoptosis (TWEAK) cytokine has now emerged as a major regulator of skeletal muscle mass and function. However, the role of TWEAK in skeletal muscle metabolic function remains less understood. Here, we demonstrate that with progressive age, skeletal muscle-specific TWEAK-transgenic (TWEAK-Tg) mice gain increased body weight ( approximately 16%) and fat mass ( approximately 64%) and show glucose intolerance and insulin insensitivity. TWEAK-Tg mice also exhibit adipocyte hypertrophy in the epididymal fat. Oxygen uptake, voluntary physical activity, and exercise capacity were significantly reduced in TWEAK-Tg mice compared with controls. Overexpression of TWEAK inhibited ( approximately 31%) 5' AMP-activated protein kinase (AMPK) and reduced ( approximately 31%) the levels of glucose transporter type 4 (GLUT4) without affecting the Akt pathway. TWEAK also inhibited insulin-stimulated glucose uptake ( approximately 32%) and repressed the levels of GLUT4 ( approximately 50%) in cultured myotubes from C57BL6 mice. TWEAK represses the levels of Kruppel-like factor 15; myocyte enhancer factor 2, and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, which are required for the activation of the GLUT4 locus. Collectively our study demonstrates that elevated levels of TWEAK in skeletal muscle cause metabolic abnormalities. Inhibition of TWEAK could be a potential approach to prevent weight gain and type 2 diabetes.-Sato, S., Ogura, Y., Tajrishi, M.M., Kumar, A. Elevated levels of TWEAK in skeletal muscle promote visceral obesity, insulin resistance, and metabolic dysfunction. |
