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 (∼ 16%) and fat mass (∼ 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 (∼ 31%) 5′ AMP-activated protein kinase (AMPK) and reduced (∼ 31%) the levels of glucose transporter type 4 (GLUT4) without affecting the Akt pathway. TWEAK also inhibited insulin-stimulated glucose uptake (∼ 32%) and repressed the levels of GLUT4 (∼ 50%) in cultured myotubes from C57BL6 mice. TWEAK represses the levels of Krüppel-like factor 15; myocyte enhancer factor 2, and peroxisome proliferator-activated receptor-γ coactivator-1α, 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, MM, Kumar, A. Elevated levels of TWEAK in skeletal muscle promote visceral obesity, insulin resistance, and metabolic dysfunction.