Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines ‘a diseasome of physical inactivity’. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.