Chronic diseases like type-2 diabetes and cardiovascular diseases affect over 1 billion people worldwide and can be prevented and treated by physical activity, usually termed as ‘exercise-is-medicine’. Surprisingly, recent evidence suggests that some drugs antagonize the health-promoting effects of exercise. Although it is inherent that every pharmaceutical drug has side-effects, blocking the beneficial effects of exercise is a severe and sobering consequence. In our laboratory, we generated preliminary data in the past 6 months illustrating perhaps the most dramatic example of it. Common over-the-counter drugs, ANTIHISTAMINES, block specific histamine receptors, thereby inhibiting the pathological events of allergies and gastric ulcers. Yet, when taking antihistamines prior to each training session, we completely inhibited the beneficial effects of exercise training (e.g. improved glucose tolerance) in humans. Apart from the far-reaching clinical consequence, this also demonstrates a crucial role for histamine signaling in the chronic adaptations of skeletal muscle and other tissues to physical activity. In this project, we will explore the physiological mechanisms and role of histamine signaling in training adaptation in humans and in in vitro cell cultures (reverse translation). Additionally, we will expand on our preliminary findings towards a clinical population, namely patients with metabolic syndrome for whom exercise is an important treatment option (translation).