1 Targeted mitochondrial uncoupling beyond UCP1 – the fine line between death 1 and metabolic health 2 Mario Ost 1,* , Susanne Keipert 2 , and Susanne Klaus 1 3 1 Research Group Physiology of Energy Metabolism, German Institute of Human Nutrition, 4 Potsdam-Rehbruecke, 14558, Germany 5 2 Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, 85764, Germany 6 * Corresponding author: 7 Mario Ost 8 Research Group Physiology of Energy Metabolism 9 German Institute of Human Nutrition Potsdam-Rehbrücke 10 Nuthetal, 14558 (Germany) 11 Phone: (0049) 33200 88-2430 12 Email: Mario.ost@dife.de 13 Highlights: 14  Ectopic mitochondrial uncoupling increases substrate oxidation in target tissues. 15  Novel chemical uncouplers tackle obesity, diabetes and fatty liver disease. 16  Targeted UCP1 overexpression ameliorates obesity, hypertriglyceridemia and insulin resistance. 17  Muscle-targeted UCP1 overexpression promotes adaptive metabolic remodeling, endocrine 18 crosstalk and survival. 19