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Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease

Review article
Authors M. J. Betz
Sven Enerbäck
Published in Nature Reviews Endocrinology
Volume 14
Issue 2
Pages 77-87
ISSN 1759-5029
Publication year 2018
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages 77-87
Language en
Keywords white adipose-tissue, diet-induced obesity, mitochondrial uncoupling, protein, induced adaptive thermogenesis, enhances energy-expenditure, central efferent pathways, messenger-rna expression, cold-acclimated, rats, age-related-changes, skeletal-muscle, Endocrinology & Metabolism
Subject categories Endocrinology


Brown fat is emerging as an interesting and promising target for therapeutic intervention in obesity and metabolic disease. Activation of brown fat in humans is associated with marked improvement in metabolic parameters such as levels of free fatty acids and insulin sensitivity. Skeletal muscle is another important organ for thermogenesis, with the capacity to induce energy-consuming futile cycles. In this Review, we focus on how these two major thermogenic organs - brown fat and muscle - act and cooperate to maintain normal body temperature. Moreover, in the light of disease-relevant mechanisms, we explore the molecular pathways that regulate thermogenesis in brown fat and muscle. Brown adipocytes possess a unique cellular mechanism to convert chemical energy into heat: uncoupling protein 1 (UCP1), which can short-circuit the mitochondrial proton gradient. However, recent research demonstrates the existence of several other energy-expending 'futile' cycles in both adipocytes and muscle, such as creatine and calcium cycling. These mechanisms can complement or even substitute for UCP1-mediated thermogenesis. Moreover, they expand our view of cold-induced thermogenesis from a special feature of brown adipocytes to a more general physiological principle. Finally, we discuss how thermogenic mechanisms can be exploited to expend energy and hence offer new therapeutic opportunities.

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