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

Key Points

  • Cold-induced thermogenesis is an important component of total energy expenditure and contributes to overall energy balance

  • Brown adipose tissue (BAT) has been known to be the effector organ for cold-induced thermogenesis for decades

  • The recent discovery of metabolically active BAT in human adults has made it clear that cold-induced thermogenesis is of physiologic and potentially therapeutic relevance

  • Cold-induced thermogenesis is a fundamental physiologic principle helping the body adapt to environmental challenges and is not limited to BAT

  • Recent research elucidated novel thermogenic mechanisms that contribute to cold-induced thermogenesis both in BAT and beige adipose tissue and in muscle

  • Targeting thermogenesis in adipose tissue and muscle might be a promising therapeutic tool against obesity and associated metabolic diseases

Abstract

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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Figure 1: Schematic model of physiologic cold response.
Figure 2: Human white adipose tissue (WAT) and brown adipose tissue (BAT).
Figure 3: Mechanisms of thermogenesis.
Figure 4: Potential therapeutic targets to expand brown adipose tissue (BAT).

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Acknowledgements

The authors apologize to those colleagues whose work has only been cursorily cited or not cited owing to space constrains. M.J.B. is supported by a grant from the Goldschmidt-Jacobson Foundation, Basel, Switzerland, and a career development grant from the Swiss National Science Foundation. S.E. is supported by grants from the Swedish Research Council (2014–2516), the Knut and Alice Wallenberg Foundation, the Sahlgrenska University Hospital (LUA-ALF), the Novo Nordisk Foundation, the Inga Britt and Arne Lundgren Foundation, the Torsten Söderberg Foundation and the King Gustaf V and Queen Victoria Freemason Foundation.

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Correspondence to Sven Enerbäck.

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Betz, M., Enerbäck, S. Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nat Rev Endocrinol 14, 77–87 (2018). https://doi.org/10.1038/nrendo.2017.132

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