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Adipose tissue

Two roads to thermogenesis: vascular and parenchymal sympathetic innervation of brown adipose tissue

Nature Reviews Endocrinology (2025)Cite this article

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The heat production and metabolic substrate clearance driven by brown adipose tissue (BAT) is a promising way to treat cardiometabolic diseases. Historically, the neural basis of BAT thermogenesis is related to the sympathetic nervous system, which provides the primary neural input to BAT. Sympathetic fibres from the stellate ganglia and thoracic branches densely innervate BAT. Cold exposure stimulates these neurons, causing noradrenaline release to activate uncoupling protein 1 (UCP1). Cold exposure also engages additional, UCP1-independent, mechanisms (futile cycles), which contribute to non-shivering thermogenesis. Although for many years the sympathetic control of thermogenesis was viewed mainly through its effects on mature brown adipocytes, it is now recognized that the organization of sympathetic innervation in BAT involves interactions with multiple cell types beyond adipocytes.

Long before the appearance of advanced approaches to visualize peripheral nerves, such as tissue-clearing techniques, light-sheet microscopy and reporter animal models, a seminal observation by Derry, Schönbaum and Steiner in 1969, using a simple fluorescence method, revealed distinct patterns of sympathetic innervation in BAT. This early finding not only anticipated concepts that were later confirmed with modern technologies but also paved the way for studies on the contribution of vascular sympathetic input as a key regulator of BAT. In their study, Derry, Schönbaum and Steiner used the formaldehyde-induced fluorescence method (Falck–Hillarp technique) to visualize noradrenergic nerve fibres in BAT. When they exposed cryostat-frozen sections of rat interscapular BAT to formaldehyde vapour, biogenic amines such as noradrenaline were converted into fluorescent derivatives issuing a yellow-green signal. Using a combination of fluorescent approaches, they identified intensely bright nerve fibres innervating both the parenchyma and the vasculature, particularly associated with arterioles, thereby challenging the dogma that in BAT, only mature brown adipocytes receive innervation from sympathetic fibres.

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References

Original article

  • Derry, D. M., Schönbaum, E. & Steiner, G. Two sympathetic nerve supplies to brown adipose tissue of the rat. Can. J. Physiol. Pharmacol. 47, 57–63 (1969)

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Acknowledgements

The author acknowledges the support of L. O. Leiria and B. Adjafre (University of São Paulo) during the preparation of this manuscript. The author also acknowledges the support of a Doctoral Research Award from the Coordination for the Improvement of Higher Education Personnel (CAPES).

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  1. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    João Manoel Alves

  2. Center for Research in Inflammatory Diseases, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    João Manoel Alves

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  1. João Manoel Alves
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Correspondence to João Manoel Alves.

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The author declares no competing interests.

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Alves, J.M. Two roads to thermogenesis: vascular and parenchymal sympathetic innervation of brown adipose tissue. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01224-7

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