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.

To address whether vascular and parenchymal innervation originate from the same ganglia projection, the researchers used two different types of sympathectomy in rats: immunosympathectomy with anti-nerve growth factor serum injection or surgical unilateral sympathetic denervation on BAT. Following these procedures, the vascular innervation was almost completely abolished, whereas parenchymal innervation remained intact. Pharmacological depletion of catecholamines with reserpine revealed distinct kinetics of recovery in vascular fibres versus parenchymal fibres, as parenchymal fibres regain catecholamine fluorescence faster than vascular fibres. This disparity suggests that vascular innervation and parenchymal innervation of BAT are maintained by distinct mechanisms of neural plasticity and that sympathetic fibres innervating the vasculature can co-store not only noradrenaline but also additional noradrenergic neuropeptides.

Although the work of Derry and colleagues was pioneering, it received little attention in subsequent years, perhaps because it was overshadowed by the focus on the mechanisms involved in the regulation of uncoupled thermogenesis in BAT. However, in retrospect, their demonstration of dual sympathetic innervation was remarkably prescient. The identification of vascular sympathetic projection to BAT opens new ways to investigate distinct roles of parenchymal and vascular innervation in BAT. This concept was further substantiated by Zhu and colleagues in 2024, when they identified vascular sympathetic projections in BAT that are positive for neuropeptide Y (NPY) and target mural cells, mediating their proliferation and commitment to the thermogenic brown adipocyte fate. Loss of vascular innervation by sympathetic NPY+ nerve fibres led to whitening of BAT, reduced energy expenditure and impaired cold tolerance, thus establishing vascular sympathetic innervation as a critical regulator of adipose tissue plasticity and systemic energy balance.

In summary, Derry, Schönbaum and Steiner were among the first to demonstrate distinct patterns of sympathetic innervation in BAT, suggesting that vascular and parenchymal inputs might serve different or even synergistic functions. These early observations anticipated the current view that adipose tissue innervation is highly heterogeneous, with neuronal subpopulations orchestrating complementary aspects of thermogenesis and metabolic regulation. Their work paved the way for subsequent studies exploring the neural control of BAT activity, particularly in thermogenesis, adipogenesis and systemic metabolic balance. Furthermore, this pioneering study opened new domains of research into the contribution of vascular function and distinct neuronal subtypes, including sensory fibres and non-canonical sympathetic inputs, in modulating BAT activity. The recognition that sympathetic innervation is present in both the vasculature and parenchyma of BAT raises critical questions about the specific roles and molecular markers that distinguish these two pathways. Whether both forms of innervation jointly regulate thermogenesis, adipogenesis and glucose metabolism or whether each structure exerts specialized functions remains unresolved and warrants further investigation.