Research led by Dr Gitalee Sarker in the Domingos Group has discovered a previously unknown population of perineurial cells that wraps around the sympathetic ganglia and sympathetic nerves supplying adipose tissue.
These sympathetic perineurial cells (SPCs) act as an important communication hub, sensing both the hormone leptin and signals from the sympathetic nervous system through the leptin receptor (LEPR) and the β2-adrenergic receptor (ADRB2). This combination of receptors is highly enriched in SPCs and is rarely found in other cell types throughout the body, making them uniquely positioned to coordinate leptin and sympathetic signalling to regulate energy expenditure without affecting food intake.
The study shows that during obesity, chronically elevated leptin levels trigger the loss of these protective cells, leading to the breakdown of the nerve barrier and loss of sympathetic neurons. This disrupts the body's ability to burn energy and contributes to further weight gain. We further show that restoring β2-adrenergic signalling or partially reducing leptin levels can preserve this protective barrier and rescue nerve function. Finally, we identified the same cell population in human sympathetic ganglia and found that common genetic variants in LEPR and ADRB2 have synergistic effects on increased obesity risk in men, highlighting the relevance of these findings to human obesity.
For decades, the perineurium has been regarded primarily as a protective sheath that surrounds the peripheral nerves, providing mechanical support. These findings redefine its biological significance by demonstrating that sympathetic perineurial cells are active regulators of metabolism, integrating hormonal and sympathetic signals to control energy expenditure. This discovery establishes an entirely new biological role for the perineurium, opens a new direction for research into neuro-metabolic regulation and identifies a potential therapeutic target for obesity that complements current appetite-based therapies.
The research was led by Dr Gitalee Sarker in DPAG but involved multidisciplinary collaboration involving researchers from Oxford and research partners across Europe and the United States, combining expertise in metabolism, neuroscience, single-cell genomics, advanced imaging, genetics, structural biology, and human cohort analysis. The study included contributions from collaborators at institutions including the Novo Nordisk Research Center Oxford (UK), Novo Nordisk (Denmark), Department of Biology, University of Oxford (UK), Universidade de Santiago de Compostela, Santiago (Spain), Institute of Pharmacology and Toxicology, Technical University Munich (Germany), IRCCS San Raffaele Scientific Institute (Italy), Instituto de Tecnologia Quimica e Biologica Antonio Xavier, ITQB NOVA (Portugal), and UT Southwestern Medical Center (USA).
You can read the paper in Nature Metabolism, which chose this at their cover story for the issue.