In a new review article, published in Annual Review of Immunology, Charles Sweeney and colleagues offer a framework of how sympathetic circuits and the immune systems cooperate to regulate body weight and how these systems can go awry in both obesity and cancer. They discuss emerging evidence implicating sympathetic neuropathy in the pathogenesis of obesity.
Under healthy conditions, sympathetic neurons send signals deep into fat tissue, instructing fat to burn energy. The review details how this signaling depends on a supporting cast of immune cells in fat: macrophages that fine-tune, monitor and respond to the local concentration of the sympathetic neurotransmitter noradrenaline; innate lymphoid cells that amplify thermogenic activity in brown fat; and T-cells that promote the conversion of energy-storing white fat into energy-burning beige fat.
A newly described cell type, the sympathetic perineurial cell (SPC), emerges as a critical rheostat in this network. SPCs constitute a physical barrier that simultaneously senses adiposity via leptin and releases the cytokine IL-33 to maintain anti-inflammatory immune populations that facilitate fat metabolism and protect sympathetic neurons and their output to fat.
In obesity, this balanced system begins to break down. Chronically elevated leptin triggers the progressive death of the SPC barrier, removing their protective anti-inflammatory function. Without the SPCs’ IL-33, inflammation of fat occurs, and sympathetic-to-adipose signaling is lost, brown fat thermogenesis is extinguished, and weight gain accelerates. The authors describe this process as sympathetic neuropathy in obesity: a slow-onset, self-reinforcing deterioration that mirrors the gradual trajectory of weight gain seen in adult-onset obesity.
Why is this work important?
The review also charts an emerging and largely unexplored link between these neuroimmune mechanisms and cancer. Tumors are known to exploit the nervous system for their own benefit, recruiting sympathetic, sensory, and parasympathetic nerve fibers to fuel growth. The authors propose that the perineurial barrier, progressively dismantled in obesity, may be the same barrier that cancer cells must breach to invade and co-opt surrounding nerves. This process, known as perineural invasion, is a recognized marker of poor prognosis across many tumor types, but its connection to obesity has never been systematically examined.
Professor Domingos, who pioneered the visualization and functional characterization of sympathetic innervation of white adipose tissue, added, 'The perineurial cell is emerging as a central node in this network. Its capacity to integrate leptin signals, neuronal and immune cues make it a compelling candidate for therapeutic intervention in obesity. My group will undertake further research as part of the InteroCANCEption Cancer Grand Challenges team to investigate how the nervous system detects and influences tumor development '
'Obesity and cancer are diseases with intersecting biology. One is defined by excess adiposity, the other capable of driving catastrophic muscle and fat loss, yet the neuroimmune mechanisms linking them remain poorly understood" comments first author Charles Sweeney. 'By mapping the sympathetic neural networks influencing fat tissue, we hope to provide a framework that points toward new treatment targets, not just for obesity, but for the cancers that so often follow it.'
The review highlights several therapeutic avenues arising from this body of work which can strengthen the sympathetic nerve-to-fat connection. Sympathetic NPY is critical for the maintenance of mural cells; progenitors that replenish the body's thermogenic fat and keep energy expenditure high. Brain-sparing sympathofacilitators, which selectively boost sympathetic activity without adverse cardiovascular effects, have already shown promise in preclinical models of obesity. Neurokinin-2 receptor agonists represent another approach, driving brown fat thermogenesis and suppressing appetite without the systemic side effects of earlier anti-obesity drugs. Looking further ahead, the authors suggest that restoring the integrity of the sympathetic-fat connection may provide a more refined and targeted treatment for obesity than manipulating appetite.
Charles Sweeney, who led this review, is a research assistant at the Domingos group, DPAG, University of Oxford, and a graduate entry-medical student at University College Dublin. His work on 'neuroimmunometabolism as a regulator of obesity', published in a recent book edited by Professor Luke O’Neill’s group at Trinity College Dublin, laid the groundwork for this review. He worked with Hanyu Liu (former member of the Domingos group), Matthew Dean, the CEO and Co-Founder of SerovaBio, and Professor of Neuroscience Ana Domingos (DPAG, University of Oxford).