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BrainBody
1-3 October 2025
 
HomeProgramSpeakersAna Domingos

Ana Domingos

Department of Physiology, Anatomy & Genetics, University of Oxford

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Title 

Sympathetic neurons in obesity

Abstract

Obesity is a public health concern with limited treatment options, mainly focusing on sup-pressing appetite. However, reduced food intake triggers a compensatory decrease in energy expenditure (EE), hindering weight loss. Effective obesity management medications that elevate energy expenditure, such as brain-acting sympathomimetics, increase widespread sympathetic activity, raising the heart rate. This often results in their market withdrawal or rejection by regulatory agencies despite their potency in reducing body weight. Thus, cardio-protective EE-boosting drugs are an unmet medical need.
My lab (1) and others have shown that directly facilitating the activity of sympathetic neurons (outside the brain) drives weight loss without suppressing food intake or inducing cardiac side effects. Our lab has demonstrated that sympathetic neurons directly burn fat (2), producing norepinephrine that simultaneously triggers lipolysis and thermogenesis, and neuropep-tide Y (NPY) that sustains the progenitors of thermogenic adipocytes3. This mechanism may explain why, in humans, defects in NPY are associated with high BMI but not with changes in feeding patterns or cardiovascular parameters (3).
Fat-burning sympathetic neurons are protected by thin anti-inflammatory IL33-expressing perineurial barrier cells (4) that shed away as leptin levels gradually rise as mice fatten up (5). The leaky perineurial barrier permits the invasion of sympathetic-associated macrophages, which contribute to obesity by importing and metabolizing norepinephrine (6). Pharmacologically re-versing any of these biological processes may pave the way towards cardioprotective EE-boosting anti-obesity drugs.


1. Mahú, I., et al, Bernardes, G. J. L. & Domingos, A. I. Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects. Cell Metab. 2020
2. Zeng, W., et al Domingos, A. I. Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis. Cell 2015
3. Zhu, Y., et al & Domingos, A. I. Sympathetic neuron derived NPY protects from obesity by sustaining the mural progenitors of thermogenic adipocytes.  Nature. 2024
4. Haberman, E. R., et al., Domingos, A. I.. Immunomodulatory Leptin Receptor+ Sympathetic Perineurial Cells Protect Against Obesity by Facilitating Neuroendocrine-Mediated Brown Adipose Tissue Thermogenesis. Immunity. 2023
5. Sarker, G., et al., Domingos, A. I. (2023) The perineurium integrates leptin with its sym-pathetic outflow to protect against obesity. Under review at Nature. bioRxiv.
6. Pirzgalska, R. M., et al Domingos, A. I. Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nature. Med. 2017.

Biosketch

Ana I. Domingos is a Professor of Neuroscience at the University of Oxford. Her laboratory discovered the sympathetic neuro-adipose axis mediating leptin's lipolytic effects, providing the first visualization of adipose sympathetic neurons essential for fat mass reduction via norepinephrine signaling. Her team identified Sympathetic neuron-Associated Macrophages (SAMs), contributing to obesity by metabolizing norepinephrine, findings that inspired the development of sympathofacilitators—a novel class of peripheral anti-obesity drugs free from central nervous system side effects. Domingos’ research focuses on the pharmacological regulation of autonomic functions to combat obesity safely, pioneering the emerging field of Neuroimmunometabolism. Her group has extensively reviewed this field (Nature Reviews Endocrinology, Annual Review of Cell and Developmental Biology, Neuron) and organized dedicated conferences, including the Keystone Symposium (2022). Domingos serves as editor-in-chief of the American Journal of Physiology - Endocrinology and Metabolism and holds editorial roles at Cell Metabolism and eLife. Her numerous accolades include the EMBO Installation Award, Human Frontiers Science Program Award, Howard Hughes Medical Institute–Wellcome International Scholar Award, ERC-Consolidator Award, Pfizer Aspire Obesity Award, Carl Ludwig Lectureship, BBSRC Grant, and NIH Opportunity Pool Award. She has been invited to speak at over 70 international conferences.