The Accelerating Medicines Partnership® in Common Metabolic Diseases brings together researchers from multiple institutions to work towards the goal of better understanding and treatment of common metabolic diseases. Get to know the members of the consortium in our CMDKP Spotlight articles.
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Professor Ana Domingos ORCID ID 0000-0002-7938-4814), a member of the AMP® CMD Portal Team, is a professor of Neuroscience at the University of Oxford, Department of Physiology, Anatomy, and Genetics.
Ana’s scientific background
Ana I. Domingos is a Portuguese neuroscientist with a focus on the biological mechanisms underlying obesity. Her research lab explores how sympathetic neurons can facilitate fat burning independently of food intake regulation. Professor Domingos is a full Professor of Neuroscience in the Department of Physiology, Anatomy, and Genetics at the University of Oxford, UK. Originally trained as a mathematician, professor Domingos transitioned to life sciences in the early 2000s, pursuing a Ph.D. in neurobiology at Rockefeller University. Under the supervision of Leslie Vosshall, she researched the sensory systems involved in our sense of smell. As a postdoctoral fellow, professor Domingos worked with Jeffrey Friedman, mapping brain circuits underlying preferences between natural and artificial sweeteners and studying the influence of the hormone leptin on sugar reward. Prior to her move to Oxford, Domingos established her own lab at the Gulbenkian Institute in her home country Portugal, where she made significant discoveries, including identifying sympathetic neurons in white adipose tissue that burn fat and macrophages that suppress this process.
Current research interests
The Domingos lab is currently exploring ways to regulate sympathetic neural networks to achieve safe metabolic control and weight loss without relying on appetite suppression. The lab’s focus is on orchestrating the action of sympathetic neurons in metabolically relevant tissues to protect against obesity by primarily targeting energy expenditure. Notably, while brain-acting sympathomimetics can effectively increase energy expenditure and reduce body weight, they also trigger widespread sympathetic activity that raises heart rate. These adverse cardiac side effects have often led to the withdrawal or rejection of such medications by regulatory agencies, despite their efficacy in weight reduction. As a result, current treatment options are largely confined to appetite suppression, which can lead to a compensatory decrease in energy expenditure and subsequent weight regain. Therefore, while reducing food intake is essential for treating obesity, maintaining higher energy expenditure is crucial for long-lasting and more effective therapies. The Domingos lab aims to achieve this by selectively manipulating subsets of sympathetic neurons to promote weight loss without suppressing appetite or causing unwanted cardiac side effects.
Reflections on AMP-CMD and the CMDKP
As a AMP-CMD grant holder, professor Domingos’ work makes a difference in the AMP-CMD program because it will expand the scientific reach by generating data on less-studied tissues within the AMP-CMD research plan, specifically on sympathetic neurons that are well-known to control various aspects of metabolism that go beyond suppression of food intake, including, lipolysis, thermogenesis, browning, and glucose homeostasis. professor Domingos’ work will bring in novel data and experimental approaches to better identify effector transcripts in sympathetic neurons and in vitro models to analyze their function in these neurons.
The AMD-CMD initiative fosters collaboration between private and public sector stakeholders to consolidate and collectivize databases, resources and capabilities to benefit from economies of scale. professor Domingos shared that she finds this initiative exciting because it will enable basic discovery science and development of therapies for obesity, her field of study and several other metabolic diseases which have common pathogenic drivers and overlapping molecular pathways.
The AMP CMD Knowledge Portal (CMD-KP) inspired the working hypothesis in professor Domingos’ recent Nature study, where they discovered that Neuropeptide Y (NPY), produced by sympathetic neurons, plays a protective role against obesity by sustaining thermogenic adipose tissue, which dissipates energy as heat. This finding in mice provides a biological explanation for a human genetic association identified by the CMD-KP. The Human Genetic Evidence (HUGE) score on the CMD-KP indicated that NPY is linked to human body mass index but not to changes in food consumption patterns. This is surprising, given that numerous studies have shown NPY's role in the brain as an orexigenic peptide, promoting food intake. How, then, could variations in NPY, known for stimulating appetite, be associated with higher BMI without affecting feeding behavior? Professor Domingo’s study offers a potential explanation, suggesting that energy dissipation might play a more significant role than appetite in maintaining body weight for some individuals, if not more.
The results indicate that NPY, produced by sympathetic nerves outside the brain, has an effect on body weight that contrasts with central NPY's role. Specifically, peripheral NPY, released by neurons of the sympathetic autonomic nervous system, supports the proliferation of a subset of progenitor cells that differentiate into a special type of adipocyte that burns fat rather than storing it. Various fat depots contribute to body weight regulation and are categorized into three types: white, beige, and brown. While white fat stores energy, beige and brown fat burn it to produce heat, dissipating energy through a process called non-shivering thermogenesis.
The CMD-KP provides genetic evidence suggesting that not all obesity is linked to changes in eating behavior; targeting specific mechanisms that regulate energy expenditure could be crucial. One promising strategy involves directly manipulating subsets of sympathetic neurons that enhance fat burning without reducing food intake.
https://www.nature.com/articles/s41586-024-07863-6
Life outside the lab
When asked about life outside the lab, professor Domingos shared that she lives in Oxford, where she enjoys hosting barbecues or dinner parties for her friends, collaborators, and research group. She also loves playing jam sessions on her flute and piano. Whenever possible, she likes to visit her beach house in Paço de Arcos, a charming fishing village in Portugal, where she catches up with old friends and family and spends time with her family dog, Bica, a lovable mutt who lives there. She also cherishes visiting her husband's family in the Netherlands. When she’s not traveling or working, she prioritizes spending quality time with her family.
