Domingos Group

The Domingos laboratory researches the neurobiological basis of obesity, focusing on sympathetic neural networks. Obesity is a modern epidemic, and understanding its biological basis is crucial to developing effective therapies that go beyond merely suppressing food intake. Current treatment options primarily focus on appetite suppression, which often leads to a compensatory decrease in energy expenditure, promoting recurrent weight gain—even with modern pharmacological interventions. While reducing food intake is important for managing obesity, sustaining a higher energy expenditure is necessary for therapies to be both effective and long-lasting. This is particularly true in certain types of obesity, where energy dissipation plays a more critical role than energy intake. 

Our recent study has uncovered 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, observed in mice, provides a biological explanation for a human genetic association recently identified by the Common Metabolic Diseases (CMD) Knowledge Portal (KP). This portal is funded by the Accelerating Medicines Partnership (AMP), an initiative of the Foundation for the National Institutes of Health (FNIH), which supports research in Professor Domingos's lab. The CMD Knowledge Portal provides a genetic score indicating the involvement of various genes in diseases and traits based on multiple human genetic datasets. The AMP-CMD-KP identified that NPY is linked to human body mass index but not to changes in food consumption patterns.

This finding is surprising, given that dozens of studies have demonstrated NPY’s role in the brain as an orexigenic peptide, promoting food intake. How, then, could changes in NPY, known for stimulating appetite, be associated with higher BMI without affecting feeding behaviour? Our study, now published in Nature, offers a potential explanation. It suggests that energy dissipation might play a more significant role than appetite in maintaining body weight for some individuals, if not more.

Our results show that peripheral NPY, produced by sympathetic nerves, has an effect on body weight that is opposite to that of central NPY. Specifically, peripheral NPY, released by neurons of the sympathetic autonomic nervous system, supports the proliferation of a subset of progenitor cells that develop into a special type of adipocyte that burns fat rather than storing it. Various fat depots contribute to body weight regulation and can be categorized into three types: white, beige, and brown. White fat stores energy, while beige and brown fat burn it to produce heat, dissipating energy through a process called non-shivering thermogenesis.

It was previously known that thermogenic adipocytes could originate from mural cells, a type of cell that surrounds arterial blood vessels—mural, derived from the Latin word for "wall." It was also known that mural cells could sense NPY because they possess NPY receptors (NPYR1). The Domingos lab now shows that, in the absence of NPY delivered locally by thin axons innervating arterial vessels—preferably medium-sized ones—mice become obese. This obesity is not due to increased food intake but because of reduced energy expenditure caused by reduced thermogenic capacity. NPY helps the proliferation of mural progenitors of thermogenic adipocytes; Ana Domingos comments: “Without NPY in sympathetic nerves, there are fewer fat-burning cells. This mechanism likely extends to other forms of obesity, as the study indicates that NPY-producing sympathetic nerves degenerate with the onset of obesity”.

Not all obesity results from overeating; targeting specific mechanisms that regulate energy expenditure could be key. One promising approach is to directly manipulate subsets of sympathetic neurons that promote fat burning without reducing food intake.

Sympathetic neurons release norepinephrine, which prompts thermogenic adipocytes to burn fat. The Domingos lab found that neuropeptide Y, also released by these neurons, supports the renewal of these fat-burning cells. Targeting these neurons could lead to obesity treatments that burn fat in a sustained manner

_{© Zhu, Y., Yao, L., Gallo-Ferraz, A.L. et al. Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat. Nature (2024)}

This research was conducted by Yitao Zhu under the guidance of Professor Ana Domingos, with the help from Dr Lu Yao and our collaborators around the world including Professor Shingo Kajimura at Harvard Medical School, and Professor Licio Velloso at Unicamp, Sao Paulo. Collaborator on this research Michael Dustin, Kennedy Trust Professor of Molecular Immunology comments, ‘It was fantastic to help visualize how sympathetic neurons supports fat-burning cells which  use energy. Loss of heat producing cells in fat increases inflammation so these new findings are central to the mission of the Kennedy Institute’.  Ana Domingos is a member of the advisory board of Cell Metabolism and her lab has been funded by HHMI, Wellcome Trust, ERC, HFSP, EMBO, among others. 

Previous discoveries by the Domingos group include: the discovery of neuro-adipose junctions, between white adipocytes and sympathetic neurons, that are necessary and sufficient for fat mass reduction via norepinephrine (NE) signalling. Moreover, they discovered Sympathetic neuron-Associated Macrophages (SAMs) that import and metabolize NE. Abrogation of SAM function promotes long-term amelioration of obesity independently of food intake. These findings inspired the development of a new class of anti-obesity compounds named sympathofacilitators, which do not enter the brain, nor have the typical cardiovascular side effects of centrally acting sympathomimetic drugs.  Sympathofacilitator drugs act as an energy sink by coupling thermogenesis to active heat dissipation