Discovered some 40 years ago, the Y neuropeptide (NPY) is one of the organism’s most abundant neurotransmitters. It has long been known that it acts on the brain, stimulating the appetite and inducing weight gain. An international group, including researchers from the University of Campinas (UNICAMP), has found that it performs a different function in the rest of the organism: secreted by the peripheral nerves that connect the brain and spinal cord to other organs and tissues, NPY promotes the formation of brown adipose tissue (body fat). Known as “good fat,” this tissue consumes a lot of energy (rather than just storing it) and generates heat, thereby protecting against obesity.
“When fed on the same balanced diet, mice genetically modified not to produce NPY in the peripheral nerves ended up weighing twice as much as animals from the control group, who secreted the neurotransmitter normally,” recounts immunologist Licio Velloso, of UNICAMP, coordinator of the Obesity and Comorbidity Research Center (OCRC), one of the Research, Innovation, and Dissemination Centers (RIDC) funded by FAPESP, and a coauthor of the article that described the discovery, published in August in the journal Nature.
Working with researchers from the UK, Japan, China, and the US, the Campinas team helped to identify and characterize the new role of NPY in experiments on laboratory animal cells. The first step was to identify and map which neurons of the sympathetic nervous system released the neurotransmitter. This part of the nervous system is activated in situations of stress or danger, and prepares the body for fight or flight. Some of these neurons also innervate the white fatty tissue, which specializes in storing energy in the form of fat; and the brown, which consumes fat and transforms it into heat.
At the UK’s University of Oxford, a group working under Portuguese neuroscientist Ana Domingos used antibodies that adhere to NPY to mark it and track its release in the fat tissue. The researchers found that some 40% of sympathetic system neurons arriving at the fat tissue produce the neurotransmitter, noting that they also connect to the mural cells, which envelop the small arteries (arterioles) but take blood laden with oxygen and nutrients to the fat tissue. Laboratory testing demonstrated that NPY induces proliferation of the neural cells, and their transformation into thermogenic adipocytes, which consume energy and release heat when the body is subjected to cold or physical activity; these cells are the key component of brown adipose tissue.
“Our work confirms that the NPY secreted by the peripheral nerve stimulates the formation of brown fat tissue,” explains Domingos, coordinator of the study, to Pesquisa FAPESP. This type of fat is rich in mitochondria, cell structures specialized in producing energy, but in a type that also generates heat. In early life, brown fat is present in large quantities in the human body, almost disappearing in adults and being replaced by a beige fat with fewer mitochondria. “It is estimated that these tissues expend 200 to 300 kilocalories per day, equivalent to around 10% of the total normally ingested by a person,” Portuguese physiologist Jorge Ruas, of the University of Michigan, who did not participate in the study, told Pesquisa FAPESP.
At UNICAMP, Velloso’s team tested the effects of an absence of NPY in the sympathetic nervous system. Mice genetically modified not to produce this neurotransmitter only in the peripheral nerves had a lower body temperature and expended some 10% less energy than those in the control group, who secreted the neuropeptide in the whole organism. With a normal diet, rodents from the first group became obese after adulthood, even when consuming the same amount of food as those in the second. “They expended less energy and stored part of it in the form of fat,” says Velloso. When fed on a hypercaloric diet rich in fats, the animals not producing the neuropeptide put on more weight more quickly.
The study’s authors also observed that fat-rich diets damaged the NPY-producing neurons in the sympathetic nervous system, and led to the reduction of mural cells around the arterioles. As a consequence, the blood vessels became more permeable and allowed the overflow of liquid and passage of defense cells, causing inflammation in the fat tissue, a characteristic of obesity.
Brazilian neuroscientist Ivan de Araújo, director of the Max Planck Institute for Biological Cybernetics in Germany, who did not participate in the study, was most surprised by the NPY stimulating the differentiation of the mural cells in thermogenic adipocytes. “For the first time, the study shows that this neurotransmitter plays an important biological role in the sympathetic nervous system, and paves the way for the creation of new medications to modulate energy expenditure,” he says.
“Our findings suggest that it would be possible to develop compounds that stimulate the basal metabolism and energy expenditure without affecting appetite,” says Oxford’s Domingos.
Medications based on GLP-1 hormone analogs, such as semaglutide or tirzepatide, which have become well-known in the treatment of diabetes and obesity, act on the brain and reduce appetite, but do not stimulate energy expenditure. “The loss of fat with this type of treatment is limited, as the body compensates the reduced ingestion by lowering energy output,” highlights Velloso. He says that a medication with similar effects to those of NPY would stimulate the formation of brown fat and energy use, prolonging weight loss caused by appetite reduction medicines.
“One of the challenges,” says Max Planck’s Araújo, “is to find a way of activating only the mural cells, as in other parts of the body the NPY receptors can have different effects.” Ruas, of Michigan, adds that it is necessary to confirm whether the increase in brown fat would in fact help a person to lose weight. “There could be an increase in body temperature and sweating, and it’s important to check whether these effects will be tolerable,” he says.
The story above was published with the title “A dual-action neurotransmitter” in issue 345 of November/2024.
Scientific article
ZHU, Y. et al. Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat. Nature. Aug. 28, 2024.
