Research by scientists at Champalimaud Research, Champalimaud Centre for the Unknown, has uncovered potential new therapeutic avenues for reducing stores of visceral fat—the type of fat that accumulates in obesity—which are associated with cardiovascular disease and different types of cancer. The findings, reported in Nature, present the first known neuro-immune process by which brain signals instruct immune function in visceral fat stores. Discovery of the brain-adipose circuit offers several novel approaches for fighting obesity and obesity-related illness.

“Excess visceral fat is very dangerous and at the same time very difficult to eliminate,” explained Henrique Veiga-Fernandes, PhD, principal investigator and co-director at the Champalimaud Research Programme in Portugal. “In this project, our team set out to explore the mechanisms that naturally reduce it, with the hope of uncovering potential clinical applications.”

The results of their mouse studies are published in a paper titled, “Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit,” in which the authors concluded, “Our work establishes an inter-organ and multi-tissue communication circuitry that integrates neuronal and mesenchymal signals to orchestrate ILC2 function and obesity.”

Obesity has been linked to no less than 13 cancers, including the two most prevalent, breast and colorectal, as well as to cardiovascular disease, a leading cause of death worldwide. The most harmful type of obesity is caused by the excessive accumulation of what’s known as deep fat. Contrary to subcutaneous fat stores that are located directly under the skin, deep, or visceral fat stores reside inside our abdominal cavity, where they envelop vital organs. At normal quantities, visceral fat supports various fundamental functions, such as reproduction. However, when it is too abundant, it produces unhealthy levels of proteins and hormones that negatively affect neighboring tissues and organs.

Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology, the authors wrote. “Interactions between the nervous and immune systems have recently emerged as important regulators of host defense and inflammation.”

Visceral fat appears as a uniform, yellow mass, but it’s actually a complex, heterogeneous tissue. In addition to fat cells, visceral fat also contains nerve fibers and many different cell types, including immune cells. However, as the authors further noted, “ … it is unclear whether neuronal and immune cells cooperate in brain–body axes to orchestrate metabolism and obesity.”

Visceral fat supports various fundamental functions. However, when it is too abundant, it produces unhealthy levels of proteins and hormones that negatively affect neighboring tissues and organs. In this study, the authors reveal the first known neuro-immune process by which brain signals instruct immune function in visceral fat stores. [@dustinhumes_photography]

The Champalimaud Research team was particularly interested in a type of immune cell called ILC2 (Type 2 Innate Lymphoid Cell). “ILC2s are essential for various immune functions in many tissues and organs, including maintaining the overall well-being of fat tissue,” explained study first author Ana Filipa Cardoso, PhD. “However, we didn’t know which cells control ILC2s in visceral fat and what molecular messages they use to communicate.”

Previous results from the lab had revealed that in the lung, the nervous system directly controls the activity of ILC2s. The team expected to find a similar mechanism in visceral fat, but instead, their studies of visceral fat in gonadal adipose tissue (GAT), discovered something completely different. “The neurons and the immune cells were not talking to each other,” Cardoso recalled. “So we investigated other candidates in the tissue, finally coming across a rather unexpected ‘middleman’.”

Remarkably, the critical mediator of neuro-immune communication in the animals’ visceral fat had been considered, until quite recently, to be just a bystander. “Mesenchymal cells (MSCs) have been widely ignored until about one to two decades ago,” said Veiga-Fernandes. “The widespread view was that they mainly produced the scaffolding of the tissue, over which other cells would ‘do the work.’ However, scientists have since discovered that MSCs carry out multiple essential active roles.”

Through a series of complex experiments, the researchers identified both the chain of command and the molecular messages exchanged across all steps. “It starts with neural signals onto MSCs. MSCs then send a message to ILC2s, to which ILC2s respond by ordering fat cells to rank up their fat metabolism,” Cardoso summarized.

“It’s as though the neural and immune cells don’t speak the same language, and the MSCs serve as an interpreter,” Veiga-Fernandes added. “Taken within the larger context, it does make sense. MSCs effectively make up the tissue’s ‘ecosystem,’ and so they are perfectly situated to fine-tune the activity of other cells.”

Once the team had pinned down the local fat burning circuit, they asked what drives the neural activity at the visceral fat stores in the first place. “The nerve fibers inside visceral fat belong to what is called the peripheral nervous system,” Cardoso explained. “It is in charge of various physiological processes, such as regulating blood pressure. But the peripheral nervous system is not the boss. It is driven by the central nervous system, to which the brain belongs. So we asked next ‘which brain structure is at the very top of the chain of command?'”

The team pinned down a region within the hypothalamus, called the paraventricular nucleus of the hypothalamus (PVH) as the source. This structure, situated near the base of the brain, is the control center of a diverse set of processes ranging from metabolism to reproduction, gastrointestinal, and cardiovascular functions.

“This finding is quite significant,” said Veiga-Fernandes. “It’s the first clear example of a cross-body neuronal circuit that translates brain information into an obesity-related immune function. It also raises many new questions. For instance, what triggers the PVH to issue the ‘fat burning’ command? Is it something related to behavior, such as eating certain foods or exercising? Or is it dependent on internal metabolic signals? Or both? It’s a white canvas—we don’t know what it is, and it’s tremendously fascinating.”

“Here we describe a neuro-mesenchymal unit that controls ILC2s, adipose tissue physiology, metabolism, and obesity via a brain–adipose circuit,” the team concluded. “Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity … our data may also improve our understanding of how abnormal neuronal and immune functions associate with obesity and metabolic disorders in humans.”

According to the team, their results provide several potential approaches for visceral-fat-burning manipulations. “The multistep axis we identified offers many access points into visceral fat metabolism,” Cardoso pointed out. “We can now start thinking about how to use this new knowledge to fight visceral obesity and hence reduce the risk of cardiovascular disease and cancer.”

These efforts are already in motion, Veiga-Fernandes noted. “This is something that we are currently pursuing …” although not in the lab, he continued, which continues to focus on fundamental research questions. Rather, a startup company, LiMM Therapeutics has been established, based at the Champalimaud Centre for the Unknown. “The most challenging thing in a project like this one is that you’re truly working at the frontier. This is not immunology anymore, and it’s not neuroscience either. You have to master technology, methods, and approaches that are cross-disciplinary or multidisciplinary. Some of them don’t even exist, and you have to develop them by scratch. Yet, at the same time, the conceptual challenge is exhilarating; we are truly venturing into the unknown,” Veiga-Fernandes concluded.

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