Study pinpoints "interpreter" cells that trigger burning of deep fat

The human body contains a number of different types of fat, and one with particularly insidious effects is visceral fat, which can be found deep inside the abdominal cavity. These deep-lying fat stores wrap around the organs and are linked to a range of health conditions, but a new study has revealed a chain of command that guides their metabolism, opening up some exciting possibilities around how they might be more effectively burned away.

Led by scientists at Portugual's Champalimaud Research Programme, the study sought to delve into the highly complex relationship between the brain and the mechanisms that maintain a healthy level of visceral fat in the body.

In normal quantities, visceral fat plays an important role in biological functions such as reproduction, but when it builds up to surplus levels it releases unhealthy proteins, hormones and chemicals that increase our vulnerability to a range of conditions. The list also includes cytokines that drive up the risk of cardiovascular disease, and free fatty acids that impact production of blood lipids.

Ultimately, visceral fat is directly linked to high-cholesterol, insulin resistance and subsequently a heightened risk of obesity, which itself is associated with all kinds of health risks, including cancer.

"Excess visceral fat is very dangerous and at the same time very difficult to eliminate," explains Henrique Veiga-Fernandes, principal investigator. "In this project, our team set out to explore the mechanisms that naturally reduce it, with the hope of uncovering potential clinical applications."

One thing that sets hidden visceral fat apart from the subcutaneous fat beneath the skin that you can grab a hold of, is the complex mix of tissues, nerve fibers and many different cell types that comprise its makeup. The authors of the new study were interested in the role an immune cell called ILC2 (Type 2 Innate Lymphoid Cell) plays in this environment, and more specifically, what might be regulating its activity.

"ILC2s are essential for various immune functions in many tissues and organs, including maintaining the overall well-being of fat tissue," explains Ana Filipa Cardoso, the first author of the study. "However, we didn't know which cells control ILC2s in visceral fat and what molecular messages they use to communicate."

Earlier experiments had shown that the nervous system can direct the activity of ILC2s in the lungs, but the team found no such interactions at play here. After carrying out a complex set of experiments the team pieced together a communication sequence tying together brain function and visceral fat burning, and it implicates a once-overlooked middle man.

The job of mesenchymal cells (MSCs) had long been thought of as predominantly providing structural scaffolds over tissues for other cells to function, but the team found them to play an influential role in this context. Neural signals are taken onboard by the MSCs, which then relay those signals to the ILC2s, which in turn respond by directing fat cells to dial up their metabolism.

"It's as though the neural and immune cells don't speak the same language, and the MSCs serve as an interpreter," Veiga-Fernandes says. "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."

Through their analysis, the scientists also found the origins of this fat-burning communication sequence, pinning it to the hypothalamus (PVH) structure near the base of the brain. According to the team, this constitutes the first known neuro-immune process through which brain signals direct immune function in visceral fat stores, and it offers up a number of interesting new possibilities for how it might be manipulated for better health outcomes.

"This finding is quite significant," says 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."

The research was published in the journal Nature. 

Source: Champalimaud Foundation