Obesity has been linked to an increased risk of 13 types of cancer, including breast and colorectal, the two most prevalent cancers, together with cardiovascular disease, one of the leading causes of death worldwide.
The most harmful type of obesity is caused by excessive accumulation of visceral fat, commonly called "deep" fat. While the most visible fat stores, or subcutaneous fat, are located directly under the skin, visceral fat is the fat stored inside our abdominal cavity, surrounding our vital internal organs. Normal amounts of visceral fat support a number of fundamental functions, such as reproduction. However, too much visceral fat produces unhealthy levels of proteins and hormones that negatively impact neighbouring tissues and organs, and it can be very difficult to eliminate.
DPAG’s Associate Professor Ana Domingos has collaborated with researchers from the Champalimaud Research Programme in Portugal and the Max Planck Institute for Metabolism Research in Germany to explore the mechanisms that naturally reduce visceral fat with the aim of uncovering potential clinical applications to benefit patients suffering from obesity. In doing so, they have uncovered the first known neuro-immune process by which brain signals instruct immune function in visceral fat stores. This discovery offers several new approaches to tackle obesity and its related illness.
Visceral fat is a complex tissue made up of many different cell types in addition to fat cells, including immune cells. The team was particularly interested in a type of adipose-resident immune cell called ILC2s (Type 2 Innate Lymphoid Cells) because they are essential to the immune functions in many tissues and organs, including the overall health of fat tissue. What was previously unknown was which cells control ILC2s in visceral fat and how these cells communicate at the molecular level. Previous related research in the lung had shown that the nervous system directly controls ILC2 activity, but in this new study, neurons and immune cells did not communicate. Instead, researchers found there is an unexpected critical mediator of neuro-immune communication in visceral fat: Mesenchymal cells (MSCs), which had previously been widely considered to be a ‘bystander’. Until recent decades, the widespread view was that MSCs are mainly involved in producing the ‘scaffolding’ of the tissue, over which other cells would carry out the rest of the work. Scientists have since discovered that MSCs in fact carry out several important and active roles within tissue.
Prof Domingos said: “We demonstrated that sympathetic neurons in visceral fat provide local signals to MSCs, and that those in turn control ILC2s. This triad of cells seems to control fat mass and could be pharmacologically exploited for the development of new anti-obesity drugs.”
The team were also able to demonstrate what area of the brain is ultimately responsible for driving this neural activity at the visceral fat stores. Researchers found that a region within the hypothalamus (called PVH), situated near the base of the brain, is the control centre of a diverse set of processes ranging from metabolism to reproduction, gastrointestinal and cardiovascular functions. Co-last author Henrique Veiga-Fernandes describes this finding as “The first clear example of a cross-body neuronal circuit that translates brain information into an obesity-related immune function.”
According to the team, these results provide not one but several potential approaches for visceral-fat-burning manipulations. First author Filipa Cardoso points out that “The multistep axis we identified offers many access points into visceral fat metabolism. 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.” Furthermore, the team’s results both verify and feed into a newly identified field of research. As Prof Domingos says: “This collaborative work body embraces neuroimmunometabolism as an emerging research area.”
The full paper “Neuro-mesenchymal units control ILC2 and obesity via a brain–adipose circuit” is available to read in Nature.
This text is adapted from a press release written by Liad Hollender, Science writer and editor of the CCU Communication, Outreach and Events team.