Role of iNKT cells and the lymphoid structures within visceral adipose tissue in the control of inflammation and obesity

Obesity has become a major health issue in most industrialised countries. It predisposes to cardiovascular disease and is associated with premature mortality. Chronic inflammation in adipose tissue is important in obesity, but use of anti-inflammatory therapies has had very modest or no efficacy in restoring metabolic health. Recent studies showed that stimulations of certain populations of immune cells in adipose tissue could improve inflammation, induce weight loss and ameliorate type 2 diabetes. But the precise mechanisms involved remain unknown. One fat depot, the omentum, is particularly rich in immune clusters where inflammatory cells are concentrating during infection and peritonitis (inflammation of the peritoneal cavity). In this project, we want to understand the role of the omentum in the regulation of inflammation and the development of obesity. In particular we wish to elucidate whether this organ is responsible for the beneficial effect of immune-intervention in obesity. We will use a mouse model of peritonitis to study the role of the omentum in inflammation. This work will enhance our knowledge concerning the mechanisms underlying inflammation and the defense of the peritoneal cavity against infections and open new roads for the development of therapeutics tools in the treatment of inflammation in obesity. Using a mouse model of obesity we will examine the role of the omentum in the development of obesity and its treatment by immune-intervention. This work will pave the way to future translational studies looking at the omentum in humans and the therapeutic benefit of their targeting in inflammatory settings (such as appendicitis and pancreatitis) and in obesity.

Adipose tissue represents an important interface between metabolism and immunity, but the molecular and cellular details of this interaction are poorly understood. Invariant Natural Killer T (iNKT) cells, a subtype of T cells enriched in adipose tissue, play a role in this interaction since extrinsic activation of these cells induces weight loss and ameliorates type 2 diabetes in mice. In addition, we recently showed that iNKT cells are also essential to the formation of Fat Associated Lymphoid Clusters (FALCs) in visceral adipose tissue during peritoneal cavity inflammation (Benezech et al, submitted). In this project, we want to determine whether the metabolic regulatory function of iNKT cells is linked to their ability to induce lymphoid cluster formation in adipose tissue. Most lymphoid clusters in the peritoneal cavity are concentrated in the omentum, but despite the omentum being known to recruit inflammatory cells into its "milky spots" (MS) during peritoneal immune challenges, the function of this organ in inflammation is poorly understood. Our preliminary experiments revealed that MS and FALCs regress during obesity. This regression is reversed by iNKT cell activation, driving a massive expansion of MS and FALCs via the recruitment of inflammatory monocytes and macrophages while their number decreases in adipose tissue. This led us to formulate the following hypothesis: MS and FALCs exert a metabolic regulatory function in the peritoneal cavity and in adipose tissue through local regulation of inflammation. Therefore, using mouse models of inflammation and obesity in relevant knockout mouse strains and omentectomised mice, we will test this hypothesis by investigating:
- The roles of MS and FALCs in the regulation of peritoneal cavity inflammation.
- The roles of MS and FALCS in the regulation of inflammation during obesity and iNKT cell treatment of obesity.
- The role played by iNKT cells in the regulation of adipose tissue macrophages during obesity.

The biological importance of the omentum and the lymphoid clusters associated with adipose tissue could be far reaching and be relevant to several aspects of health and wealth. The ultimate beneficiaries of this research project will be the patients in the following areas:

Obesity: Obesity, has become a major health issue worldwide but effective therapies are currently lacking. The work that will be performed as part of this proposal will significantly improve our understanding of the relation between adipose tissue, inflammation and obesity. It will provide significant advances at the basic science level identifying the role of the omentum and milky spots in obesity and whether the immunological properties of the omentum needs to be harnessed during iNKT cells therapies. This project will offer a new vision on the obesity-associated chronic inflammation, which may lead to the development of much needed novel therapeutic interventions.

Visceral Surgery, Peritonitis:
This study, by giving a new understanding of the role of the omentum and milky spots in inflammation, may lead to a better treatment of peritonitis.

Cancer:
The omentum and the milky spots play a role in the progression and metastasis of tumours arising in the peritoneal cavity (eg ovarian and pancreatic carcinomas). This work, by providing a better understanding of the role played by milky spots in inflammation and in metabolism, will help the design of future studies and therapeutic tools targeting the omentum and milky spots in tumor metastasis.

In exploring these opportunities, there are implications for wealth generation, including industrial partners who will potentially have access to outputs from the research that could provide opportunities to develop new patient treatments.