Lymphotoxin Beta Receptor Signalling Effects on Adipogenic Differentiation

All living organisms have specific mechanisms that protect them from invading pathogens. Humans and mammals have a highly developed immune system to contain and eliminate infectious agents. While most immune responses are beneficial for the body, uncontrolled responses during chronic inflammatory diseases such as rheumatoid arthritis result in destruction of tissues and organs.
Several different cells types with specific roles form part of the immune system. Interactions between different immune cells take place in a coordinated manner to produce the proper immune response to deal with the infecting pathogen. Such cell-cell interactions must be orchestrated in specific environments that are part of organs called lymphoid tissues such as lymph nodes. Stromal cells form the supporting structure of the lymph nodes and contribute to immune responses and inflammation. Our previous work has demonstrated that a specific signal is necessary for lymph node stromal cells to mature and form these organs. More recently we have shown that the signal mentioned above is sufficient to induce changes in fat cells present in adipose tissues to become part of the lymph nodes. The current project would study how this signal is transmitted inside the fat cell and the reprogramming effects in its genetic information that results in the loss of characteristics of adipose cells and the appearance of new features proper of lymph node cells.
Our findings suggest that fat cells can change their properties and support inflammation and immune responses. Thus the importance of this project is based on the understanding of the signals and mechanisms that can induce adipose tissue cells to change their features resulting in the induction of inflammation characteristic of obese patients.
As a result of this project we will identify modifications in genetic information in fat cells induced by specific signals. These changes will be analyzed and compared to the effect of similar signals in vivo in situations were a large number of fat cells are present and thus contribute to inflammation.

Obesity is among the main health problems affecting the Western world and the developing countries with a major impact on lifelong health quality. The latest statistics show that a quarter of adults were obese in England in 2008 (NHS Report Feb. 2010). Obesity is directly linked to the development of chronic diseases that result in a reduced quality of life and premature death. Thus, the importance of research in understanding the factors that drive adipocyte differentiation and the mechanisms of hyperplasia and hypertrophy of adipose tissues underlying obesity cannot be overstated. Although obese patients suffer low levels of systemic inflammation, the links between obesity and inflammation are not clear.
Our recent work has shown that adipocyte precursor cells and stromal cells from lymphoid tissues might have a common origin. Signalling through the Lymphotoxin Beta Receptor controls the fate of adipocyte precursor cells by blocking adipogenesis and instead promoting lymphoid tissue stromal cell differentiation. We propose that adipose tissues act as a reservoir of lymphoid stroma for lymphoid structures associated with fat. During inflammation adipocyte progenitor cells will respond to environmental signals and differentiate into lymphoid tissue stromal cells that support immune function and contribute to inflammation. Our hypothesis is that LTbR-signalling functions as a switch between adipogenesis and inflammatory responses.
This project aims at unraveling the novel role of the Lymphotoxin Beta Receptor signalling pathway during adipogenic differentiation and its contribution to inflammation. We will use cellular and molecular approaches combined with mouse genetics to address this topic.
Our objectives are: 1- To dissect the Lymphotoxin Beta Receptor signalling mechanism that blocks adipogenic differentiation, 2- To identify the LTbR-NF-kB target genes and the effects on chromatin configuration of this signalling pathway during adipogenic differentiation.

Adipocyte precursor cells have the capacity to differentiate into adipocytes in vivo. Hyperplasia and hypertrophy of adipose tissue cells contribute to obesity and its related diseases including chronic inflammation. Our recent work has shown that adipocyte precursor cells might have a common origin with lymphoid tissue stromal cells. Moreover we have shown that adipocyte progenitor cells contribute to the structure of lymphoid tissues in vivo and that respond to stimulation through the Lymphotoxin beta receptor by blocking their adipogenic differentiation and becoming lymphoid tissue stromal cells capable of supporting immune functions. Based on our results we propose that adipose tissues act as reservoirs of lymphoid stroma.
Our hypothesis is that Lymphotoxin beta Receptor signalling functions as a switch between adipogenesis and inflammatory responses and the formation of tertiary lymphoid tissues. During inflammation adipocyte progenitor cells will respond to environmental signals and differentiate into lymphoid tissue stromal cells that support lymphocyte survival and formation of ectopic lymphoid tissues.
This project will investigate the mechanism by which the Lymphotoxin beta receptor and its downstream effectors block adipocyte differentiation. Thus, this project links adipogenesis and inflammation using specific models to study the link between them.

Who will benefit from this research and how?
Short term beneficiaries of this research are:
- Basic research scientists in the field of inflammatory diseases as well as obesity and its related diseases. Our findings will provide a better understanding of the cells and molecular mechanisms that contribute to obesity and inflammation. More broadly speaking, this knowledge will be useful to scientists interested in the mechanisms controlling stemcellness and the exhaustion of stem cells (including satellite cells) during muscular dystrophies. Finally, it is envisaged that the findings from this study will help researchers working in
Longer term beneficiaries of this research are:
- Clinical scientists working with patients suffering of obesity and/or chronic inflammatory diseases. Our data may help clinical scientists in their diagnosis by providing novel markers to assess the inflammatory syndrome that accompanies obesity. The signaling pathway and its intracellular effectors involved in the block of adipogenic differentiation also induce the expression of molecules that attract and support lymphocyte survival in adipose tissues. This latter effect will contribute to inflammation so it would be beneficial if this pathway can be targeted and manipulated through small drugs. This provides a mean for future translational studies aiming at blocking LTbR signalling in adipose tissue cells in mouse models of obesity. Further studies will be necessary to provide additional understanding, and perhaps lead to potential clinical applications in humans.
- Biotechnology and Pharmaceutical companies interested in new drug discoveries to alleviate obesity-related inflammation, as the focus of this proposal could be used as a target for future drugs.
- Patients, as mentioned above, it is possible that patients suffering obesity, or chronic inflammatory diseases would obviously benefit from any discoveries and applications coming out of this study.