Final Progress Report
Proposal No. IBD-0001
Principal Investigator: Giamila Fantuzzi, Ph.D.
Applicant Organization: University of Colorado (Denver, U.S.A.)
Project Title: The leptin receptor: Role in inflammatory bowel disease
Period of Award: January 1, 2002 - February 29, 2004
A. Summary of project aims.
The goal of this project was to investigate the role of leptin and the long form of its receptor (OB-Rb) in the susceptibility to intestinal inflammation in mice. In addition to acting as a regulator of food intake, leptin also modulates the immune and inflammatory response. Preliminary data indicated that leptin-deficient (ob/ob) and OB-Rb-deficient (db/db) mice are resistant to colitis induced by chronic administration of dextran sodium sulphate (DSS). The hypothesis of this proposal was that leptin, acting through OB-Rb, modulates responsivity to intestinal inflammation. In specific aim #1, the mechanism(s) by which leptin influences disease development in the chronic model of DSS-induced colitis was investigated. In specific aim #2, the role of OB-Rb in intestinal inflammation induced by transfer of CD4+ CD45RBhigh cells was investigated by comparing the effect of transferring WT or db/db CD4+ CD45RBhigh cells into scid recipients.
The project was funded for one more year beyond the original submission. Specific aims for the second year included the evaluation of the relative role of neuronal versus T lymphocyte expression of Ob-R in regulating intestinal inflammation.
B. Accomplishments towards meeting those aims.
Concerning specific aim #1, we have performed detailed experiments looking at the role of leptin and leptin receptors in DSS-induced colitis. Results obtained using leptin-deficient mice have been published in Gastroenterology 122:2011-2025, 2002. See the article for details on the results obtained. Because results obtained using leptin receptor-deficient mice were overlapping with those obtained using leptin-deficient, we have not yet published those data and are planning on incorporating them inside a more extensive report.
The goal of the second aim for to investigate the role of leptin receptors in colitis induced by transfer of CD4+ CD45RBhigh cells. The majority of the experiments planned in the proposal have been performed and are published in Gut 53:965-972, 2004, which was accompanied by a comment article written by Dr. G. Matarese, an expert in the field of leptin and immunity. The comment article highlighted the importance of the results obtained. See the article for details on the results obtained using this model.
Unfortunately, due to technical problems in breeding mice with specific deletion of leptin receptors on neurons or T lymphocytes, we have currently been unable to perform most of the experiments proposed for the second year. We have however recently overcome those problems and have begun characterizing the immune response in tissue-specific leptin receptor-deficient mice. This part of the project will be continued under funding from NIDDK.
Because IFNγ seemed to be a critical factor in mediating the effects of leptin in intestinal inflammation, we have performed some studies that were not originally planned in the proposal in order to evaluate the role of IRF-1, a transcription factor that controls production of IFNg and other inflammatory mediators, in colitis. These results are reported in the European Journal of Immunology 34:2356-2364, 2004. See the article for details on the results obtained using this model. Because of the potential importance of the results obtained, the manuscript was chosen as a Flagship Article and was especially highlighted.
C. List of significant results (positive or negative).
1) Leptin and leptin receptors are involved in regulating experimental intestinal inflammation in three different models.
2) The role of leptin in regulating intestinal inflammation is mediated by its effects – direct or indirect – on immune cells and products synthesized by these cells.
3) Leptin is produced at the site of intestinal inflammation by immune cells.
4) Expression of leptin receptors by immune cells homing to the intestine modulates intestinal inflammation.
D. Lay summary of this report.
The goal of this project was to study the role of leptin in experimental models of inflammatory bowel disease (IBD) in mice. Leptin is a protein produced by fat cells. Leptin exerts its effects by binding to its receptor, called OB-Rb, which is present on the surface of many types of cells. Leptin regulates appetite, but also modulates immunity and inflammation. Since in IBD immune cells and inflammatory mediators are responsible for initiation and chronicity of disease, we believe leptin could be an important factor regulating IBD. To study the role of leptin and its receptor in IBD, we used mice which do not produce leptin or its receptor and investigated their response in different models of IBD. We demonstrated that the lack of leptin or of its receptor leads to resistance in models of IBD and that this resistance is due to the effect of leptin in regulating the activity of cells of the immune system.