The goal of this project is to investigate the mechanisms by which leptin deficiency regulates susceptibility to intestinal inflammation in mice. In addition to act as a regulator of food intake and energy expenditure, leptin also modulates the immune and inflammatory response. Preliminary data indicate that leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice are resistant to colitis induced by chronic administration of DSS or TNBS. The current application will attempt to identify the cell populations responsible for the observed effects.
In Specific Aim 1, to evaluate the relative role played by neuronal leptin receptors (Ob-R) in regulation of intestinal inflammation. DSS and TNBS will be administered to mice with a selective deficiency of Ob-R in neurons and their response compared with that of WF mice. To analyze in more detail the role of hypothalamic Ob-R, DSS- and TNBS-induced intestinal inflammation will be studied in mice in which Ob-R have been specifically deleted in the arcuate and ventromedial nuclei of the hypothalamus by injecting a vector expressing cre recombinase into Ob-Rflox/flox mice. Because the effects of leptin on both bone marrow- and non-bone marrow-derived cells could contribute to modulation of colitis in the models of DSS and TNBS administration, in Specific Aim 2 the relative contribution of Ob-R expression in these two cell populations will be investigated using bone marrow chimeras for Ob-R. WT bone marrow will be transplanted into db/db mice, while WT mice will receive db/db bone marrow and colitis development will be studied. Furthermore, the direct effects of leptin on T lymphocytes . Preliminary data indicate that Ob-R expression on donor T lymphocytes regulates induction of colitis in the model of CD4+ CD45RBhigh cells transfer into SCID mice. The transfer model will be employed in the attempt to dissect the relative role played by Ob-R expression in donor T lymphocytes versus cells in the recipient mouse. To investigate the direct role of Ob-R expression in T lymphocytes in the modulation of colitis induced by DSS or TNBS, mice with a selective deletion of Ob-R in T lymphocytes will be employed. Finally, in Specific Aim 3 production of leptin by immune cells at the site of intestinal inflammation will be evaluated in murine models and in biopsies of patients with IBD. The possible participation of immune-derived leptin in the local inflammatory network will also be investigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061483-06
Application #
7277821
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
2003-09-30
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
6
Fiscal Year
2007
Total Cost
$295,586
Indirect Cost
Name
University of Illinois at Chicago
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ponemone, Venkatesh; Fayad, Raja; Gove, Melissa E et al. (2010) Effect of adiponectin deficiency on intestinal damage and hematopoietic responses of mice exposed to gamma radiation. Mutat Res 690:102-7
Pini, Maria; Fantuzzi, Giamila (2010) Enhanced production of IL-17A during zymosan-induced peritonitis in obese mice. J Leukoc Biol 87:51-8
Gove, Melissa E; Sherry, Christina L; Pini, Maria et al. (2010) Generation of leptin receptor bone marrow chimeras: recovery from irradiation, immune cellularity, cytokine expression, and metabolic parameters. Obesity (Silver Spring) 18:2274-81
Gove, Melissa E; Pini, Maria; Fayad, Raja et al. (2009) Adiponectin deficiency modulates adhesion molecules expression and cytokine production but does not affect disease severity in the transfer model of colitis. Cytokine 47:119-25
Gove, Melissa E; Rhodes, Davina H; Pini, Maria et al. (2009) Role of leptin receptor-induced STAT3 signaling in modulation of intestinal and hepatic inflammation in mice. J Leukoc Biol 85:491-6
Pini, Maria; Gove, Melissa E; Fayad, Raja et al. (2009) Adiponectin deficiency does not affect development and progression of spontaneous colitis in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol 296:G382-7
Fantuzzi, Giamila (2009) Three questions about leptin and immunity. Brain Behav Immun 23:405-10
Pini, Maria; Gove, Melissa E; Sennello, Joseph A et al. (2008) Role and regulation of adipokines during zymosan-induced peritoneal inflammation in mice. Endocrinology 149:4080-5
Fantuzzi, Giamila (2008) Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol 121:326-30
Fayad, Raja; Pini, Maria; Sennello, Joseph A et al. (2007) Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology 132:601-14

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