Scientific Abstract

Proposal No.  IBD-0168R
Principal Investigator:  Razvan I. Arsenescu, M.D.
Applicant Organization:  University of Kentucky Research Foundation, Inc. (Lexington, U.S.A.)
Project Title:  Adiponectin in Crohn's disease.  Phenotype-genotype correlations and implications in management. 
Period of Award:  December 1, 2005 - November 30, 2008

Adiponectin is a hormone secreted exclusively by adipocytes that circulates at high concentrations (5-10 μg/mL) to influence metabolic functions.  It decreases triglyceride production and gluconeogenesis while increasing fatty acid oxidation and insulin sensitivity.  Adiponectin spontaneously self-associates into larger structures.  Multimers appear more potent then monomers.  Mutations in the human adiponectin gene that are associated with diabetes result in hypoadiponectemia and absence of HMW forms.  Thus, not only the adiponectin level, but the multimer distribution, should be evaluated in relation to various disease states.

Adiponectin has been shown to exert important immuno-regulatory functions.  The structural features of adiponectin suggest that it belongs to a family of proteins identified as soluble defense collagens, including complement C1q.  Adiponectin negatively regulates TNFα production in adipocytes and macrophages.  The three-dimensional structure of the globular region shows a striking similarity to TNFα, despite unrelated protein sequences, which raises the possibility of competitive inhibition.  Adiponectin can also induce IL10, IL1-RA expression in human monocyte-derived macrophages, thus exerting an anti-inflammatory action.  This results in impaired phagocytic activity and IFNγ production.

Crohn’s disease is thought to result from inappropriate and ongoing activation of the mucosal immune system driven by the presence of normal luminal flora.  Genetic factors contribute to susceptibility in inflammatory bowel disease and several genomic regions were identified.  PPAR-γ (peroxisome proliferator activated receptors gamma), a candidate gene in one of these genetic loci, is known to bind the adiponectin promoter and induce its expression.  Environmental factors such as smoking can modify the phenotype and increase the risk for Crohn’s disease.  Interestingly, smoking significantly decreases the level of adiponectin.

We propose to study the role of adiponectin in Crohn’s disease.  We hypothesize that low adiponectin levels and/or impaired high molecular adiponectin multimer formation may underlie the chronic inflammatory changes in Crohn’s disease patients.  Patients with established Crohn’s disease will be followed prospectively for six months.  This study aims to define a subgroup of Crohn’s disease patients with low adiponectin level and/or abnormal multimer distribution as well as to correlate adiponectin abnormalities with phenotype, genotype and response to conventional therapy.  Selected healthy controls will serve as an age-gender matched control group.

Replacement therapy with recombinant adiponectin would offer a safer anti-TNF therapy with added, beneficial, immunomodulatory properties (IL10) and anti-fibrotic activity.  Thiazolidinediones (PPAR-γ agonists) increase the level of circulating adiponectin and are readily available.