Studies of fatty acid binding proteins and inflammatory lipids in adipose biology

Abstract

There are a number of factors spurred by obesity that contribute to the development of insulin resistance, such as adipose tissue inflammation and elevated circulating fatty acid levels. Fatty Acid Binding Proteins (FABP) are soluble proteins that bind long chain fatty acids and other hydrophobic molecules and facilitate their intracellular transport. Mice with genetic disruption of Adipocyte FABP (AFABP) exhibit an insulin sensitizing and anti-inflammatory phenotype on a high-fat diet compared to wild type littermates, however the molecular mechanisms are not completely understood. The goal of the studies presented herein was to gain further insights into the role of AFABP in the development of obesity-related insulin resistance. We identified a small molecule inhibitor of AFABP, HTS01037, that upon treatment of cultured cells recapitulates the beneficial phenotypes observed in AFABP knock out mice. Structural studies were undertaken to characterize the effect of ligand binding to AFABP utilizing x-ray crystallography. More specifically the structures of AFABP bound to one inflammatory lipid, 4-HNE, and the pan-specific FABP inhibitor, HTS01037 were determined. In addition, we found that inflammatory lipids, particularly leukotriene C4, are elevated in obese adipose tissue and are produced by macrophages in response to fatty acid treatment in a FABP-dependent manner.