Abstract
While leptin deficiency or dysfunction leads to morbid obesity, obese subjects are characterized paradoxically by hyperleptinemia indicating lack of response to leptin. C-reactive protein (CRP) has been suggested to be a key plasma protein that could bind to leptin. To examine whether CRP interferes with leptin action, mediated through its cell surface receptor, docking studies of CRP with the extracellular domain of the leptin receptor were done employing bioinformatics tools. Monomeric CRP docked with better Z-rank score and more non-bond interactions than pentameric CRP at the CRH2–FNIII domain proximal to the cell membrane, distinct from the leptin-docking site. Interaction of CRP with leptin receptor was validated by solid phase binding assay and co-immunoprecipitation of CRP and soluble leptin receptor (sOb R) from human plasma. Analysis of the serum levels of leptin, CRP, and sOb R by ELISA showed that CRP levels were significantly elevated (p < 0.0001) in non-morbid obese subjects (n = 42) compared to lean subjects (n = 32) and correlated positively with body mass index (BMI) (r = 0.74, p < 0.0001) and leptin (r = 0.8, p < 0.0001); levels of sOb R were significantly low in obese subjects (p < 0.001) and showed a negative correlation with BMI (r = −0.26, p < 0.05) and leptin (r = −0.23, p < 0.05) indicating a minimal role for sOb R in sequestering leptin.
Highlights
Chronic low grade inflammation underlies the development and progression of a number of pathological conditions associated with obesity and insulin resistance in human subjects
Similar docking studies using pentameric C-reactive protein (CRP) with leptin receptor showed that the best pose gave a poor Z-rank score and less number of non-bond interactions than those shown by monomeric CRP (mCRP) (Table S1C in Supplementary Material)
These results suggest that leptin mostly docks to the residues toward the N-terminal region of the CRH2 domain, while mCRP docks to residues toward its C-terminal region closer to the plasma membrane
Summary
Chronic low grade inflammation underlies the development and progression of a number of pathological conditions associated with obesity and insulin resistance in human subjects. It has been suggested that these proteins are not merely markers or mediators of the inflammatory process but they affect the action of adipokines, having a direct role in the regulation of adiposity. In this context, the potential role of CRP in modulating the action of leptin in obesity is relevant. The protomers, each containing 206 amino acid residues, associate non-covalently. It binds to a variety of autologous and extrinsic ligands [2]. The pentameric form has been reported to dissociate into a more physiologically active and pro-inflammatory monomeric form (mCRP) which can bind to cell surface receptors [3] and has been implicated in the pathogenesis of inflammatory diseases [4]
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