Resistin, a cysteine-rich adipocytokine, proposed as a link between obesity and diabetes in mice, was shown as a proinflammatory molecule in humans. We earlier reported that human resistin (hRes), a trimer, was resistant to heat and urea denaturation, existed in an oligomeric polydispersed state, and showed a concentrationdependent conformational change. These properties and an intimate correlation of hRes expression with cellular stress prompted us to investigate hRes as a possible chaperone. Here, we show that recombinant human resistin was able to protect the heat-labile enzymes citrate synthase and Nde1 from thermal aggregation and inactivation and was able to refold and restore their enzymatic activities after heat/guanidinium chloride denaturation. Furthermore, recombinant human resistin could bind misfolded proteins only. Molecular dynamics-based association-dissociation kinetics of hRes subunits pointed to resistin being a molecular chaperone. Bis-ANS, which blocks surface hydrophobicity, abrogated the chaperone activity of hRes, establishing the importance of surface hydrophobicity for chaperone activity. Replacement of Phe49 with Tyr (F49YhRes), a critical residue within the hydrophobic patch of hRes, although it could prevent thermal aggregation of citrate synthase and Nde1, was unable to refold and restore their activities. Treatment of U937 cells with tunicamycin/thapsigargin resulted in reduced hRes secretion and concomitant localization in the endoplasmic reticulum. Escherichia coli transformants expressing hRes could be rescued from thermal stress, pointing to hRes's chaperone-like function in vivo. HeLa cells transfected with hRes showed protection from thapsigargin-induced apoptosis. In conclusion, hRes, an inflammatory protein, additionally exhibited chaperone-like properties, suggesting a possible link between inflammation and cellular stress.protein folding | chaperokine R esistin, a small cysteine-rich secreted protein, is predominantly produced in human macrophages (1, 2). Resistin levels in human serum could neither be associated with obesity nor linked with insulin resistance (3), pointing to possible other role(s) for this hormone. We, and later others, showed that human resistin (hRes) is a proinflammatory molecule that stimulates the synthesis and secretion of TNF-α and IL-12 from macrophages through an NF-κB-activated pathway (4, 5). hRes mRNA levels are strongly induced by TNF-α and IL-6 in human peripheral blood mononuclear cells (6, 7). Although human and mouse resistin share 64.4 and 59% sequence homology at mRNA and amino acids levels, respectively, they differ considerably in terms of their structural organization (8). We earlier reported, based on extensive biophysical analyses, that recombinant human resistin (rhRes) is a highly stable molecule that exists in oligomeric states as a function of concentration with no major loss in helicity and displays slightly altered tertiary structure with an increase in temperature (9, 10). The variable oligomeric states and poly-dispersity...

Studies on the association of the Pro12Ala and C1431T polymorphisms of PPAR? with diabetes and obesity have revealed extensive population-dependent variations. However, association of these polymorphisms with the metabolic syndrome and its individual components has not been well investigated in the Indian population. The Indian population harbours the maximum number of diabetics in the world who are thus more susceptible to metabolic disorders. We screened a South Indian population (N=699) for a possible association of these polymorphisms with the metabolic syndrome (MS) and type 2 diabetes. We also investigated the correlation of these two single-nucleotide polymorphisms (SNPs) with plasma resistin levels. The C1431T SNP was associated with higher levels of plasma resistin (P=0.017). Furthermore, C1431T was associated with resistin in different tertiles. Prevalence of the 'Pro-C' haplotype decreased with increasing tertiles of resistin (84.1% to 75.4%, P=0.037). Plasma resistin levels were not found to be associated with MS and type 2 diabetes. These results point to a likely association of plasma resistin levels with PPAR? polymorphisms in the Indian population.

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