Abstract
BackgroundAdiponectin is an adipocyte-secreted hormone with insulin-sensitizing and anti-inflammatory actions. The assembly of trimeric, hexameric, and higher molecular weight (HMW) species of adiponectin is a topic of significant interest because physiological actions of adiponectin are oligomer-specific. In addition, adiponectin assembly is an example of oxidative oligomerization of multi-subunit protein complexes in endoplasmic reticulum (ER).ResultsWe previously reported that trimers assemble into HMW adiponectin via intermediates stabilized by disulfide bonds, and complete oxidation of available cysteines locks adiponectin in hexameric conformation. In this study, we examined the effects of redox environment on the rate of oligomer formation and the distribution of oligomers. Reassembly of adiponectin under oxidizing conditions accelerated disulfide bonding but favored formation of hexamers over the HMW species. Increased ratios of HMW to hexameric adiponectin could be achieved rapidly under oxidizing conditions by promoting disulfide rearrangement.ConclusionsBased upon these observations, we propose oxidative assembly of multi-subunit adiponectin complexes in a defined and stable redox environment is favored under oxidizing conditions coupled with high rates of disulfide rearrangement.
Highlights
Adiponectin is an adipocyte-secreted hormone with insulin-sensitizing and anti-inflammatory actions
We addressed this paradox in our previous report by demonstrating that disulfide bonds are not required for stability of the mature higher molecular weight (HMW) species, they are necessary for oligomerization [21]
Our model predicts that oxidizing conditions will accelerate disulfide bonding and favor the formation of fully oxidized hexamers that are unable to assemble further into HMW adiponectin
Summary
Adiponectin is an adipocyte-secreted hormone with insulin-sensitizing and anti-inflammatory actions. The assembly of trimeric, hexameric, and higher molecular weight (HMW) species of adiponectin is a topic of significant interest because physiological actions of adiponectin are oligomer-specific. The adipocyte-secreted hormone adiponectin contributes to the maintenance of whole body insulin action and normal cardiovascular and endothelial functions [1,2,3,4,5,6,7]. Adiponectin homo-oligomerizes into different isoforms: trimer, hexamer and several higher molecular weight (HMW) species, the largest and the most abundant of which is the octadecamer [8,9,10]. The HMW adiponectin species are decreased in insulin resistance to a larger extent than the other isoforms [12,13,14,15,16]. Changes in gene expression alone could not account for TZD-stimulated increase in HMW adiponectin levels [17], it is important to understand the mechanisms that impair the formation of HMW adiponectin in adipocytes
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