Selective regulation of cellular and secreted multimeric adiponectin by antidiabetic therapies in humans
- 1 September 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 297 (3), E767-E773
- https://doi.org/10.1152/ajpendo.00378.2009
Abstract
Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low- or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg + 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazone-metformin combination therapy (8 mg + 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-Lα expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44.Keywords
This publication has 41 references indexed in Scilit:
- Pioglitazone acutely stimulates adiponectin secretion from mouse and human adipocytes via activation of the phosphatidylinositol 3′-kinaseLife Sciences, 2008
- High molecular weight adiponectin activates AMPK and suppresses cytokine‐induced NF‐κB activation in vascular endothelial cellsFEBS Letters, 2008
- Plasma Adiponectin Complexes Have Distinct Biochemical CharacteristicsEndocrinology, 2008
- Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesisThe EMBO Journal, 2007
- Adiponectin Secretion Is Regulated by SIRT1 and the Endoplasmic Reticulum Oxidoreductase Ero1-LαMolecular and Cellular Biology, 2007
- Secretion of the Adipocyte-Specific Secretory Protein Adiponectin Critically Depends on Thiol-Mediated Protein RetentionMolecular and Cellular Biology, 2007
- Selective purification and characterization of adiponectin multimer species from human plasmaBiochemical and Biophysical Research Communications, 2007
- Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissueAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Impaired Multimerization of Human Adiponectin Mutants Associated with DiabetesJournal of Biological Chemistry, 2003
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970