Adiponectin induces NF-κB activation that leads to suppression of cytokine-induced NF-κB activation in vascular endothelial cells: globular adiponectin vs. high molecular weight adiponectin

Abstract

Adiponectin circulates in plasma as various isoforms. However, the biological activity of each isoform has not been firmly established. High molecular weight (HMW) adiponectin may be the active form of adiponectin, while a proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), has recently been shown to activate vascular endothelial cells. We compared HMW adiponectin with gAd to investigate whether they could activate nuclear factor kappa B (NF-κB) and suppress cytokine-induced NF-κB activation in vascular endothelial cells. HMW adiponectin was found to activate NF-κB modestly compared to the activation observed with gAd. HMW adiponectin requires a shorter incubation period to demonstrate inhibition against tumour necrosis factor alpha (TNFα)-induced NF-κB activation, compared with gAd. gAd strongly activates NF-κB, thereby inducing the expression of various pro-inflammatory and adhesion molecule genes, and requires a longer incubation period to show inhibition against cytokine-induced NF-κB activation. Thus, HMW adiponectin might function to protect against inflammatory stimuli, while cleavage of adiponectin at inflammatory sites might enhance the inflammatory process.

Keywords

globular adiponectin high molecular weight adiponectin NF-κB vascular endothelial cells

References

1. Berg AH Combs TP , Du X , Brownlee M , Scherer EP. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947–53.

2. Yamauchi T Kamon J , Waki H et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941–6.

3. Nakano Y Tobe T , Choi-Miura NH , Mazda T , Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem (Tokyo) 1996;120:803–12.

4. Pajvani UB Du X , Combs TP et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin: implications for metabolic regulation and bioactivity. J Biol Chem 2003;278:9073–85.

5. Tsao TS Tomas E , Murrey HE et al. Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity: different oligomers activate different signal transduction pathways. J Biol Chem 2003;278:50810–17.

6. Waki H Yamauchi T , Kamon J et al. Impaired multimerization of human adiponectin mutants associated with diabetes: molecular structure and multimer formation of adiponectin. J Biol Chem 2003;278:40352–63.

7. Fruebis J Tsao TS , Javorschi S et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001;98:2005–10.

8. Waki H Yamauchi T , Kamon J et al. Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1. Endocrinology 2005;146:790–6.

9. Pajvani UB Hawkins M , Combs TP et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 2004;279:12152–62.

10.

10. Tonelli J Li W , Kishore P et al. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 2004;53:1621–9.

11.

11. Hattori Y Hattori S , Kasai K. Globular adiponectin activates nuclear factor-{kappa}B in vascular endothelial cells, which in turn induces expression of proinflammatory and adhesion molecule genes. Diabetes Care 2006;29:139–41.

12.

12. Hattori Y Hattori S , Akimoto K et al. Globular adiponectin activates nuclear factor-{kappa}B and activating protein-1 and enhances angiotensin II-induced proliferation in cardiac fibroblasts. Diabetes 2007;56:804–08.

13.

13. Scherer PE. Adipose tissue: lipid storage compartment to endocrine organ. Diabetes 2006;55:1537–45.

14.

14. Hattori Y Suzuki M , Hattori S , Kasai K. Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). Hypertension 2002;39:22–8.

15.

15. Pierce JW Schoenleber R , Jesmok G. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effect. in vivo. J Biol Chem 1997;272:21096–103.