The multimerization and secretion of adiponectin are regulated by TNF-alpha

Obesity is often associated with insulin resistance, mild systemic inflammation, and decreased blood adiponectin. However, some adipokines are increased in the adipose tissue of obese individuals, and whether these adipokines are directly related to the reductions in serum adiponectin levels in an autocrine or paracrine manner remains unknown. This study indicates that the tumor necrosis factor alpha (TNF-alpha) suppresses the multimerization and secretion of adiponectin both in vitro and in vivo. Additionally, TNF-alpha remarkably suppressed the expression of the ER-resident chaperone proteins ERO1-La, DsbA-L, and ERp44. Overexpression of the transcription factor PPAR gamma antagonized the suppressive effect of TNF-alpha on ERO1-La and DsbA-L expressions. Further study revealed that PPAR gamma enhanced the transcription of ERO1-La and DsbA-L by directly binding to the PPRE element of ERO1-La and DsbA-L promoters. TNF-alpha treatment decreased this binding activity. Furthermore, TNF-alpha treatment enhanced the interaction between adiponectin and ERp44. In this study, we show that TNF-alpha impairs adiponectin multimerization and consequently decreases adiponectin secretion by altering disulfide bond modification in the endoplasmic reticulum. Altered adiponectin multimerization could explain declined adiponectin levels and altered distribution of adiponectin complexes in the plasma of obese insulin-resistant individuals.