Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication

Abstract

Adiponectin has been receiving a great deal of attention due to its potential therapeutic use for metabolic and cardiovascular disorders. Adiponectin expression levels and multimerization are down-regulated in obesity and up-regulated by insulin sensitizers such as thiazolidinediones (TZDs), metformin, sulfonylurea and resveratrol (RSV). The precise mechanisms underlying adiponectin up- and down-regulation remain largely unknown, but recent studies indicate that the cellular and plasma levels of adiponectin could be regulated at both transcriptional and post-transcriptional levels. At the post-translational level, TZDs and resveratrol promote adiponectin levels and multimerization via up-regulation of disulfide-bond-A oxidoreductase-like protein (DsbA-L). Adiponectin levels are also stimulated by FOXO1 and AMP-activated protein kinase (AMPK), and are suppressed by PKA or silencing mediator of retinoid and thyroid hormone receptors (SMRT). Since multimerization is important not only for adiponectin function but also for stability, increasing adiponectin multimerization has become a promising drug target for the treatment of metabolic diseases and other related disorders.

Fig. 1

TZDs and resveratrol promote adiponectin multimerization through regulation of ER chaperones. TZD-activated PPARγ binds to the promoter of DsbA-L, Ero1-Lα or ERp44, leading to enhanced transcriptions of DsbA-L and Ero1-Lα, but repression of ERp44 transcription. Elevated cellular levels of DsbA-L and Ero1-Lα promote adiponectin multimerization in the ER. Resveratrol enhances adiponectin production and secretion mainly through increasing the expression levels of DsbA-L, which leads to elevated adiponectin multimerization and stability. Activation of AMPK or Foxo1 mediates the stimulatory effect of resveratrol on DsbA-L expression, but the underlying mechanism remains to be established.

Fig. 2

PPARγ transcriptional activity is regulated by phosphorylation. High fat diet induces CDK5 activation in mouse white fat tissue, leading to phosphorylation of PPARγ at Ser²⁷³. Phosphorylation at this site reduces PPARγ transcriptional activity towards specific genes such as adiponectin. TZDs or MRL24 protects obesity-induced adiponectin down-regulation by suppressing CDK5-meidated PPARγ phosphorylation.

Fig. 3

SMRT acts as a corepressor to regulate PPARγ activity and adiponectin transcription. The ligand-dependent nuclear corepressor SMRT interacts with RAR and PPARγ through receptor interacting domain 1 and 2 (RID1/2), respectively. The interaction of SMRT represses the transcriptional activity of RAR and PPARγ. Retinoid and thyroid hormone deficiency leads to dissociation of SMRT from PPARγ and subsequently activation of PPARγ and enhanced adiponectin transcription.