Adiponectin Synthesis, Secretion and Extravasation from Circulation to Interstitial Space

Abstract

Adiponectin, an adipokine that circulates as multiple multimeric complexes at high levels in serum, has antidiabetic, anti-inflammatory, antiatherogenic, and cardioprotective properties. Understanding the mechanisms regulating adiponectin's physiological effects is likely to provide critical insight into the development of adiponectin-based therapeutics to treat various metabolic-related diseases. In this review, we summarize our current understanding on adiponectin action in its various target tissues and in cellular models. We also focus on recent advances in two particular regulatory aspects; namely, the regulation of adiponectin gene expression, multimerization, and secretion, as well as extravasation of circulating adiponectin to the interstitial space and its degradation. Finally, we discuss some potential therapeutic approaches using adiponectin as a target and the current challenges facing adiponectin-based therapeutic interventions.

Keywords: adiponectin; cardiovascular; diabetes; endothelial; synthesis.

FIGURE 1.

Adiponectin synthesis and multimerizationAdiponectin exists as a full-length protein of 30 kDa, circulating in serum as three major isoforms: trimer, hexamer, and high-molecular weight (HMW) multimer. Adiponectin is mostly secreted by the adipose tissue, highly regulated by the PPARγ signaling pathway. Hydroxylation and subsequent glycosylation of lysine residues in the collagenous domain of adiponectin are required for intracellular assembly of the trimer of adiponectin into the HMW multimer. Additionally, the multimerization and secretion of adiponectin are controlled by molecular chaperones in the ER (endoplasmic reticulum), including ERp44 (ER protein of 44 kDa), Ero1-Lα (ER oxidoreductase 1-Lα) and DsbA-L. The ERp44 forms a mixed disulfide bond (S-S) with adiponectin at the NH₂-terminal region and inhibits the secretion of adiponectin multimers. In contrast, Ero1-Lα enhances the secretion of HMW adiponectin through releasing adiponectin trapped by ERp44 and by transferring its own disulfide bond to protein disulfide-isomerase, allowing disulfide bond formation and adiponectin multimerization. Lastly, DsbA-L also play a role in specifically recognizing the LMW and MMW, and enhancing HMW assembly. This figure was created using Servier Medical Art (available at https://smart.servier.com/) and PAGES software.

FIGURE 2.

Adiponectin extravasation into the circulationA: paracellular and transcellular movement. B: adiponectin extravasation from circulation into interstitial space on target tissue. Process mediated through paracellular movement across the endothelium. Decreased tightness of junctions allows higher amounts of full-length adiponectin extravasation into the interstitial space. This figure was created using Servier Medical Art (available at https://smart.servier.com/) and PAGES software.