Selective regulation of cellular and secreted multimeric adiponectin by antidiabetic therapies in humans

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 ϩ 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazonemetformin combination therapy (8 mg ϩ 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-L␣ 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. thiazolidinedione; adipocyte; ERp44; Ero1-L␣; chaperone proteins AS THE PREVALENCE OF OBESITY CONTINUES to rise at an alarming rate, so do associated rates of obesity-related metabolic dysfunction; among these are coagulation abnormalities, dyslipidemia, hyperinsulinemia, glucose intolerance, and type 2 diabetes (13, 34). Although long recognized to play a role in fat metabolism, the endocrine role of adipose tissue is a relatively recent and important discovery, potentially providing a link between obesity and disorders of metabolism. Among the growing list of identified adipose endocrine products, adiponectin is uniquely related to changes in insulin sensitivity. Low levels are seen in obesity and insulin-resistant states and are predictive of type 2 diabetes (15), whereas high levels are associated with leanness and greater insulin sensitivity (28, 40) and reduced risk for development of type 2 diabetes (14).Although synthesized as a 32-kDa monomeric protein, adiponectin undergoes extensive posttranslational processing and assembly into low-molecular-weight (LMW) trimers, middlemolecular-weight (MMW) heximers, and high-molecularweight (HMW) complexes prior to secretion (38). In vitro, the HM...

The impact of obesity on secretion of adiponectin multimeric isoforms differs in visceral and subcutaneous adipose tissue

“…14 We have shown and confirmed here that the profile of adiponectin multimers secreted by AT explants derived from needle biopsies of abdominal SAT differs from their plasma profile 26 and that the main isoform secreted by SAT and VAT explants is the HMW isoform. This is in agreement with other studies, showing HMW as the predominant form secreted by subcutaneous fat.…”

“…3,10 --13 Adiponectin is a protein abundantly secreted by AT and is present intracellularly and in the plasma in different multimeric isoforms. 14,15 Polypeptides of 30 kDa are assembled into different multimers. The basic adiponectin multimer is represented by low-molecular weight (LMW) trimers formed through hydrophobic interactions.…”

Golgi and Related Vesicle Proteomics: Simplify to Identify

“…The answer found in the spatial and temporal requirements of protein maturation where ERp44 acts as a retention protein for ERO1, the IP3 receptor and adiponectin, retrieving these proteins as they escape from the ER. For adiponectin, its regulated secretion in fat cells is a consequence of a signaling pathway that abrogates its recycling via ERp44 Wang et al 2008;Wolf 2008;Phillips et al 2009;Long et al 2010). Importantly, client proteins that do not associate via cysteine residue oxidation to the thioredoxin motifs of ERp44 include the formylglycine-activating enzyme (Mariappan et al 2008).…”

Effects of Delayed Sample Processing on Determination of Total and High Molecular Weight (HMW) Adiponectin in Serum and Plasma: A Pilot Study

“…All analyses were performed using IBM SPSS Statistics for Windows (version 22.0, Armonk, NY: IBM Corp). A greater than 15% difference in samples was deemed clinically significant as this is a change typically observed in studies with drug therapy targets (Gaich et al, 2013;Phillips et al, 2009). …”