PPARγ Ligands Increase Expression and Plasma Concentrations of Adiponectin, an Adipose-Derived Protein

Abstract

Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPAR␥ ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose-and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-␣, which is produced more in an insulinresistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-␣. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-␣ on the adiponectin promoter.

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity

“…These data show that low adiponectin level might be one of the primary determinants of type 2 diabetes, which is in part genetically determined, a hypothesis that we recently evidenced further in the prospectively followed French Caucasian DESIR population [12]. The PPARG agonists, glitazones, increase adiponectin levels, suggesting that part of their hypoglycaemic action is mediated by the hormone release [13]. The PPARG Pro12Ala SNP is well established as a candidate gene for common forms of type 2 diabetes [14].…”

Adiponectin, insulin resistance and clinical expression of the metabolic syndrome in patients with Type 2 diabetes

“…Some other studies have reported similar disassociation between adiponectin levels and insulin resistance 28,29 and the relationship between adiponectin and IR is probably not one of the direct cause and effect in all patients. It is possible that their inverse relationship may be mediated not only by insulin levels but also by other hormones such as catecholamines or androgens, [30][31][32] as well as by pro-inflammatory cytokines, 33,34 and some medications. 31,35 Our results also depict the prominent role that adipose tissue plays in both insulin resistance and the clinical expression of the metabolic syndrome (Figures 1 and 2).…”

“…It is possible that their inverse relationship may be mediated not only by insulin levels but also by other hormones such as catecholamines or androgens, [30][31][32] as well as by pro-inflammatory cytokines, 33,34 and some medications. 31,35 Our results also depict the prominent role that adipose tissue plays in both insulin resistance and the clinical expression of the metabolic syndrome (Figures 1 and 2). Adiponectin and the metabolic syndrome OA Mojiminiyi et al However, as the adipokines and number of the standard criteria for the metabolic syndrome change in proportion with the degree of obesity, it is not clear why some obese individuals do not present with the clinical and metabolic features of the syndrome.…”

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

“…40 Given this observation and the fact that both TZDs and adiponectin affect hepatic insulin sensitivity in similar ways, several laboratories have raised the possibility that the TZD-mediated effects in the liver may be mediated through the upregulation and increased secretion of adiponectin from adipocytes. [41][42][43][44] A common observation in all studies published to date is that the vast majority of patients or mice treated with TZD respond with an upregulation of serum adiponectin levels. We have demonstrated that a daily gavage of db/db mice or a chemically induced type 2 diabetes model (high-fat fed combined with low-dose streptozotocin treatment) with rosiglitazone for 11 days significantly decreased serum triglycerides and fasting glucose levels while leading to a dramatic three-to four-fold increase in serum adiponectin serum levels.…”