A Transgenic Mouse with a Deletion in the Collagenous Domain of Adiponectin Displays Elevated Circulating Adiponectin and Improved Insulin Sensitivity

Abstract

Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor gamma2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor gamma agonists.

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

“…Therefore, it is possible that in our animals, oestrogens decrease adiponectin levels by acting through ERβ. Low levels of adiponectin are associated with obesity, insulin resistance and type-2 diabetes [46], while transgenic mice overexpressing adiponectin showed increased adiponectin levels and improved insulin sensitivity [47]. Adiponectin activates AMP-activated protein kinase resulting in phosphorylation of acetyl CoA carboxylase and thereby increased fatty acid oxidation and glucose uptake in the muscle and decreased hepatic gluconeogenesis [48].…”

Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

“…We also explored a gain-offunction model in which adiponectin overexpression is driven by the aP2 promoter. 19 After TAA-induced injury, collagen production in adiponectin-overexpressing mice was reduced, compared with controls ( Figure 3, C and D). Additionally, expression of collagen ␣1(I) and ␣-SMA mRNA was significantly lower in adiponectin-overexpressing animals ( Figure 3, C and D).…”

“…18,19 Male mice between the ages of 12 and 16 weeks were used for this study. All animals were maintained under temperature-controlled conditions (22 Ϯ 2°C) in 12-hour light/dark cycles with unlimited access to food and water.…”

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

“…levels displays remarkable parallels to prolonged exposure to TZDs, including a marked improvement in insulin sensitivity in the liver. 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.…”