The role of adiponectin as an important regulator of insulin sensitivity was first reported by Fruebis and colleagues in 2001 (16). The authors found that injection of a COOH-terminal globular adiponectin into mice acutely decreased postprandial blood glucose levels and enhance lipid clearance via increasing fatty acid ^-oxidation in skeletal muscles. This observation was subsequently confirmed and extended by several pharmacological studies using different forms of recombinant adiponectin. Yamauchi's group demonstrated that chronic infusion of full-length or globular adiponectin produced from E. coli significantly ameliorated insulin resistance and improved lipid profiles in both lipoatrophic diabetic mice and diet-induced obese mice (17). On the other hand, Berg's group showed that intraperitoneal injection of full-length adiponectin expressed in mammalian cells triggered a significant and transient decrease in basal blood glucose levels by inhibiting the rates of endogenous glucose production in both wild type mice and several diabetic mouse models (18).
The chronic effects of adiponectin on insulin sensitivity and energy metabolism were also investigated in adiponectin transgenic mice or adiponectin knockout (KO) mice. Scherer's group generated a transgenic mouse model with approximately threefold elevation of native adiponectin oligomers (19). The authors demonstrated that hyper-adiponectinemia significantly increased lipid clearance and lipoprotein lipase activity, and enhanced insulin-mediated suppression of hepatic glucose production, thereby improving insulin sensitivity. Kadowaki's group showed that transgenic overexpression of globular adiponectin in the genetic background of ob/ob obese mice led to partial amelioration of insulin resistance, hyperinsulinemia, and hyperglycemia (20). Conflicting results have been obtained from adiponectin KO mice studies. Yamauchi et al. found no impact of adiponectin depletion on insulin sensitivity under either normal chow or after 7 mo of feeding with a high-fat diet (21). In contrast, adiponectin KO mice reported by Maeda et al. exhibited more severe high-fat diet induced insulin resistance and dyslipidemia, despite having normal glucose tolerance when fed with regular chow (22). Kubota et al. observed mild insulin resistance in the heterozygous adiponectin KO mice and moderate insulin resistance in the homozygous adiponectin KO mice even when fed with a regular chow (23). The latter two studies support the role of adiponectin as an endogenous insulin sensitizer in mice.
The insulin-sensitizing effect of adiponectin appears to be primarily attributed to its direct actions in skeletal muscle and liver, through the activation of AMPK and peroxi-some proliferator-activated receptor (PPAR)a (24,25). In liver, stimulation of AMPK by full-length adiponectin leads to decreased expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which may account for its glucose-lowering effect in vivo (19,24). In skeletal muscle, activation of AMPK by globular or full-length adiponectin causes increased expression of proteins involved in fatty acid transport (such as CD36), fatty acid oxidation (such as acyl-coenzyme A oxidase) and energy dissipation (such as uncoupling protein-2), resulting in enhanced fatty acid oxidation and energy dissipation, and decreased tissue triglyceride (TG) accumulation. Excessive tissue TG accumulation has been proposed to be a major causative factor of insulin resistance in skeletal muscle (26). Therefore, reduction of tissue TG's contents by adiponectin might be the major contributor to the insulin-sensitizing activity of this adipokine.
In addition to liver and muscle, adiponectin can also act in an autocrine manner on adipocytes. It can antagonize the inhibitory effect of TNF-a on insulin-stimulated glucose uptake (27), and blocks the release of insulin resistance-inducing factors from adipocytes (28). Furthermore, it has recently been suggested that adiponectin also acts in the brain to increase energy expenditure and cause weight loss (29).
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...