Pharmacological and epidemiological studies of the adipocyte secretory protein Acrp30 /adiponectin

Abstract

The hypothesis of this dissertation is that the adipocyte complement-related protein of 30 kDa (Acrp30) is an adipocyte-secreted circulating protein which acts as an insulin sensitizer whose deficiency in obese states is at least partially responsible for obesity-associated insulin resistance. The experimental procedures used to test this hypothesis include development of purified protein ligands for use in pharmacological experiments of functional and metabolic activity and measurement of Acrp30 serum levels and adipocyte expression/secretion in various metabolic states. These investigations found that Acrp30 has an insulin sensitizing effect on the liver, causing decreases in fasting serum glucose levels in mice, and euglycemic insulin clamp studies which showed that the glucose-lowering activity was mediated solely through the liver, with little effects on muscle glucose uptake. Effects of Acrp30 on primary hepatocytes demonstrated that the effects on gluconeogenesis were mediated directly by Acrp30, and signaling experiments suggested that the activity may be mediated by the AMP-activated and Akt protein kinases. Epidemiological studies demonstrated consistent trends where insulin resistant metabolic states had consistently decreased Acrp30 levels. Genetic mouse models with disrupted insulin signaling demonstrated increased Acrp30 levels, consistent with a compensatory regulation. Mice and humans treated with the insulin-sensitizing PPARgamma agonist drugs were shown to have associated increases in Acrp30 levels, suggesting a role in these drugs' hypoglycemic effects. Finally, partial characterization of genetically modified Acrp30 mouse models corroborated the hypothesized functions in insulin action, glucose and lipid metabolism. The conclusions of this work support our original hypothesis, and indicate roles for Acrp30 in the whole-body regulation of glucose as well as lipid metabolism by mediating important signals between adipose and the liver.