Investigating the role of Class-1 Phosphoinositide 3 Kinases (PI3Ks) in insulin signaling and obesity

Abstract

Obesity and obesity related diseases such as type 2 diabetes, cardiovascular disorders, and different types of cancer are leading causes of mortality and morbidity in modern society. However, the mechanism that links obesity to these diseases remains largely unresolved. Class 1 phosphatidylinositide 3 kinases (PI3Ka; PI3Kb; PI3Kd and PI3Kg) play a major role in several physiological processes such as the immune response, the metabolic insulin action, and tissues homeostasis. This thesis aims at a better understanding of the role of the different PI3K isoforms in obesity and insulin signaling. PI3Kg plays an important role in leukocyte recruitment during inflammation, in the inhibition of classical macrophage activation and in promoting diet-induced obesity and insulin resistance. In PAPER I we have investigated the PI3Kg mechanisms of action and we have found that the activity of PI3Kg in hematopoietic cells is dispensable in hepatic inflammation, liver steatosis, adiposity and macrophage recruitment in adipose tissue. However, PI3Kg activity promotes insulin resistance, the pro-inflammatory M1 macrophage phenotype and neutrophils recruitment in the adipose tissue of obese mice. This observation challenges the concept that PI3Kg activity is a general inhibitor of classical macrophage activation. In PAPER II, we aim to define the role of class-1 PI3K isoforms and RAS in insulin signaling in hepatocytes. Our data lead to a new and improved mechanism for insulin signaling where insulin-driven PI3K-AKT signaling is mediated by the activities of PI3Ka and PI3Kb, with RAS promoting PI3Ka-dependent insulin signaling. We conclude that PI3K inhibitors discriminating between PI3Ka and PI3Kb should be used at doses below their hyperglycemic threshold to preserve isoform specificity and achieve optimal therapeutic index. In PAPER III, we have found that compared to primary hepatocytes, three most commonly used hepatoma cell lines display aberrant insulin signaling, gluconeogenic genes expression, glucose production and different electrophoretic profiles, but similar among the hepatoma cell lines. We conclude that, because the hepatoma cell lines appear to converge to a common aberrant phenotype, these cells can be a valuable tool to study the metabolic aberrations in hepatocellular carcinoma. General conclusion: Altogether this thesis supports the concept that the therapeutic effects of PI3K inhibitors on obesity, insulin resistance and tumor promotion could be largely dissociated from their deleterious effects on glucose homeostasis by using isoform-selective inhibitors discriminating between PI3Ka and PI3Kb.