Conférence donnée dans le cadre de la procédure d’appel Cell or develop Biology par Dr. Giovanni Solinas

Résumé: Class-1 phosphoinositide 3 kinases (PI3K) play a central role in the signal transduction of growthfactors and insulin, and physiological PI3K activity maintains tissue and metabolic homeostasis. Genetic activation of PI3K signaling is a most frequent alteration in cancer, but our capacity to exploit PI3K-targeted therapy is limited by on-target adverse effects on insulin signaling driving systemic metabolic feedback loops conferring resistance to inhibitors (PI3Ki). Indeed, inhibition of all PI3K isoforms causes severe hyperglycemia and hyperinsulinemia, which induces PI3K activity in the tumor, causing resistance to pan PI3Ki . Thus, avoiding PI3Ki-induced hyperinsulinemia is key to harness the full therapeutic potential of PI3K-targeted therapies. Furthermore, several studies indicate that the insulin-PI3K pathway plays a major role in the development of obesity by inhibiting adipose tissue lipolysis and thermogenesis, indicating the possibility to treat obesity and obesityrelated diseases with a specific PI3K-targeted therapy. There are four PI3K catalytic subunits: PI3Kα; PI3Kβ; PI3Kγ; and PI3Kδ, and it was long believed that insulin signaling is mediated exclusively by the PI3Kα isoform, the most frequently mutated PI3K in cancer. However, we have found that insulin signaling in the hepatocyte and in glycemic control is mediated by redundant PI3Kα and PI3Kβ activities. This discovery indicates that it could be possible to selectively target PI3K action in tumor-promotion and in lipid metabolism without affecting glucose homeostasis by using isoform-selective PI3Ki discriminating between PI3Kα and PI3Kβ. Furthermore, we recently reported that free fatty acids may play a major role in driving fasting hyperinsulinemia in human obese with normal glycemic control. The role for each specific PI3K isoform in adiposity, metabolic homeostasis, and in the metabolic loops controlling insulinemia remains largely unresolved. However, we have found that PI3Kγ activity in a non-hematopoietic cell type, not yet identified, promotes adiposity in high-fat diet fed mice, in a leptin dependent manner via inhibition of PKA-driven lipolysis; we have found that PI3Kγ activity in leukocytes promotes macrophage M1 polarization and neutrophil recruitment in the obese adipose tissue, further promoting insulin resistance; and that systemic PI3Kγ ablation preserves β-cell mass and fasting insulin levels in the db/db mouse model of obesity-driven diabetes.