PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 42; pp. E854 - E863
• Main Authors: Becattini, Barbara, Marone, Romina, Zani, Fabio, Arsenijevic, Denis, Seydoux, Josiane, Montani, Jean-Pierre, Dulloo, Abdul G, Thorens, Bernard, Preitner, Frédéric, Wymann, Matthias P, Solinas, Giovanni
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.10.2011; National Acad Sciences
• Series: PNAS Plus
• Subjects: Adipose Tissue, White - enzymology; Adiposity; Animals; Basic Medicine; Biological Sciences; Class Ib Phosphatidylinositol 3-Kinase - deficiency; Class Ib Phosphatidylinositol 3-Kinase - genetics; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Diabetes; Diet, High-Fat - adverse effects; Energy Balance; energy efficiency; energy intake; fatty liver; Fatty Liver - enzymology; Fatty Liver - etiology; Fatty Liver - prevention & control; Inflammation; Inflammation - enzymology; insulin resistance; Insulin Resistance - physiology; Male; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; noninsulin-dependent diabetes mellitus; Obesity; Obesity - enzymology; Obesity - etiology; Obesity - prevention & control; obesity-related diseases; Phenotype; PI3K; PNAS Plus; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Sterol Esterase - metabolism; thermic effect of food; Thermogenesis - physiology; Thinness - enzymology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1106698108

Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications.