title: PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance.
abstract: 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.
authors.affiliation: Laboratory of Metabolic Stress Biology, Division of Physiology, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Becattini
authors.forename: Romina
authors.initials: R
authors.lastname: Marone
authors.forename: Fabio
authors.initials: F
authors.lastname: Zani
authors.forename: Denis
authors.initials: D
authors.lastname: Arsenijevic
authors.forename: Josiane
authors.initials: J
authors.lastname: Seydoux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Montani
authors.forename: Abdul G
authors.initials: AG
authors.lastname: Dulloo
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.forename: Frédéric
authors.initials: F
authors.lastname: Preitner
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Giovanni
authors.initials: G
authors.lastname: Solinas
mesh_terms: D052436:Adipose Tissue, White / Q000201:enzymology*; D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D007249:Inflammation / Q000201:enzymology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009765:Obesity / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D002787:Sterol Esterase / Q000378:metabolism; D022722:Thermogenesis / Q000502:physiology*; D013851:Thinness / Q000201:enzymology
chemical_list: D012333:RNA, Messenger; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D002787:Sterol Esterase