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PI3Kγ within a Nonhematopoietic Cell Type Negatively Regulates Diet-Induced Thermogenesis and Promotes Obesity and Insulin Resistance.

Journal article
Authors Barbara Becattini
Romina Marone
Fabio Zan
Denis Arsenijevic
Josiane Seydoux
Jean-Pierre Montan
Abdul G. Dulloo
Bernard Thorens
Frédéric Preitner
Matthias P. Wymann
Giovanni Solinas
Published in Proceedings of the National Academy of Science of the United States of America
Volume 108
Issue 42
Pages E854–E863
ISSN 0027-8424
Publication year 2011
Published at Wallenberg Laboratory
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages E854–E863
Language en
Links www.pnas.org/content/108/42/E854.lo...
Keywords Obesity, Diabetes, Inflammation, Adiposity, Energy Balance, PI3K
Subject categories Basic Medicine

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.

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