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Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3K\u03b3 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 PI3K\u03b3 action on diet-induced obesity depends on PI3K\u03b3 activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3K\u03b3 depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3K\u03b3 is an unexpected but promising drug target for the treatment of obesity and its complications.<\/jats:p>","DOI":"10.1073\/pnas.1106698108","type":"journal-article","created":{"date-parts":[[2011,9,27]],"date-time":"2011-09-27T02:26:14Z","timestamp":1317090374000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":56,"title":["PI3K\u03b3 within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance"],"prefix":"10.1073","volume":"108","author":[{"given":"Barbara","family":"Becattini","sequence":"first","affiliation":[{"name":"Laboratory of Metabolic Stress Biology, Division of Physiology, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Marone","sequence":"additional","affiliation":[{"name":"Cancer and Immunobiology Laboratory, Department of Biomedicine, Institute of Biochemistry &amp; Genetics, CH-4058 Basel, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Zani","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Stress Biology, Division of Physiology, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Arsenijevic","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josiane","family":"Seydoux","sequence":"additional","affiliation":[{"name":"Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Montani","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul G.","family":"Dulloo","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Thorens","sequence":"additional","affiliation":[{"name":"Mouse Metabolic Facility (MEF), Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Preitner","sequence":"additional","affiliation":[{"name":"Mouse Metabolic Facility (MEF), Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias P.","family":"Wymann","sequence":"additional","affiliation":[{"name":"Cancer and Immunobiology Laboratory, Department of Biomedicine, Institute of Biochemistry &amp; 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