Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 42, Pages E854-E863Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1106698108
Keywords
energy balance; ectopic lipids; metabolic stress
Categories
Funding
- Novartis Research Foundation
- Swiss National Science Foundation [310030-127574, 31EM30-126143, 31003A-118172, 31003A_135684]
- European Foundation for the Study of Diabetes (EFSD)/Lilly
- EFSD
- Swiss National Science Foundation (SNF) [31EM30-126143, 310030_127574, 31003A-118172, 31003A_135684] Funding Source: Swiss National Science Foundation (SNF)
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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 PI3K gamma 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 PI3K gamma 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 PI3K gamma 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 gamma action on diet-induced obesity depends on PI3K gamma activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3K gamma depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3K gamma is an unexpected but promising drug target for the treatment of obesity and its complications.
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