PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance
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 leukocy...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 42; pp. E854 - E863 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
18.10.2011
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.1106698108 |
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| 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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| AbstractList | 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. 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. 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. We conclude that PI3Kγ should be evaluated as a valuable target of drug therapy for obesity and its associated complications. An effective drug candidate targeting the PI3Kγ pathway should be able to efficiently inhibit PI3Kγ activity in nonhematopoietic cells, which are responsible for the obese phenotype of mice, compared with the lean phenotype of PI3Kγ −/− mice. A PI3Kγ lipid kinase-independent pathway was shown to repress PKA signaling, which is involved in lipid metabolism in the heart, where sympathetic activity is elevated by overfeeding. In this study, we showed that a PI3Kγ lipid kinase-independent pathway is a negative regulator of the PKA-mediated activation of hormone-sensitive lipase, an enzyme that breaks down fat molecules in white adipose tissue. An important factor involved in the resistance to obesity in mice lacking PI3Kγ lipid kinase activity may be the reduced ratio of two types of cell-signaling molecules or cytokines (i.e., IL-1Ra and IL-1β) in the white adipose tissue of these mice. Indeed, it has been reported that mice lacking IL-1 type I receptor maintained on a standard diet develop mature onset obesity, whereas mice that do not express IL-1Ra are resistant to diet-induced obesity because of a high metabolic rate. Furthermore, it was shown that the thermogenic effects of leptin, a central hormone that regulates energy intake and expenditure, can be blocked with IL-1Ra. The molecular mechanisms by which PI3Kγ promotes diet-induced obesity remain to be identified. However, we showed that both PI3Kγ lipid kinase-dependent and -independent pathways (mediated by protein–protein interaction) potentially contribute to weight gain ( Fig. P1 B ). PI3Kγ is an important enzyme in signaling pathways that are activated in obesity. On activation, PI3Kγ negatively regulates adaptive heat production (thermogenesis) by an unknown mechanism operating within a nonhematopoietic cell type, and the mechanism possibly involves PI3Kγ lipid kinase-dependent and -independent scaffolding function. We showed that diet-induced obesity, glucose intolerance, fatty liver, and metabolic inflammation depend on PI3Kγ activity in nonblood cells (nonhematopoietic cells). By contrast, PI3Kγ activity in blood cells (hematopoietic cells) did not affect glucose tolerance, fatty liver, or metabolic inflammation in mice, including mice that were overtly obese (weight ∼42 g). The work by Kobayashi et al. ( 5 ) reported that selective ablation of PI3Kγ activity in hematopoietic cells ameliorates glucose tolerance in morbidly obese ob/ob mice but not mice in which obesity was induced by HFD ( 5 ). We conclude that PI3Kγ activity in hematopoietic cells does not significantly contribute to glucose intolerance or the inflammation of fat tissues until mice develop morbid obesity. Thus, in mice, including overtly obese animals, the promotion of diet-induced obesity involving nonhematopoietic cells seems to be the main pathogenic role of PI3Kγ ( Fig. P1 A ). Using mice lacking the PI3Kγ gene ( PI3Kγ −/− mice), we showed that resistance to diet-induced obesity is the main mechanism by which PI3Kγ inactivation protects mice from diet-induced insulin resistance, inflammation, and fat accumulation in liver cells (fatty liver). The impact of PI3Kγ gene deletion on diet-induced obesity was striking and comparable with the results typically obtained after weight loss surgery. We fed mice a high-fat diet (HFD) for 12 wk and observed a 20% reduction in body weight in PI3Kγ −/− mice compared with WT mice; this difference was largely attributable to a reduction in body fat. Obesity is the main cause of diabetes, a disease characterized by high blood sugar levels. Obese patients display chronic low-grade inflammation, and treatment with antiinflammatory drugs (high doses of salicylates, TNF-α–neutralizing antibodies infliximab, and recombinant IL-1Ra anakinra) can often improve glucose homeostasis in these patients ( 1 ). The lipid kinase PI3Kγ is an important signaling molecule that plays a major role in promoting inflammation. Previous studies have implicated PI3Kγ in the controlled secretion of the blood sugar-regulating hormone insulin, suggesting that reduced PI3Kγ activity may be a predisposing factor for glucose intolerance ( 2 – 4 ). In striking contrast to the results of these previous studies, results presented here and in a recent study by Kobayashi et al. ( 5 ) show that mice lacking PI3Kγ are dramatically protected from diet-induced glucose intolerance. The work by Kobayashi et al. ( 5 ) also suggested that inactivation of PI3Kγ reduces the sugar-lowering activity of insulin by directly affecting leukocytes (white blood cells): in other words, PI3Kγ activity within leukocytes was suggested to promote insulin resistance ( 5 ). 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.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. |
| Author | Becattini, Barbara Wymann, Matthias P Zani, Fabio Solinas, Giovanni Preitner, Frédéric Arsenijevic, Denis Seydoux, Josiane Dulloo, Abdul G Montani, Jean-Pierre Marone, Romina Thorens, Bernard |
| Author_xml | – sequence: 1 fullname: Becattini, Barbara – sequence: 2 fullname: Marone, Romina – sequence: 3 fullname: Zani, Fabio – sequence: 4 fullname: Arsenijevic, Denis – sequence: 5 fullname: Seydoux, Josiane – sequence: 6 fullname: Montani, Jean-Pierre – sequence: 7 fullname: Dulloo, Abdul G – sequence: 8 fullname: Thorens, Bernard – sequence: 9 fullname: Preitner, Frédéric – sequence: 10 fullname: Wymann, Matthias P – sequence: 11 fullname: Solinas, Giovanni |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21949398$$D View this record in MEDLINE/PubMed https://gup.ub.gu.se/publication/241721$$DView record from Swedish Publication Index |
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| Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Author contributions: M.P.W. and G.S. designed research; B.B., R.M., F.Z., D.A., J.S., F.P., and G.S. performed research; J.-P.M. and B.T. contributed new reagents/analytic tools; B.B., R.M., F.Z., D.A., J.S., A.G.D., F.P., M.P.W., and G.S. analyzed data; and B.B., R.M., M.P.W., and G.S. wrote the paper. Edited* by Michael Karin, University of California at San Diego School of Medicine, La Jolla, CA, and approved August 30, 2011 (received for review April 29, 2011) 1B.B., R.M., F.Z., M.P.W., and G.S. contributed equally to this work. |
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| SubjectTerms | 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 |
| Title | PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance |
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