Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Chang, James D.; Sukhova, Galina K.; Libby, Peter; Schvartz, Eugenia; Lichtenstein, Alice H.; Field, Seth J.; Kennedy, Caitlin; Madhavarapu, Swetha; Luo, Ji; Wu, Dianqing; Cantley, Lewis C.

doi:10.1073/pnas.0702663104

Cited by 99 publications

(74 citation statements)

References 41 publications

(60 reference statements)

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“…Our results, together with the results from the study by Kobayashi et al (23) and previous reports on PI3Kγ in models of atherosclerosis (46,47) and angiotensin II-mediated vasculotoxic and hypertensive effects (16), strongly suggest that PI3Kγ should be regarded as a most valuable drug target for the treatment of obesity-related diseases. Our data also suggest that a most effective drug targeting this pathway should efficiently inhibit PI3Kγ within the nonhematopoietic compartment responsible for the leaner phenotype of PI3Kγ −/− mice.…”

Section: Discussionsupporting

confidence: 54%

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Becattini

Marone²,

Zani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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 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.energy balance | ectopic lipids | metabolic stress O besity is characterized by a chronic low-grade inflammation (1-5), and clinical studies suggest that antiinflammatory treatments may improve glucose homeostasis in diabetics (6-9). Thus, the identification of the molecular links between inflammation and metabolic homeostasis is fundamental to a better understanding of the pathophysiology of type 2 diabetes and other obesity-related diseases. Here, we have investigated the role of the lipid kinase PI3Kγ in diet-induced obesity, metabolic inflammation, and insulin resistance. PI3Kγ is the only class IB member of the PI3K family, and unlike the class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ), it was not implicated in insulin or insulin-like growth factor 1 (IGF-1) signaling (10-13). PI3Kγ is selectively recruited to G protein-coupled receptors implicated in inflammation and metabolic homeostasis, including chemokine receptors, β-adrenergic signaling, and angiotensin II receptors (13-17). On activation, PI3Kγ controls two major second messengers: phosphatidylinositol(3,4,5)-tris-phosphate (PIP 3 ) through direct phosphorylation of phosphatidylinositol 4,5 bisphosphate and cAMP by a kinase-independent mechanism (18). PI3Kγ is most abundant in cells of hematopoietic origin, but it is also expressed, at a much lower level, in a variety of nonhematopoietic cell types (19). Previous studies proposed a role for PI3Kγ in the control of insulin secretion, thereby suggesting that loss of PI3Kγ may predispose to glucose intolerance (20)(21)(22). By contrast, the results presented in this manuscript together with a recent study (23) show that mice lacking PI3Kγ are dramatically protected from diet-induced obesity and glucose intolerance. Kobayashi et al. (23) concluded that the ...

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Section: Discussionsupporting

confidence: 54%

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Becattini

Marone²,

Zani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, pharmacological inhibition of PI3Kγ ameliorates rheumatoid arthritis, lupus nephritis, and atherosclerosis in mouse models (25,27,34,36), and here we provide evidence that the PI3Kγ inhibition is also promising for treatment of obesity-induced diabetes. Because multiple chemokine-signaling pathways can be involved in macrophage infiltration and inflammation in an obese context, and because inhibition of PI3Kγ could suppress macrophage migration caused by all these chemokines (8,34), blockade of PI3Kγ appears to have advantages compared with the strategies to inhibit single chemokine signaling, such as MCP-1 or CCR2, which have been shown to improve insulin sensitivity in obese mice (6,23,28).…”

Section: -8) (E) Phosphorylation Of Akt In Livers and Skeletal Musclmentioning

confidence: 81%

Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance

Kobayashi¹,

Ueki

Okazaki³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, lowgrade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg −/− ), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg −/− mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.

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“…PI3K␥ isoform knockout not embryo lethal (others are) (277). While having pro-survival effects with PKB activation, expression of endothelial E-selectin appears to be dependent on PI3K␥ (1441).…”

Section: Gab1 Ec-specific Gab1mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

384

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Cited by 99 publications

References 41 publications

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance

Molecular Biology of Atherosclerosis

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