Research ArticleImmunometabolism

PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity

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Sci. Signal.  18 Jul 2017:
Vol. 10, Issue 488, eaaf2969
DOI: 10.1126/scisignal.aaf2969

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Dual modulator of macrophages

The kinase PI3Kγ is thought to inhibit classical macrophage activation, an effect that enables tumor progression. However, Breasson et al. found that PI3Kγ promoted the activation of macrophages in two different mouse models of obesity. Analysis of mice with whole-body or tissue-specific deficiencies in PI3Kγ revealed that PI3Kγ in a nonhematopoietic cell type regulated adiposity but that PI3Kγ in leukocytes was required for the recruitment of neutrophils to adipose tissue, which was associated with macrophage activation and inflammation. Thus, PI3Kγ can either inhibit or stimulate macrophages depending on the pathophysiological context.

Abstract

The phosphoinositide 3-kinase γ (PI3Kγ) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3Kγ plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3Kγ action in high-fat diet–induced inflammation and insulin resistance depended largely on its role in the control of adiposity, which was due to PI3Kγ activity in a nonhematopoietic cell type. However, PI3Kγ activity in leukocytes was required for efficient neutrophil recruitment to adipose tissue. Neutrophil recruitment was correlated with proinflammatory gene expression in macrophages in adipose tissue, which triggered insulin resistance early during the development of obesity. Our data challenge the concept that PI3Kγ is a general suppressor of classical macrophage activation and indicate that PI3Kγ controls macrophage gene expression by non–cell-autonomous mechanisms, the outcome of which is context-dependent.

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