IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

Ricardo-González, Roberto R.; Eagle, Alex Red; Odegaard, Justin I.; Jouihan, Hani; Morel, Christine R.; Heredia, Jose; Mukundan, Lata; Wu, Davina; Locksley, Richard M.; Chawla, Ajay

doi:10.1073/pnas.1009152108

Cited by 216 publications

(207 citation statements)

References 42 publications

(55 reference statements)

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“…To determine whether the beneficial effects of N. brasiliensis infection on obesity and the associated metabolic dysfunction were dependent on IL-4/IL-13 activation of STAT6, we employed diet-induced obesity in STAT6 Ϫ/Ϫ or IL-13 Ϫ/Ϫ mice. STAT6 Ϫ/Ϫ mice fed the HFD for 12 weeks gained significantly more body weight than STAT6 Ϫ/Ϫ mice fed the NCD (40.6 Ϯ 1.1 versus 33.1 Ϯ 0.9 g), but less than the respective WT mice fed the HFD (45.3 Ϯ 1.2 g), consistent with a previous report (15). N. brasiliensis infection caused ϳ5% body weight loss in obese STAT6…”

Section: Resultssupporting

confidence: 81%

“…6). Accumulating evidence has pointed out a role of IL-4 induction of the M2 phenotype via STAT6 in restoring glucose homeostasis (15,19,28), yet our current study indicates that N. brasiliensis infection could still improve the glucose metabolism of obese mice in the absence of STAT6-mediated M2 development (Fig. 6), thereby excluding IL-4 as the major player.…”

Section: Discussionmentioning

confidence: 61%

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Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity

et al. 2013

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Obesity is associated with a chronic low-grade inflammation characterized by increased levels of proinflammatory cytokines that are implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been explored to treat autoimmune diseases. We investigated the effects of nematode infection against obesity and the associated metabolic dysfunction. Infection of RIP2-Opa1KO mice or C57BL/6 mice fed a high-fat diet (HFD) with Nippostrongylus brasiliensis decreased weight gain and was associated with improved glucose metabolism. Infection of obese mice fed the HFD reduced body weight and adipose tissue mass, ameliorated hepatic steatosis associated with a decreased expression of key lipogenic enzymes/mediators, and improved glucose metabolism, accompanied by changes in the profile of metabolic hormones. The infection resulted in a phenotypic change in adipose tissue macrophages that was characterized by upregulation of alternative activation markers. Interleukin-13 (IL-13) activation of the STAT6 signaling pathway was required for the infection-induced attenuation of steatosis but not for improved glucose metabolism, whereas weight loss was attributed to both IL-13/STAT6-dependent and -independent mechanisms. Parasitic nematode infection has both preventive and therapeutic effects against the development of obesity and associated features of metabolic dysfunction in mice.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 61%

Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity

et al. 2013

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“…In particular, studies in mice fed a high fat diet have demonstrated that obesity is associated with a switch in the activation of adipose-resident macrophages towards an inflammatory, classically activated phenotype and away from the alternatively activated phenotype associated with lean, healthy adipose tissue [102]. These observations have been extended with the finding that the Th2-linked IL-4/STAT6 immune axis affects insulin sensitivity and peripheral nutrient metabolism, suggesting that immune pathways activated by exposure to helminths or their products might foster insulin responsiveness [103]. Further linking modulation of insulin sensitivity to cell populations associated with immunity to helminths, eosinophils and type 2 innate lymphoid cells have recently been identified as two adipose-resident immune populations with critical roles in maintaining the alternative activation of macrophages in metabolically active adipose tissue [104,105].…”

Section: Extending the Hygiene Hypothesismentioning

confidence: 49%

Helminth Infection and Type 1 Diabetes

Zaccone¹,

Hall²

2012

Rev Diabet Stud

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■ AbstractThe increasing incidence of type 1 diabetes (T1D) and autoimmune diseases in industrialized countries cannot be exclusively explained by genetic factors. Human epidemiological studies and animal experimental data provide accumulating evidence for the role of environmental factors, such as infections, in the regulation of allergy and autoimmune diseases. The hygiene hypothesis has formally provided a rationale for these observations, suggesting that our coevolution with pathogens has contributed to the shaping of the present-day human immune system. Therefore, improved sanitation, together with infection control, has removed immunoregulatory mechanisms on which our immune system may depend. Helminths are multicellular organisms that have developed a wide range of strategies to manipulate the host immune system to survive and complete their reproductive cycles successfully. Immunity to helminths involves profound changes in both the innate and adaptive immune compartments, which can have a protective effect in inflammation and autoimmunity. Recently, helminth-derived antigens and molecules have been tested in vitro and in vivo to explore possible applications in the treatment of inflammatory and autoimmune diseases, including T1D. This exciting approach presents numerous challenges that will need to be addressed before it can reach safe clinical application. This review outlines basic insight into the ability of helminths to modulate the onset and progression of T1D, and frames some of the challenges that helminth-derived therapies may face in the context of clinical translation.

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“…ATMs by Th2 cytokines such as IL-4 and IL-13 contributes to relieve metabolic complication and to restore insulin sensitivity (9,10). Thereby, the balance shifting between M1 and M2 ATMs appears to be crucial for inflammatory responses in adipose tissue of obesity.…”

mentioning

confidence: 99%

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Choe

Shin

et al. 2014

Diabetes

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In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α–overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fed Hif-2α heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.

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IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

Cited by 216 publications

References 42 publications

Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity

Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity

Helminth Infection and Type 1 Diabetes

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

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