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

Yang, Zhonghan; Grinchuk, Viktoriya; Smith, Allen; Qin, Bolin; Bohl, Jennifer A.; Sun, Rex; Notari, Luigi; Zhang, Zhongyan; Sesaki, Hiromi; Urban, Joseph F.; Shea‐Donohue, Terez; Zhao, Aiping

doi:10.1128/iai.00053-13

Cited by 94 publications

(109 citation statements)

References 28 publications

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“…These effects were dependent on IFN-γ, as IFNγR1 deficient co-infected mice did not display impaired ILC2 activation or Treg cell expansion (data not shown). Helminth infection is protective in mouse models of type 2 diabetes (Hussaarts et al, 2015; Wu et al, 2011; Yang et al, 2013), promoting short-term VAT ILC2 activation and eosinophilia (Molofsky et al, 2013). We found VAT ILC2, Th2 and eosinophils remain elevated one month after helminth infection, and VAT eosinophils are elevated up to ten months post-infection (Figure S7J, K).…”

Section: Resultsmentioning

confidence: 99%

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

et al. 2015

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SUMMARY Group 2 innate lymphoid cells (ILC2) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show interleukin-33 (IL-33) mediates activation of ILC2 and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo, and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2 are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host.

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Section: Resultsmentioning

confidence: 99%

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

et al. 2015

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“…Translating our results to a therapeutic perspective, we find it tempting to speculate on the Th2 response as a treatment for obesity and its metabolic sequels under certain conditions (27). The appropriate dietary regimen to be administered during an anti-inflammatory metabolic treatment is also a relevant issue, since some forms of lipids are known to positively or negatively affect the inflammatory response (28,29).…”

Section: Itchmentioning

confidence: 95%

ITCH Deficiency Protects From Diet-Induced Obesity

et al. 2014

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Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesityrelated inflammation and insulin resistance, we compared wild-type and Itch 2/2 mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch 2/2 mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from Itch 2/2 mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity.

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“…A score of 0–3 was assigned to describe the extent of steatosis based on lipid accumulation in the hepatocytes (0, <5%; 1, 5–33%; 2, 33–66%; 3, >66%). Immunofluorescent staining of mouse liver sections was carried out as described previously (17). Briefly, the slides were blocked with 5% normal donkey serum and then incubated with anti-F4/80 (BioLegend, San Diego, CA) and anti-YM-1 (R&D Systems, Minneapolis, MN) antibodies overnight.…”

Section: Methodsmentioning

confidence: 99%

IL-25 or IL-17E Protects against High-Fat Diet–Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6

Wang

Yang

Grinchuk

et al. 2015

The Journal of Immunology

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Interleukin-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet proteins were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased lipid droplet proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively-activated Kupffer cells/macrophages, and decreased expression of lipid droplet proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in down-regulation of lipid droplet proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, while exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.

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

Cited by 94 publications

References 28 publications

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation

ITCH Deficiency Protects From Diet-Induced Obesity

IL-25 or IL-17E Protects against High-Fat Diet–Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6

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