Short-term dietary restriction rescues mice from lethal abdominal sepsis and endotoxemia and reduces the inflammatory/coagulant potential of adipose tissue

Marlene E. Starr, Allison M. Steele, Donald A. Cohen, Hiroshi Saito

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Objectives: Visceral adipose tissue is a major site for expression of proinflammatory and procoagulant genes during acute systemic inflammation. In this study, we tested whether the loss of fat mass by dietary restriction would remove the major source of these factors resulting in improved tolerance to sepsis and endotoxemia. Design: Prospective, laboratory controlled experiments. Setting: Aging and critical care research laboratory in a university hospital. Subjects: Middle-aged (12-month old) male C57BL/6 mice. Interventions: Mice were subjected to 40% dietary restriction for 3 weeks followed by induction of abdominal sepsis or endotoxemia by intraperitoneal injection with cecal slurry or lipopolysaccharide, respectively. Measurements and Main Results: Compared with freely fed mice, dietary restricted mice exhibited dramatically improved survival (80% vs 0% after sepsis; p < 0.001 and 86% vs 12% after endotoxemia; p = 0.013) and significantly reduced visceral fat-derived messenger RNA expression of interleukin-6, thrombospondin-1, plasminogen activator inhibitor-1, and tissue factor, which positively correlated with fat mass. Plasma levels of interleukin-6 were significantly reduced by dietary restriction and correlated with adipose interleukin-6 messenger RNA levels and fat mass (p < 0.001; R2= 0.64 and 0.89). In vitro culture of visceral fat explants from naive dietary restricted mice showed significantly reduced interleukin-6 secretion compared with that from freely fed mice in response to lipopolysaccharide. Analysis of major adipose immune cell populations by flow cytometry demonstrated that macrophages were the only cell population reduced by dietary restriction and that CD11c+/CD206+(M2-type) and CD11c-/CD206- (double negative) macrophages, in addition to T cells, are the major immune cell populations that produce interleukin-6 in middle-aged mice during systemic inflammation. Conclusions: Short-term dietary restriction drastically improved the survival outcome of middle-aged mice during both polymicrobial sepsis and sterile endotoxemia. Improved survival was accompanied by a significantly attenuated inflammatory response in adipose tissue, which is likely due to alterations of both fat mass quantity and qualitative changes, including a reduction in macrophage populations.

Original languageEnglish
Pages (from-to)e509-e519
JournalCritical Care Medicine
Volume44
Issue number7
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Funding Information:
Supported, in part, by National Institute on Aging/National Institutes of Health and an National Cancer Institute Center Core Support Grant P30 CA177558.

Publisher Copyright:
© 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

Keywords

  • adipose tissue
  • caloric/dietary restriction
  • endotoxemia
  • macrophage
  • mortality
  • sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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