TY - JOUR
T1 - Short-term dietary restriction rescues mice from lethal abdominal sepsis and endotoxemia and reduces the inflammatory/coagulant potential of adipose tissue
AU - Starr, Marlene E.
AU - Steele, Allison M.
AU - Cohen, Donald A.
AU - Saito, Hiroshi
N1 - Publisher Copyright:
© 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - adipose tissue
KW - caloric/dietary restriction
KW - endotoxemia
KW - macrophage
KW - mortality
KW - sepsis
UR - http://www.scopus.com/inward/record.url?scp=84949477400&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84949477400&partnerID=8YFLogxK
U2 - 10.1097/CCM.0000000000001475
DO - 10.1097/CCM.0000000000001475
M3 - Article
C2 - 26646465
AN - SCOPUS:84949477400
SN - 0090-3493
VL - 44
SP - e509-e519
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 7
ER -