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Short-Term Dietary Restriction Rescues Mice From Lethalabdominal Sepsis and Endotoxemia, and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue #MMPMID26646465
Starr ME; MSteele A; Cohen DA; Saito H
Crit Care Med 2016[Jul]; 44 (7): e509-19 PMID26646465show ga
Objective: Visceral adipose tissue is a major site for expression of pro-inflammatory and pro-coagulant genes during acute systemic inflammation. In this study, we tested whether loss of fat mass by dietary restriction (DR) 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% DR for three weeks followed by induction of abdominal sepsis or endotoxemia by intraperitoneal injection with cecal slurry or lipopolysaccharide (LPS), respectively. Measurements and main results: Compared to freely-fed mice, DR mice exhibited dramatically improved survival (80% vs 0% after sepsis, p<0.001;86% vs 12%after endotoxemia, p=0.013) and significantly reduced visceral fat-derived mRNA expression of interleukin-6 (IL-6), thrombospondin-1, plasminogen activator inhibitor-1, and tissue factor which positively correlated with fat mass. Plasma levels of IL-6 were significantly reduced by DR and correlated with adipose IL-6 mRNAlevels and fat mass (p<0.001, R2=0.64 and 0.89). In vitro culture of visceral fat explants from naïve DR mice showed significantly reduced IL-6 secretion compared to that from freely-fed mice in response to LPS. Analysis of major adipose immune cell populations by flow cytometry demonstrated that macrophages were the only cell population reduced by DR 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 IL-6 in middle-age during systemic inflammation. Conclusions: Short-term DR 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.