Short-Term Dietary Restriction Rescues Mice From Lethal Abdominal Sepsis and Endotoxemia and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue

Abstract

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.

Antinociceptive effects of caloric restriction on post-incisional pain in nonobese rats

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Late Therapeutic Intervention with Antibiotics and Fluid Resuscitation Allows for a Prolonged Disease Course with High Survival in a Severe Murine Model of Sepsis

“…Additionally, it is highly reproducible using our new CS preparation protocol (22, 29). Using this model, we showed that bacteria are not always detectable in the circulation of animals until 12 hours after injection with a lethal dose of CS.…”

Dietary intake regulates the circulating inflammatory monocyte pool

“…Accordingly, the recent diet westernization of developing countries has been associated with an increased prevalence of inflammatory or autoimmune disorders (Manzel et al, 2014). In contrast, reduced caloric intake is associated with improved outcomes for metabolic, autoimmune and inflammatory diseases, including NAFLD (Kani et al, 2017), T2DM , CVD (Wei et al,10 2017), multiple sclerosis (Choi et al, 2016;Jahromi et al, 2014), rheumatoid arthritis (Choi et al, 2017;Kjeldsen-Kragh et al, 1991), asthma (Johnson et al, 2007), psoriasis (Jensen et al, 2016), colitis (Shibolet et al, 2002), and sepsis (Starr et al, 2016;Wannemacher et al, 1979) and has been shown to prolong the lifespan of rodents, monkeys, and humans (Fontana et al, 2010;Picca et al, 2017). However, the molecular mechanisms by which caloric restriction 15 modulates systemic inflammation remain poorly understood.…”