Hematopoietic Cell-Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance.

OBJECTIVE: Mice genetically deficient in endothelial nitric oxide synthase (Nos3-/-) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow-derived cells also express Nos3. The aim of this study was to investigate whether bone marrow-derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow-derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow-derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow-derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow-derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. CONCLUSIONS: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow-derived cells, not in endothelial cells.

PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis.

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara-/-) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara-/- mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara-/- mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara-/- mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. NEW & NOTEWORTHY: In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.