Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target

Two phases model of ageing in mice: towards a better identification of age-related and late-life metabolic decline [Registered Report Stage 1 Protocol]

Abstract: Since being described in Drosophila melanogaster in 2011, the Smurf phenotype, has been seen to be evolutionarily conserved in nematode and zebrafish, and has helped to identify the discontinuous nature of ageing and predict impending death from natural causes as well as from environmental stresses. This phenotype allowed us to model ageing as being made of two successive phases : a phase A where individuals are healthy and have no risk of mortality but an age-dependent increasing risk of entering phase B, followed by a phase B where individuals show the so-called hallmarks of ageing and a high risk of death. We will test here whether these two consecutive phases of ageing separated by the Smurf transition are a conserved feature of ageing in the classical mammalian laboratory model Mus musculus. Thanks to a longitudinal longevity study using both males and females from two different mouse genetic backgrounds and by integrating physiological, metabolic and molecular measurements with the life history of approximately 150 mice, we are attempting to identify a phenotypic signature typical of the last phase of life, observable at any chronological age. Validating the two-phase ageing model in a mammalian organism would allow the high risk of imminent death to be better characterized in this model and would extend its implications to a broader range of species for aging research. </p

Soat2 ties cholesterol metabolism to beta-oxidation and glucose tolerance in male mice

International audienceBackground Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins. Objectives We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice. Methods Soat2(-/-) and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed. Results Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2(-/-) mice, irrespective of the dietary regimes (2-way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA-IR (r = 0.86, p < 0.05), Adipo-IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very-low-density lipoprotein (VLDL)-TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild-type mice disappeared in Soat2(-/-) mice. Genetic depletion of Soat2 also increased whole-body oxidation by 30% (p < 0.05) compared to wild-type mice. Conclusion Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways