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A 6-month weight loss program consisting of energy restriction (1,200 kcal) in combination with phentermine hydrocholoride (Fastin) treatment evaluated changes in plasma leptin, insulin, and glucose concentrations in 39 obese postmenopausal women (body mass index 30-38 kg/m2). Values for these parameters were correlated with plasma lipids concentrations and body composition measurements previously reported for this population. Over 6 months, participants had a 9% weight loss (P < 0.001) and a 9% reduction in body mass index (P < 0.001) compared to baseline with a 20% reduction in total fat mass and 25.8% in trunk fat (P < 0.001). Plasma leptin levels were reduced by 27% (P < 0.001) at 3 months and by 32% (P < 0.001) at 6 months. In contrast, plasma glucose and insulin levels did not change over time. Significant positive correlations were found between changes in plasma leptin and changes in LDL cholesterol (r = 0.366), weight (r = 0.570) and trunk fat (r = 0.362) over 6 months indicating that reductions in leptin are associated with improved parameters in plasma lipids and body composition. [ABSTRACT FROM AUTHOR]

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood 1,2 . 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 cells 3,4 . However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome 5-9 and may promote atherosclerosis and vascular inflammation 6 , suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity 10-13 , 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.

Aims: Abdominal aortic aneurysm (AAA) is an age-associated disease characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix degradation. Despite considerable progress in identifying targets involved in these processes, therapeutic approaches aiming to reduce aneurysm growth and rupture are still scarce. Indoleamine 2-3 dioxygenase 1 (IDO) is the first and rate-limiting enzyme involved in the conversion of tryptophan (Trp) into kynurenine (Kyn) pathway. In this study, we investigated the role of IDO in two different models of AAA in mice., Methods and Results: Mice with deficiencies in both low density receptor-deficient (Ldlr-/-) and IDO (Ldlr-/-Ido1-/-) were generated by cross-breeding Ido1-/- mice with Ldlr-/-mice. To induce aneurysm, these mice were infused with angiotensin II (Ang II) (1000 ng/min/kg) and fed with high fat diet (HFD) during 28 days. AAAs were present in almost all Ldlr-/- infused with AngII, but only in 50% of Ldlr-/-Ido1-/- mice. Immunohistochemistry at an early time point (day 7) revealed no changes in macrophage and T lymphocyte infiltration within the vessel wall, but showed reduced apoptosis, as assessed by TUNEL assay, and increased α-actin staining within the media of Ldlr-/-Ido1-/- mice, suggesting enhanced survival of vascular smooth muscle cells (VSMCs) in the absence of IDO. In another model of elastase-induced AAA in C57Bl/6 mice, IDO deficiency had no effect on aneurysm formation., Conclusion: Our study showed that the knockout of IDO prevented VSMC apoptosis in AngII -treated Ldlr-/- mice fed with HFD, suggesting a detrimental role of IDO in AAA formation and thus would be an important target for the treatment of aneurysm.

Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α + subset of dendritic cells (CD8α + DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis., Objective: We sought to address the impact of total, bone marrow-restricted, or CD8α + DC-restricted deletion of DNGR-1 on atherosclerosis development., Methods and Results: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)-deficient mice ( Apoe -/- ) and bone marrow-restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)-deficient mice ( Ldlr -/- ) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow-derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α + DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis., Conclusions: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation., (© 2017 American Heart Association, Inc.)

Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the effects of a culturally sensitive diabetes education program for Hispanics with type 2 diabetes., Methods: This study is a prospective cohort study to test the impact of a comprehensive diabetes education program on blood glucose control on Hispanics with type 2 diabetes. The educational program focused on maintaining glycemic control and general aspects of managing diabetes and complications. The study participants were recruited by flyers placed in Hispanic markets and in ambulatory care clinics. A total of 34 Hispanic male and female subjects with type 2 diabetes participated in the study. The concentrations of glucose, insulin, hemoglobin A1c (HbA1c), total cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein (HDL) cholesterol were analyzed at baseline and at 3 months., Results: A significant mean change was observed for HbA1c, fasting plasma glucose, cholesterol/HDL ratio, and HDL after 3 months of education compared with baseline. There were significant reductions in weight, total fat, percent fat, trunk fat, and waist-to-hip ratio compared with baseline. After 3 months, subjects showed a significant positive correlation between changes in body mass index and insulin and weight, total fat, trunk fat, and fat free mass and insulin., Conclusions: A culturally sensitive program conducted in Spanish had a significant impact on important clinical parameters in Hispanic subjects with diabetes in a relatively short time period. The study demonstrates the importance of designing education intervention studies that are sensitive to cultural diversity, particularly in at-risk diabetic subjects.

A total of 39 postmenopausal women 40-70 years of age and undergoing hormone replacement therapy participated in a 6-month weight reduction program, which consisted of a low calorie diet (5040 KJ/day) and phentermine hydrochloride therapy. Subjects had an average body mass index of 35.95+/-5.32 kg/m(2) and 42.20+/-11.0 kg of total fat. Body mass index, plasma lipids, total and trunk fat, and plasma apoproteins were measured at baseline and after 3 and 6 months of the weight reduction program. Subjects experienced an overall 10% weight loss during the treatment period (P<0.001). Plasma LDL cholesterol and triglycerides were reduced by 18% and 15% (P<0.01) respectively, whereas HDL cholesterol was increased by 9% (P<0.01) over the 6-month period. Plasma apoproteins were significantly affected by weight loss. Plasma apolipoprotein (apo) B concentrations were reduced 6.5% (P<0.01), and apo C-III and apo E were reduced by 9% over 6 months (P<0.01). The observed decreases in plasma apo B were significantly correlated with the observed changes in plasma cholesterol (r=0.356, P<0.01) over 3 months. In addition, changes in plasma triglycerides were correlated with changes in both apo C-III (r=0.436) and apo E (r=0.354) over 6 months. These results suggest that weight loss may have multifactorial effects on lipoprotein metabolism, resulting in better plasma lipid and apoprotein profiles.