Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome\u27s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity

CCN2/Connective Tissue Growth Factor Is Essential for Pericyte Adhesion and Endothelial Basement Membrane Formation during Angiogenesis

CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

The Mediating Role of Overweight and Obesity in the Prospective Association between Overall Dietary Quality and Healthy Aging

Background: Our objective was to quantify to what extent the association between adherence to the French nutritional recommendations at midlife, measured by the Programme National Nutrition Sant&eacute;-Guideline Score (PNNS-GS), and healthy aging (HA) is mediated by body mass index (BMI) status. Methods: We analyzed data from 2249 participants of the French &lsquo;Supplementation with Vitamins and Mineral Antioxidants&rsquo; (SU.VI.MAX-&lsquo;SUppl&eacute;mentation en VItamines et Min&eacute;raux AntioXydants&rsquo;) cohort. At baseline (1994&ndash;1995), data on BMI status (&lt;25 vs. &ge;25 and &lt;30 vs. &ge;30) and diet were collected. At follow-up (2007&ndash;2009), HA status (yes/no) was evaluated via a multidimensional concept focusing on chronic disease incidence, physical and cognitive functioning, mental and social health, pain, and perceived health. Relative risks (RR) were estimated by extensively adjusted robust-error-variance Poisson regression, and counterfactual-based mediation analysis was performed. Results: Our HA criteria were met by 39% of participants. We identified a positive direct relation of a greater adherence to the French nutritional recommendations, with the probability of HA (RRQuartile 4 vs. quartile 1 = 1.31 (95% confidence interval (CI) = 1.13, 1.53)), and an indirect relation mediated by BMI status (1.01 (95% CI: 1.01, 1.02)), accounting for 5% of the total relation. Conclusion: These results indicate that high dietary quality may contribute to the preservation of overall health during aging, partly via obesity prevention and partly via other mechanisms

Influence of shelf break processes on the transport of warm waters onto the eastern Amundsen Sea continental shelf

The heat transported onto the continental shelf by Circumpolar Deep Water (CDW) is the main driver of ice shelf basal melting in the Amundsen Sea. Here, we investigate the slope current system and the variability of the heat transported through the Pine Island- Thwaites central and eastern troughs using data from 5 moorings deployed in the region between 05 March 2012 and 07 February 2016. Substantial variability on intermonthly time scales (3–4 months) is observed in the onshore heat flux, driven primarily by zonal wind stress north of the shelf break. Heat content, onshore flow and heat flux are highly correlated between central and eastern troughs, which are most likely dynamically linked by the zonal wind stress forcing. This is the first time this dynamic link between troughs is observed. In the eastern the Amundsen Sea, during the El Niño of 2015/2016, strong eastward winds led to lower temperatures over the continental shelf while the onshore heat flux is intensified. We hypothesize that this anti-correlation between heat content and heat flux results from a strengthened eastward undercurrent leading to upwelling of a colder and deeper CDW variety. These results highlight the complex and heterogeneous response of this region to environmental and the importance of velocity data for understanding the dynamics in this region. It also suggests that the hypothesized link between large scale atmospheric forcing (e.g. El El Niño-Southern Oscillation) and ice-shelf melt is not produced via changes in heat content, but instead via changes in onshore heat flux

Association between adherence to the Mediterranean diet at midlife and healthy aging in a cohort of French adults

International audienceBackground The Mediterranean diet has been suggested as a key element for the prevention of age-related chronic diseases. However, very few studies have examined its relation with multidimensional concepts of healthy aging (HA). Our objective was thus to investigate the association between adherence to the Mediterranean diet at midlife and HA. Methods We analyzed data from 3,012 participants of the French SUpplémentation en Vitamines et Minéraux AntioXydants (SU.VI.MAX) study aged 45–60 years at baseline (1994–1995) and initially free of major chronic diseases, with available data on HA status in 2007–2009. We defined HA as not developing major chronic disease (cancer, cardiovascular disease, or diabetes), good physical and cognitive functioning (evaluated by validated, standardized tests), independence in instrumental activities of daily living, no depressive symptoms, good social functioning, good self-perceived health, and no function-limiting pain. An index assessing adherence to the Mediterranean diet, the Literature-based Adherence Score to the Mediterranean Diet (LAMD) was calculated using baseline data from repeated 24-hour dietary records. Results In 2007–2009, 38% of participants met the HA criteria. Multivariable logistic regression revealed that higher scores on the LAMD (ORTertile 3 vs Tertile 1: 1.36 [1.12; 1.65]) were associated with higher odds of HA. Supplementary analyses using structural equation modeling revealed a potential mediation of the observed associations by metabolic health-related factors. Conclusions Our results suggest a favorable role of a high adherence to the Mediterranean diet at midlife for maintaining good overall health during aging

How Healthy Lifestyle Factors at Midlife Relate to Healthy Aging

With increasing life expectancies worldwide, it is an important public health issue to identify factors that influence the quality of aging. We aimed to investigate the individual and combined roles of lifestyle factors at midlife for healthy aging (HA). We analyzed data from 2203 participants of the French &rdquo;Suppl&eacute;mentation en Vitamines et Min&eacute;raux Antioxydants&rdquo; (SU.VI.MAX) cohort aged 45&ndash;60 years at baseline (1994&ndash;1995), and assessed the combined impact of lifestyle factors (weight, smoking status, physical activity, alcohol consumption, and diet) on HA (absence of chronic diseases and function-limiting pain, good physical and cognitive functioning, functional independence, no depressive symptoms, and good social and self-perceived health) with a five-component healthy lifestyle index (HLI). Relative risks (RR) and 95% confidence intervals (CIs) were estimated using a robust-error-variance Poisson regression. Approximately 39% of our sample aged healthily. After adjustment for potential confounders, a one-point increase in HLI was related to an 11% higher probability of HA (95% CI = 6%, 16%; p &lt; 0.001). The proportions of HA attributable to specific factors based on the &ldquo;population attributable risk&rdquo; concept were 7.6%, 6.0%, 7.8%, and 16.5% for body mass index (BMI), physical activity, diet quality, and smoking status, respectively. This study highlights the importance of healthy lifestyle habits at midlife for the promotion of good overall health during aging

Prospective association between combined healthy lifestyles and risk of depressive symptoms in the French NutriNet-Sante cohort

Background: Several modifiable lifestyle indicators, including diet, smoking, alcohol consumption, weight and physical activity have been associated with depression; however, their combined effect has been less studied. The aim of this study was to calculate a Healthy Lifestyle Index (HLI) composed of the 5 above-mentioned indicators and investigate its association with incident depressive symptoms. Methods: The study sample consisted of 25,837 participants from the NutriNet-Sante study, initially free of depressive symptoms. The HLI was computed by assigning 1 point to each lifestyle indicator namely healthy diet, healthy weight, moderate or high physical activity, never smoking and low alcohol consumption. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D). Hazard Ratios were estimated using Cox proportional hazards models and population attributable risks (PAR) were calculated. Results: A total of 2112 incident cases of depressive symptoms were identified over a mean follow-up of 5 years. After accounting for a wide range of potential confounders, a 1-point increase in the HLI was associated with a 10% (95% CI 6%; 13%) reduction in the risk of depressive symptoms. The estimated PAR representing the proportion of cases that are attributable to non-adherence to specific healthy lifestyle indicators were 8% for healthy diet, 5% for healthy weight, 5% for non-smoking and 14% for the non-adherence to a combination of healthy diet, healthy weight and non-smoking. Limitations: Some unmeasured factors related to both depression and lifestyle indicators, such as family history of depressive disorder, stressful life events, and sleep disorders might have led to potential residual confounding. Conclusions: Modifying unhealthy lifestyles, especially diet, weight and smoking, is a potential target of major interest in the prevention of depressive symptoms in adults

Prospective association between adherence to dietary recommendations and incident depressive symptoms in the French NutriNet-Sante cohort

International audienceA posteriori healthier dietary patterns and several nutrients have been associated with lower risks of depression in various studies; however, evidence is lacking with regard to the prospective association between adherence to nutritional recommendations (food-based and nutrient-based recommendations) and incident depression or depressive symptoms. In this study, we investigate such associations in the NutriNet Sante cohort. The study sample included 26 225 participants (aged 18-86 years) who were initially free of depressive symptoms. Adherence to nutritional recommendations was measured by four scores namely modified French Programme National Nutrition Sante-Guideline Score (mPNNS-GS), Alternative Healthy Eating Index-2010 (AHEI-2010), Probability of Adequate Nutrient Intake Dietary Score (PANDiet) and Diet Quality Index-International (DQI-I), using non-consecutive dietary record data during the first 2 years of follow-up (mean number of recording days=8, sd 2). Depressive symptoms were defined by a Center for Epidemiologic Studies Depression Scale (CES-D) score >= 17 for men and 23 for women. We used Cox proportional hazards models to estimate hazard ratios and 95 % CI, modelling the dietary scores as standardised continuous variables and as tertiles. Over a mean follow-up of 6 years, we identified 2166 incident cases of depressive symptoms. All dietary scores with the exception of the AHEI-2010 were significantly inversely associated with incident depressive symptoms. In the fully adjusted model, an increase of 1 sd in the mPNNS-GS, PANDiet and DQI-I was, respectively, associated with an 8 % (95 % CI 4, 13), 5 % (95 % CI 1, 9) and 9 % (95 % CI 5, 13) reduction in the risk of depressive symptoms. Overall, these findings suggest that diet in accordance with national or international guidelines could have beneficial effects with regard to mental health