Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles.

Microbiome and metabolome features of the cardiometabolic disease spectrum.

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome.

Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease.

Complex diseases, such as coronary artery disease (CAD), are often multifactorial, caused by multiple underlying pathological mechanisms. Here, to study the multifactorial nature of CAD, we performed comprehensive clinical and multi-omic profiling, including serum metabolomics and gut microbiome data, for 199 patients with acute coronary syndrome (ACS) recruited from two major Israeli hospitals, and validated these results in a geographically distinct cohort. ACS patients had distinct serum metabolome and gut microbial signatures as compared with control individuals, and were depleted in a previously unknown bacterial species of the Clostridiaceae family.

UCP1 expression-associated gene signatures of human epicardial adipose tissue.

Multiple reports of uncoupling protein 1 (UCP1) expression have established its presence in human epicardial adipose tissue (eAT). Its functional relevance to eAT, however, remains largely unknown. In a recent study, we reported that adrenergic stimulation of eAT was associated with downregulation of secreted proteins involved in oxidative stress-related and immune-related pathways.

Functional characterization of the Ucp1-associated oxidative phenotype of human epicardial adipose tissue.

Brown fat presence and metabolic activity has been associated with lower body mass index, higher insulin sensitivity and better cardiometabolic profile in humans. We, and others, have previously reported the presence of Ucp1, a marker of brown adipocytes, in human epicardial adipose tissue (eAT). Characterization of the metabolic activity and associated physiological relevance of Ucp1 within eAT, however, is still awaited.

Brown and beige adipose tissues: phenotype and metabolic potential in mice and men.

With the recent rediscovery of brown fat in adult humans, our outlook on adipose tissue biology has undergone a paradigm shift. While we attempt to identify, recruit, and activate classic brown fat stores in humans, identification of beige fat has also raised the possibility of browning our white fat stores. Whether such transformation of human white fat depots can be achieved to enhance the whole body oxidative potential remains to be seen.

Metabolic activity of brown, "beige," and white adipose tissues in response to chronic adrenergic stimulation in male mice.

Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g.

Understanding the brown adipocyte as a contributor to energy homeostasis.

Brown adipocytes are specialized cells capable of undergoing thermogenesis, a phenomenon regulated by the sympathetic nervous system, due to the presence of uncoupling protein 1 (UCP1). The recent demonstrations of their presence in adult humans, and the discovery that brown adipocytes can be derived from distinct precursors and express specific genes depending on their anatomic location, have sparked intense interest in enhancing the current understanding of their biology and relevance to human energy homeostasis. We provide an overview of the latest advances related to the developmental origins of brown adipocytes, discuss their regulation and function in both rodents and humans, and offer a critical perspective on the relevance of brown adipocyte-mediated thermogenesis in human physiology.

Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL-cholesterol and triglycerides in patients with coronary artery disease.

Background: Recent evidence indicates that epicardial adipose tissue (EAT) expresses uncoupling protein-1 (UCP1), a marker of brown adipocytes. However, the putative effects of the presence of brown adipocytes in EAT remain unknown.

Methods: The mRNA expression of genes related to brown adipocyte-mediated thermogenesis was measured in the fat samples collected from the epicardial-, mediastinal- and subcutaneous-depots of patients undergoing coronary artery bypass grafting.

Control and physiological determinants of sympathetically mediated brown adipose tissue thermogenesis.

Brown adipose tissue (BAT) represents a remarkable heat-producing tissue. The thermogenic potential of BAT is conferred by uncoupling protein 1, a protein found uniquely in brown adipocytes. BAT activity and capacity is controlled by the sympathetic nervous system (SNS), which densely innervates brown fat depots.

Validation of reference genes for the relative quantification of gene expression in human epicardial adipose tissue.

Background: Relative quantification is a commonly used method for assessing gene expression, however its accuracy and reliability is dependent upon the choice of an optimal endogenous control gene, and such choice cannot be made a priori. There is limited information available on suitable reference genes to be used for studies involving human epicardial adipose tissue. The objective of the current study was to evaluate and identify optimal reference genes for use in the relative quantification of gene expression in human epicardial fat depots of lean, overweight and obese subjects.

Maternal dietary fat intake during gestation and lactation alters tissue fatty acid composition in the adult offspring of C57Bl/6 mice.

We investigated the effects of maternal dietary fat intake during gestation and lactation on the tissue fatty acid composition of the adult offspring. Female C57Bl/6 mice were fed high fat diets enriched with lard or safflower oil or chow during mating, gestation and lactation. The offspring obtained from each group of mothers were continued on diets rich in lard, safflower oil or chow post-weaning until 11 weeks of age.

Flax oil-mediated activation of PPAR-γ correlates with reduction of hepatic lipid accumulation in obese spontaneously hypertensive/NDmcr-cp rats, a model of the metabolic syndrome.

Flax oil feeding has been proposed to have beneficial effects on the outcome of the metabolic syndrome due to the high n-3 fatty acid content of flax oil; however, the mechanisms of its action remain largely unknown. We investigated the effects of flax oil feeding on hyperlipidaemia, hyperglycaemia, hepatic steatosis and oxidative stress in the spontaneously hypertensive (SHR)/NDmcr-cp rats, a genetic model of the metabolic syndrome. Hepatic gene expression of PPAR-α, PPAR-γ and sterol-regulatory element-binding protein-1c was also assessed in order to investigate the possible underlying mechanisms.

An interaction of the pre- and post-weaning diets rich in omega-6 polyunsaturated fats alters plasma lipids, hepatic gene expression and aortic vascular reactivity in adult C57BL/6 mice.

Aim: To investigate the effects of diets rich in n-6 polyunsaturated fats (PUFA) fed during pre- and post-weaning time periods on the lipid metabolism and vascular reactivity in adult C57Bl/6 mice, in order to assess the impact of maternal nutrition and its interaction with the offspring diet on the metabolism of adult offspring.

Methods: Female C57Bl/6 mice were fed a high-fat diet enriched with n-6 PUFA (P) or control diet (C) for 2-weeks before, during mating, gestation and lactation, while their pups received either P or C for 8-weeks post-weaning.

Results: A significant interaction between the maternal and post-weaning diets was observed for the offspring body weight, food-, caloric-intake, plasma lipids, hepatic mRNA expression of lecithin cholesterol acyltransferase, aortic contractile and relaxation responses (P < 0.

Developmental programming of lipid metabolism and aortic vascular function in C57BL/6 mice: a novel study suggesting an involvement of LDL-receptor.

We have previously shown that a maternal high-fat diet, rich in saturated fatty acids (SFA), alters the lipid metabolism of their adult offspring. The present study was designed to investigate 1) whether alterations in hepatic LDL-receptor (LDL-r) expression may serve as a potential mechanism of developmental programming behind the altered lipid metabolism of the offspring, 2) whether altered lipid metabolism leads to aortic vascular dysfunction in the offspring, 3) whether deleterious effects of SFA exposure preweaning are influenced by postweaning diet, and 4) whether gender-specific programming effects are observed. Female C57Bl/6 mice were fed a high-SFA diet or regular chow during gestation and lactation while their pups, both male and female, received either SFA or a chow diet after weaning.

Maternal diet rich in saturated fats has deleterious effects on plasma lipids of mice.

Background And Objectives: High dietary fat intake has been reported to cause an alteration in lipid metabolism that is associated with an increased risk of cardiovascular disease. In the present study, an animal model was used to evaluate the effects of feeding diets rich in different fatty acids to mothers during pregnancy and lactation, and the effects of the maternal diet on parameters of lipid metabolism in adult offspring. The interaction between the offspring's own diet and the programming due to the maternal diet was also evaluated.