Development Of Cardiometabolic Diseases Research Articles

Association Between Maternal Prepregnancy Body Mass Index and Anthropometric Parameters, Blood Pressure, and Retinal Microvasculature in Children Age 4 to 6 Years

Maternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) has previously been associated with offspring cardiometabolic risk factors, such as fat mass, glucose and insulin levels, and blood pressure, but these associations appear to be largely mediated by offspring BMI. To our knowledge, no studies have assessed alterations in the retinal microvasculature in association with maternal prepregnancy BMI. To investigate the association between maternal prepregnancy BMI and anthropometric parameters, blood pressure, and retinal vessel parameters in children age 4 to 6 years. Participants included mother-child pairs of the population-based Environmental Influence on Early Aging (ENVIRONAGE) birth cohort study (Flanders, Belgium) who were recruited at birth from February 2010 to June 2014 and followed-up at age 4 to 6 years between October 2014 and July 2018. Data were analyzed from February 2019 to April 2019. Maternal prepregnancy BMI based on height and weight measurements at the first antenatal visit (weeks 7-9 of gestation). Children's anthropometric, blood pressure, and retinal microcirculation measurements at age 4 to 6 years. Retinal vessel diameters and the tortuosity index, a measure for the curvature of the retinal vasculature, were obtained by fundus image analysis. This study included 240 mothers and children with a mean (SD) age of 29. 9 (4.2) years and 54.8 (4.7) months, respectively. Of these, 114 children (47.5%) were boys. Maternal prepregnancy BMI was positively associated with the child's birth weight, BMI, waist circumference, blood pressure, and retinal vessel tortuosity. A 1-point increase in maternal prepregnancy BMI was associated with a 0.26-mm Hg (95% CI, 0.08-0.44) higher mean arterial pressure for their children, with similar estimates for systolic and diastolic blood pressure. Independent from the association with blood pressure, a 1-point increase in maternal prepregnancy BMI was associated with a 0.40 (95% CI, 0.01-0.80) higher retinal tortuosity index (× 103). The hypothesis that these associations reflect direct intrauterine mechanisms is supported by the following observations: associations were independent of the current child's BMI and the estimates for paternal BMI at the follow-up visit did not reach significance. Considering that blood pressure tracks from childhood into adulthood and microvascular changes may be early markers of cardiometabolic disease development, our results suggest that maternal prepregnancy BMI is an important modifiable risk factor for later-life cardiovascular health of the offspring.

Multidisciplinary lifestyle intervention in children and adolescents - results of the project GRIT (Growth, Resilience, Insights, Thrive) pilot study

BackgroundDuring childhood and adolescence leading behavioural risk factors for the development of cardiometabolic diseases include poor diet quality and sedentary lifestyle. The aim of this study was to determine the feasibility and effect of a real-world group-based multidisciplinary intervention on cardiorespiratory fitness, diet quality and self-concept in sedentary children and adolescents aged 9 to 15 years.MethodsProject GRIT (Growth, Resilience, Insights, Thrive) was a pilot single-arm intervention study. The 12-week intervention involved up to three outdoor High Intensity Interval Training (HIIT) running sessions per week, five healthy eating education or cooking demonstration sessions, and one mindful eating and Emotional Freedom Technique psychology session. Outcome measures at baseline and 12-week follow-up included maximal graded cardiorespiratory testing, the Australian Child and Adolescent Eating Survey, and Piers-Harris 2 children’s self-concept scale. Paired samples t-test or Wilcoxon signed-rank test were used to compare baseline and follow-up outcome measures in study completers only.ResultsOf the 38 recruited participants (median age 11.4 years, 53% male), 24 (63%) completed the 12-week intervention. Dropouts had significantly higher diet quality at baseline than completers. Completers attended a median 58 (IQR 55–75) % of the 33 exercise sessions, 60 (IQR 40–95) % of the dietary sessions, and 42% attended the psychology session. No serious adverse events were reported. Absolute VO2peak at 12 weeks changed by 96.2 ± 239.4 mL/min (p = 0.06). As a percentage contribution to energy intake, participants increased their intake of healthy core foods by 6.0 ± 11.1% (p = 0.02) and reduced median intake of confectionary (− 2.0 [IQR 0.0–3.0] %, p = 0.003) and baked products (− 1.0 [IQR 0.0–5.0] %, p = 0.02). Participants significantly improved self-concept with an increase in average T-Score for the total scale by 2.8 ± 5.3 (p = 0.02) and the ‘physical appearance and attributes’ domain scale by median 4.0 [IQR 0.5–4.0] (p = 0.02).ConclusionsThe 12-week group-based multidisciplinary lifestyle intervention for children and adolescents improved diet quality and self-concept in study completers. Future practice and research should focus on providing sustainable multidisciplinary lifestyle interventions for children and adolescents aiming to improve long-term health and wellbeing.Trial registrationANZCTR, ACTRN12618001249246. Registered 24 July 2019 - Retrospectively registered

The Optimal Range of Serum Uric Acid for Cardiometabolic Diseases: A 5-Year Japanese Cohort Study.

The optimal range of serum uric acid (urate) associated with the lowest risk for developing cardiometabolic diseases is unknown in a generally healthy population. This 5-year cohort study is designed to identify the optimal range of serum urate. The data were collected from 13,070 Japanese between ages 30 and 85 at the baseline (2004) from the Center for Preventive Medicine, St. Luke’s International Hospital, Tokyo. We evaluated the number of subjects (and prevalence) of those free of the following conditions: hypertension, diabetes, dyslipidemia, and chronic kidney disease (CKD) over 5 years for each 1 mg/dL of serum urate stratified by sex. Furthermore, the odds ratios (ORs) for remaining free of these conditions were calculated with multiple adjustments. Except for truly hypouricemic subjects, having lower serum urate was an independent factor for predicting the absence of hypertension, dyslipidemia, and CKD, but not diabetes. The OR of each 1 mg/dL serum urate decrease as a protective factor for hypertension, dyslipidemia, and CKD was 1.153 (95% confidence interval, 1.068–1.245), 1.164 (1.077–1.258), and 1.226 (1.152–1.306) in men; 1.306 (1.169–1.459), 1.121 (1.022–1.230), and 1.424 (1.311–1.547) in women, respectively. Moreover, comparing serum urate of 3–5 mg/dL in men and 2–4 mg/dL in women, hypouricemia could be a higher risk for developing hypertension (OR: 4.532; 0.943–21.78) and CKD (OR: 4.052; 1.181–13.90) in women, but not in men. The optimal serum urate range associated with the lowest development of cardiometabolic diseases was less than 5 mg/dL for men and 2–4 mg/dL for women, respectively.

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Current metabolic perspective on malnutrition in obesity: towards more subgroup-based nutritional approaches?

Lifestyle intervention may be effective in reducing type 2 diabetes mellitus incidence and cardiometabolic risk. A more personalised nutritional approach based on an individual or subgroup-based metabolic profile may optimise intervention outcome. Whole body insulin resistance (IR) reflects defective insulin action in tissues such as muscle, liver, adipose tissue, gut and brain, which may precede the development of cardiometabolic diseases. IR may develop in different organs but the severity may vary between organs. Individuals with more pronounced hepatic IR have a distinct plasma metabolome and lipidome profile as compared with individuals with more pronounced muscle IR. Additionally, genes related to extracellular modelling were upregulated in abdominal subcutaneous adipose tissue in individuals with more pronounced hepatic IR, whilst genes related to inflammation as well as systemic low-grade inflammation were upregulated in individuals with primarily muscle IR. There are indications that these distinct IR phenotypes may also respond differentially to dietary macronutrient composition. Besides metabolic phenotype, microbial phenotype may be of importance in personalising the response to diet. In particular fibres or fibre mixtures, leading to a high distal acetate and SCFA production may have more pronounced effects on metabolic health. Notably, individuals with prediabetes may have a reduced response to diet-induced microbiota modulation with respect to host insulin sensitivity and metabolic health outcomes. Overall, we need more research to relate metabolic subphenotypes to intervention outcomes to define more optimal diets for individuals with or predisposed to chronic metabolic diseases.

Skeletal muscle area and density are associated with lipid and lipoprotein cholesterol levels: The Multi-Ethnic Study of Atherosclerosis

Loss of muscle mass with age may be a key player in metabolic dysregulation. We examined the associations between abdominal muscle areaanddensitywith lipids and lipoproteins. One thousand eight hundred and sixty eight adults completed health history and physical activity questionnaires, provided venous blood samples for lipids and inflammatory biomarkers, and underwent computed tomography to quantify body composition. Associations between muscle area and density with multiple lipid measures were assessed with multivariable linear and logistic regression. The mean age and body mass index of participants was 65years and 28kg/m2, respectively, and 50% were female. After adjustment for demographics, cardiovascular disease risk factors, lipid-lowering medications, physical activity, sedentary behavior, inflammatory biomarkers, and central obesity, a 1-standard deviation increase in total abdominal, stability, and locomotor muscle areas was associated with a 13%, 11%, and 8% lower high-density lipoprotein cholesterol level, respectively (P<.05). With similar adjustment, a 1-standard deviation increase in total abdominal and stability muscle area was associated with a 13% and 12% lower total cholesterol level, respectively (P<.01). Compared to the lowest quartiles of total, stability, and locomotor muscle area, those in the higher quartiles of muscle area had over a 40% reduction in the odds of triglyceride levels greater than 150mg/dL (P<.05). Total abdominal muscle density was positively associated with total cholesterol (P<.05) but was not associated with the other lipid outcomes. Maintaining adequate skeletal muscle mass with age may decrease specific lipid levels related to hyperlipidemia and development of cardiometabolic disease.

Sarcoplasmic reticulum and calcium signaling in muscle cells: Homeostasis and disease.

The sarco/endoplasmic reticulum is an extensive, dynamic and heterogeneous membranous network that fulfills multiple homeostatic functions. Among them, it compartmentalizes, stores and releases calcium within the intracellular space. In the case of muscle cells, calcium released from the sarco/endoplasmic reticulum in the vicinity of the contractile machinery induces cell contraction. Furthermore, sarco/endoplasmic reticulum-derived calcium also regulates gene transcription in the nucleus, energy metabolism in mitochondria and cytosolic signaling pathways. These diverse and overlapping processes require a highly complex fine-tuning that the sarco/endoplasmic reticulum provides by means of its numerous tubules and cisternae, specialized domains and contacts with other organelles. The sarco/endoplasmic reticulum also possesses a rich calcium-handling machinery, functionally coupled to both contraction-inducing stimuli and the contractile apparatus. Such is the importance of the sarco/endoplasmic reticulum for muscle cell physiology, that alterations in its structure, function or its calcium-handling machinery are intimately associated with the development of cardiometabolic diseases. Cardiac hypertrophy, insulin resistance and arterial hypertension are age-related pathologies with a common mechanism at the muscle cell level: the accumulation of damaged proteins at the sarco/endoplasmic reticulum induces a stress response condition termed endoplasmic reticulum stress, which impairs proper organelle function, ultimately leading to pathogenesis.

Impact of high-fat overfeeding on white adipose tissue and systemic metabolic and inflammatory responses

AbstractWhite adipose tissue (WAT) inflammation is linked to the development of cardiometabolic disease. A high intake of saturated fatty acids (SFA) may promote a more pro-inflammatory WAT gene expression profile, compared to monounsaturated fatty acids(1,2). This is concerning as the UK adult population currently exceeds the SFA intake target of &lt; 10% total energy (TE), at 11.9%TE(3). However, further research is needed to understand how SFA ingestion impacts the protein content and phosphorylation of key targets involved in WAT inflammatory signalling. Therefore, this study investigated the effect of short-term, high-fat overfeeding on WAT and systemic metabolic and inflammatory responses in healthy, non-obese individuals.Fifteen (9 men, 6 women) apparently healthy participants (mean (SE) age; 26.6 (1.2) y, BMI; 24.4 (0.6) kg/m2) consumed a high-fat (dietary target: 65.0%TE total fat; 32.5%TE SFA), high-calorie (+ 50% estimated energy requirements) diet for 7 days. Fasted venous blood and WAT samples were collected pre- and post-intervention.Body mass increased following the intervention (pre-intervention vs. post-intervention: 75.2 (2.9) kg vs. 76.4 (2.9) kg; P &lt; 0.0001). The intervention also led to increases in glucose (4.4 (0.1) vs. 4.6 (0.1) mmol/L; P = 0.022) and lipopolysaccharide-binding protein (12.9 (1.3) vs. 17.7 (3.0) μg/mL; P = 0.038), and a decrease in triacylglycerol (0.91 (0.08) vs. 0.72 (0.05) mmol/L; P = 0.007). Insulin, IL-6 and soluble CD14 concentrations remained unchanged (all P &gt; 0.05). At the WAT level, total protein (TLR4; NF-κB; IKβα; P38; MCP-1) and phosphorylation (p) of proteins (p-NF-κB; p-IKβα; p-P38) involved in inflammatory signalling were unchanged following the intervention (all P &gt; 0.05).In conclusion, although short-term, high-fat overfeeding led to an increase in body mass as well as systemic metabolic alterations, the content and phosphorylation of proteins involved in WAT inflammatory signalling were unaltered in healthy, non-obese individuals. Further analysis will reveal the impact of high-fat overfeeding on peripheral blood monocyte populations, which are involved in mediating pro- and anti-inflammatory responses.This research was supported by a Society for Endocrinology Early Career Grant.

Trimethylamine-N-oxide is present in human follicular fluid and is a negative predictor of embryo quality.

STUDY QUESTIONAre levels of trimethylamine-N-oxide (TMAO) in human follicular fluid (FF) related to IVF outcomes?SUMMARY ANSWERHigher levels of TMAO are a negative predictor of oocyte fertilization and embryo quality.WHAT IS KNOWN ALREADYTMAO is a metabolic product of dietary choline and l-carnitine produced via subsequent enzymatic modifications by the intestinal microbiota and hepatocytes. TMAO promotes inflammatory and oxidative stress pathways and has been characterized as a causative biomarker for the development of cardiometabolic disease.STUDY DESIGN, SIZE, DURATIONFor the present cross-sectional study, samples (FF and plasma) from 431 modified natural cycle (MNC)-IVF cycles of 132 patients were collected prospectively between October 2014 and March 2018 in a single academic medical center.PARTICIPANTS/MATERIALS, SETTING, METHODSTMAO and its precursors (choline, l-carnitine and gamma-butyrobetaine) were measured by ultra-high-performance liquid chromatography/mass spectrometry in (i) matched FF and plasma from 63 MNC-IVF cycles, in order to compare metabolite levels in the two matrices and (ii) FF from 232 MNC-IVF cycles in which only one oocyte was retrieved at follicular puncture. The association between metabolite levels and oocyte fertilization, embryo fragmentation percentage, embryo quality and the occurrence of pregnancy was analyzed using multilevel generalized estimating equations with adjustment for patient and cycle characteristics.MAIN RESULTS AND THE ROLE OF CHANCEThe level of choline was higher in FF as compared to matched plasma (P < 0.001). Conversely, the levels of TMAO and gamma-butyrobetaine were lower in FF as compared to plasma (P = 0.001 and P = 0.075, respectively). For all metabolites, there was a positive correlation between FF and plasma levels. Finally, levels of TMAO and its gut-derived precursor gamma-butyrobetaine were lower in FF from oocytes that underwent normal fertilization (TMAO: odds ratio [OR] 0.66 [0.49–0.90], P = 0.008 per 1.0-μmol/L increase; gamma-butyrobetaine: OR 0.77 [0.60–1.00], P = 0.047 per 0.1-μmol/L increase) and developed into top-quality embryos (TMAO: OR 0.56 [0.42–0.76], P < 0.001 per 1.0-μmol/L increase; gamma-butyrobetaine: OR 0.79 [0.62–1.00], P = 0.050 per 0.1-μmol/L increase) than in FF from oocytes of suboptimal development.LIMITATIONS, REASONS FOR CAUTIONThe individual contributions of diet, gut bacteria and liver to the metabolite pools have not been quantified in this analysis.WIDER IMPLICATIONS OF THE FINDINGSMore research on the contribution of diet and the effect of gut bacteria on FF TMAO is warranted. Since TMAO integrates diet, microbiota and genetic setup of the person, our results indicate potential important clinical implications for its use as biomarker for lifestyle interventions to improve fertility.STUDY FUNDING/COMPETING INTEREST(S)No external funding was received for this project. The Department of Obstetrics and Gynecology of the University Medical Center Groningen received an unrestricted educational grant of Ferring Pharmaceutical BV, the Netherlands. The authors have no other conflicts of interest.TRIAL REGISTRATION NUMBERNetherlands Trial Register number NTR4409.

Associação entre qualidade do sono e doenças cardiometabólicas de pacientes da Atenção Primária à Saúde

A privação do sono está relacionada ao desenvolvimento de doenças cardiometabólicas. O objetivo deste estudo foi analisar a associação entre qualidade do sono e ocorrência de doenças cardiometabólicas em adultos atendidos na Atenção Primária à Saúde. Estudo longitudinal composto por 169 adultos (68,6% do sexo feminino), média de idade 61,80 (desvio padrão = 8,80), acompanhados por 30 meses. A presença das doenças hipertensão arterial, dislipidemia, diabetes mellitus e ocorrência de infarto e a qualidade do sono foram mensuradas por meio de questionários. Os participantes foram divididos em grupos de acordo com a qualidade do sono (adequada/inadequada). Para verificar a diferença de idade, classe econômica, atividade física habitual e circunferência de cintura, entre os grupos a e b, utilizou-se o teste t de Student para amostras independentes. Para comparar a proporção das doenças (hipertensão arterial, infarto, diabetes e dislipidemias) entre os grupos, utilizou-se o teste Qui-quadrado com correção de Yates. A regressão logística binária foi utilizada para testar a magnitude de tais associações, ajustadas por sexo, idade, atividade física, obesidade abdominal, etilismo e tabagismo. As análises estatísticas foram realizadas no software BioEstat (versão 5.0) e o nível de significância adotado foi de p &lt; 0,05. Verificou-se que 83,4% dos adultos reportaram ao menos uma alteração na qualidade do sono e os que apresentaram inadequada qualidade do sono tiveram 3,4 vezes mais chances de reportar diabetes (OR = 3,47; IC95%: 1,06 - 11,30), comparados aos com o sono adequado. Inadequada qualidade do sono parece contribuir para o aumento da ocorrência de diabetes mellitus, independente do tempo de prática de atividade física e a obesidade abdominal.

Effects of chronic cadmium exposure at food limitation-relevant levels on energy metabolism in mice

Cadmium (Cd) exposure has been implicated in the perturbation of energy metabolism and the development of cardiometabolic disease, but disease predisposition from chronic low-dose Cd exposure remains unclear. This study employed a mouse model to investigate the toxic effects of chronic Cd exposure at food limitation-relevant levels on energy metabolism and the associated liver and gut microbiome functions. Results showed that the Cd exposure induced the perturbation of energy metabolism in mice, evidenced by the alteration of various metabolites associated with the phosphorogen (adenosine triphosphate-creatine phosphate) system, tricarboxylic acid cycle, and lipid metabolism, as well as the increase of the cardiometabolic risk factor, triglyceride. Moreover, both liver and gut microbiome underwent marked structural/histological and functional alterations, prone to the onset of cardiometabolic disease following the Cd exposure. Certain hepatic transcription factors and gut microbes, specifically PPARα, SREBP1c, HNF4A and the Clostridiales_vadinBB60_group, were identified to be highly correlated with altered urinary metabolites, revealing potential toxicological interactions between the liver and gut microbiome, and energy metabolism. Our findings provide new insights into the progression of metabolic diseases induced by Cd exposure. We also propose a stricter Cd limitation in future food safety standards.

Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease. Since the effect of empagliflozin or other SGLT2 inhibitors on the whole cardiac metabolic profile was never analysed before, and with the purpose to contribute to elucidate the benefits at cardiac level of the use of empagliflozin, we explored the effect of the treatment with empagliflozin for six weeks on the cardiac metabolomic profile of Zucker diabetic fatty rats, a model of early stage T2DM, using untargeted metabolomics approach. Empagliflozin reduced significantly the cardiac content of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (major bioactive contributing factors linking insulin resistance to cardiac damage) and decreased the cardiac content of the fatty acid transporter cluster of differentiation 36 (CD36); induced significant decreases of the cardiac levels of essential glycolysis intermediaries 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated the abundance of several amino acids of relevance as tricarboxylic acid suppliers and/or in the metabolic control of the cardiac function as glutamic acid, gamma-aminobutyric acid and sarcosine. Empagliflozin treatment activated the cardioprotective master regulator of cellular energyhomeostasis AMP-activatedproteinkinase (AMPK) and enhanced autophagy at cardiac level, while it decreased significantly the cardiac mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6), chemerin, TNF-α and MCP-1, reinforcing the hypothesis of a direct role for empagliflozin in attenuating cardiac inflammation. Our results provide an advancement on the knowledge of the mechanisms linking the therapy with empagliflozin with protective effects on the development of cardiometabolic diseases whose course is associated with remarkable cardiac bioenergetics dysregulation and disarrangement in cardiac metabolome and lipidome.

Growth During Infancy and Early Childhood and Its Association With Metabolic Risk Biomarkers at 11.5 Years of Age.

The evidence that fetal life and early infancy are "critical" or "sensitive" ages for later development of cardiometabolic disease is based on flawed methods for comparing different age periods. Moreover, most previous studies have limited their focus to weight gain, rather than growth in length/height or body mass index (weight (kg)/height (m)2). We undertook a secondary analysis of data from the Promotion of Breastfeeding Intervention Trial (1996-2010), a birth cohort study nested within a large cluster-randomized trial in the Republic of Belarus, that had repeated measurements of weight and length/height taken from birth to 11.5 years of age. We used mixed-effects linear models to analyze associations of changes in standardized weight, length/height, and body mass index during 5 age periods (conception to birth, birth to age 3 months, ages 3-12 months, ages 12 months-6.5 years, and ages 6.5-11.5 years) with fasting glucose, insulin, insulin resistance, β-cell function, and adiponectin at age 11.5 years. We observed strong associations between the metabolic markers and all 3 growth measures, with the largest magnitudes being observed during the latest age period (ages 6.5-11.5 years) and negligible associations during gestation and the first year of life. Later age periods appear more "sensitive" than earlier periods to the adverse metabolic association with rapid growth in childhood.

30 - Multiomics Profiling of Rat Offspring Exposed to Gestational Diabetes Reveals Cardiometabolic Disease Development With Age

Through unknown mechanisms, fetal exposure to gestational diabetes mellitus (GDM) increases the risk for cardiometabolic disease development later in life. We hypothesize that fetal exposure to GDM alters cardiomyocyte metabolism and induces left ventricular (LV) dysfunction with age. To induce GDM, we fed female rats a high-fat (45% kcal) and sucrose diet prior to mating and throughout pregnancy. Lean control females received a low-fat (10% kcal) diet. Fetal rat ventricular cardiomyocytes (FRVC) were isolated from embryonic day (e) 20.5 offspring for U-13C glucose metabolic flux analysis.

Increased risk of thyroid disease in Danish women with polycystic ovary syndrome: a cohort study.

AimTo investigate risk of thyroid disease in Danish women with PCOS.DesignNational register-based study on women with PCOS in Denmark. 18,476 women had a diagnosis of PCOS in the Danish National Patient Register. PCOS Odense University Hospital (PCOS OUH, n = 1146) was an embedded cohort of women with PCOS and clinical and biochemical examination. Three age-matched controls were included for each woman with PCOS (n = 54,757). The main outcome measures were thyroid disease (hypothyroidism, Graves’ disease, goiter, thyroiditis) according to hospital diagnosis codes and/or inferred from filled medicine prescriptions. Associations between baseline TSH and development of cardio-metabolic disease was examined in PCOS OUH.ResultsThe median (quartiles) age at inclusion was 29 (23–35) years and follow-up duration was 11.1 (6.9–16.0) years. The hazard ratio (95% CI) for thyroid disease development was 2.5 (2.3–2.7) (P < 0.001). The event rate of thyroid disease was 6.0 per 1000 patient-years in PCOS Denmark versus 2.4 per 1000 patient-years in controls (P < 0.001). Women in PCOS OUH with TSH ≥2.5 mIU/L (n = 133) had higher BMI (median 29 vs 27 kg/m2), wider waist, higher triglycerides and free testosterone by the time of PCOS diagnosis compared to women in PCOS OUH with TSH <2.5 mIU/L (n = 588). Baseline TSH did not predict later development of cardio-metabolic diseases in PCOS OUH.ConclusionsThe event rate of thyroid disease was significantly and substantially higher in women with PCOS compared to controls.

The endocrine function of adipose tissues in health and cardiometabolic disease.

In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease.

Near-roadway air pollution exposure and altered fatty acid oxidation among adolescents and young adults – The interplay with obesity

BackgroundAir pollution exposure has been shown to increase the risk of obesity and metabolic dysfunction in animal models and human studies. However, the metabolic pathways altered by air pollution exposure are unclear, especially in adolescents and young adults who are at a critical period in the development of cardio-metabolic diseases. ObjectivesThe aim of this study was to examine the associations between air pollution exposure and indices of fatty acid and amino acid metabolism. MethodsA total of 173 young adults (18–23 years) from eight Children's Health Study (CHS) Southern California communities were examined from 2014 to 2018. Near-roadway air pollution (NRAP) exposure (freeway and non-freeway) and regional air pollution exposure (nitrogen dioxide, ozone and particulate matter) during one year before the study visit were estimated based on participants' residential addresses. Serum concentrations of 64 targeted metabolites including amino acids, acylcarnitines, non-esterified fatty acid (NEFA) and glycerol were measured in fasting serum samples. Principal component analysis of metabolites was performed to identify metabolite clusters that represent key metabolic pathways. Mixed effects models were used to analyze the associations of air pollution exposure with metabolomic principal component (PC) scores and individual metabolite concentrations adjusting for potential confounders. ResultsHigher lagged one-year averaged non-freeway NRAP exposure was associated with higher concentrations of NEFA oxidation byproducts and higher NEFA-related PC score (all p's ≤ 0.038). The effect sizes were larger among obese individuals (interaction p = 0.047). Among females, higher freeway NRAP exposure was also associated with a higher NEFA-related PC score (p = 0.042). Among all participants, higher freeway NRAP exposure was associated with a lower PC score for lower concentrations of short- and median-chain acylcarnitines (p = 0.044). ConclusionsResults of this study indicate that NRAP exposure is associated with altered fatty acid metabolism, which could contribute to the metabolic perturbation in obese youth.

Umbilical Cord miRNAs in Small-for-Gestational-Age Children and Association With Catch-Up Growth: A Pilot Study.

Catch-up growth in infants who are small for gestational age (SGA) is a risk factor for the development of cardiometabolic diseases in adulthood. The basis and mechanisms underpinning catch-up growth in newborns who are SGA are unknown. To identify umbilical cord miRNAs associated with catch-up growth in infants who are SGA and study their relationship with offspring's cardiometabolic parameters. miRNA PCR panels were used to study the miRNA profile in umbilical cord tissue of five infants who were SGA with catch-up (SGA-CU), five without catch-up (SGA-nonCU), and five control infants [appropriate for gestational age (AGA)]. The miRNAs with the smallest nominal P values were validated in 64 infants (22 AGA, 18 SGA-nonCU, and 24 SGA-CU) and correlated with anthropometric parameters at 1 (n = 64) and 6 years of age (n = 30). miR-501-3p, miR-576-5p, miR-770-5p, and miR-876-3p had nominally significant associations with increased weight, height, weight catch-up, and height catch-up at 1 year, and miR-374b-3p, miR-548c-5p, and miR-576-5p had nominally significant associations with increased weight, height, waist, hip, and renal fat at 6 years. Multivariate analysis suggested miR-576-5p as a predictor of weight catch-up and height catch-up at 1 year, as well as weight, waist, and renal fat at 6 years. In silico studies suggested that miR-576-5p participates in the regulation of inflammatory, growth, and proliferation signaling pathways. Umbilical cord miRNAs could be novel biomarkers for the early identification of catch-up growth in infants who are SGA. miR-576-5p may contribute to the regulation of postnatal growth and influence the risk for cardiometabolic diseases associated with a mismatch between prenatal and postnatal weight gain.

Senescent cells in the development of cardiometabolic disease.

Purpose of reviewSenescent cells have recently been identified as key players in the development of metabolic dysfunction. In this review, we will highlight recent developments in this field and discuss the concept of targeting these cells to prevent or treat cardiometabolic diseases.Recent findingsEvidence is accumulating that cellular senescence contributes to adipose tissue dysfunction, presumably through induction of low-grade inflammation and inhibition of adipogenic differentiation leading to insulin resistance and dyslipidaemia. Senescent cells modulate their surroundings through their bioactive secretome and only a relatively small number of senescent cells is sufficient to cause persistent physical dysfunction even in young mice. Proof-of-principle studies showed that selective elimination of senescent cells can prevent or delay the development of cardiometabolic diseases in mice.SummaryThe metabolic consequences of senescent cell accumulation in various tissues are now unravelling and point to new therapeutic opportunities for the treatment of cardiometabolic diseases.

Childhood Assets and Cardiometabolic Health in Adolescence.

Research shows that the development of cardiometabolic disease can begin early in life with risk factors accumulating over time, but less is known about protective pathways to positive health. In this study, we use prospective data to test whether childhood assets predict a greater likelihood of being in optimal cardiometabolic health by age 17. Data are from 3074 participants in the Avon Longitudinal Study of Parents and Children (mean age = 17.8). Four childhood assets were prospectively assessed via cognitive tests and parent report when children were between ages 8 and 10: strong executive functioning skills, prosocial behaviors, and low levels of internalizing and externalizing problems. Cardiometabolic health was assessed at ages 9 and 17 by using a composite dysregulation score derived from multiple biological parameters, including cholesterol, blood pressure, C-reactive protein, insulin resistance, and BMI. Associations between assets and optimal health at age 17 (ie, a dysregulation score of ≤1) were evaluated with Poisson regression models with robust error variances. After controlling for covariates (including sociodemographics, correlates of cardiometabolic health, and dysregulation scores at age 9), participants with multiple assets were 1.08 to 1.27 times more likely to be in optimal cardiometabolic health at age 17 compared with those with 0 or 1 asset. Each additional asset conferred a 6% greater likelihood of optimal health over time (relative risk = 1.06 [95% confidence interval: 1.01 to 1.11]). Childhood assets predicted cardiometabolic health with seemingly cumulative impacts. Identifying early assets may provide novel targets for prevention and elucidate pathways to positive adult health.