RESUMEN
Crosstalk between peripheral metabolic organs and the central nervous system is essential for body weight control. At the base of the hypothalamus, ß-tanycytes surround the portal capillaries and function as gatekeepers to facilitate transfer of substances from the circulation into the cerebrospinal fluid and vice versa. Here, we investigated the role of the neuroplasticity gene doublecortin-like (DCL), highly expressed by ß-tanycytes, in body weight control and whole-body energy metabolism. We demonstrated that DCL-knockdown through a doxycycline-inducible shRNA expression system prevents body weight gain by reducing adiposity in mice. DCL-knockdown slightly increased whole-body energy expenditure possibly as a result of elevated circulating thyroid hormones. In white adipose tissue (WAT) triglyceride uptake was increased while the average adipocyte cell size was reduced. At histological level we observed clear signs of browning, and thus increased thermogenesis in WAT. We found no indications for stimulated thermogenesis in brown adipose tissue (BAT). Altogether, we demonstrate an important, though subtle, role of tanycytic DCL in body weight control through regulation of energy expenditure, and specifically WAT browning. Elucidating mechanisms underlying the role of DCL in regulating brain-peripheral crosstalk further might identify new treatment targets for obesity.
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Tejido Adiposo Blanco , Metabolismo Energético , Obesidad , Animales , Ratones , Obesidad/metabolismo , Obesidad/genética , Tejido Adiposo Blanco/metabolismo , Masculino , Tejido Adiposo Pardo/metabolismo , Termogénesis/genética , Técnicas de Silenciamiento del Gen , Proteínas de Dominio Doblecortina , Peso Corporal , Ratones Endogámicos C57BL , Tejido Adiposo/metabolismo , Adiposidad/genéticaRESUMEN
PURPOSE: The causal relationship between life course adiposity with metabolic dysfunction-associated steatotic liver disease (MASLD) is ambiguous. We aimed to investigate whether there is an independent genetic causal relationship between body size at various life course and MASLD. METHODS: We performed univariable and multivariable Mendelian randomization (MR) to estimate the causal effect of body size at different life stages on MASLD (i.e., defined by the clinical comprehensive diagnosis from the electronic health record [HER] codes [ICD9/ICD10] or diagnostic phrases), including birthweight, childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), body fat percentage (BFP). RESULTS: In univariate analyses, higher genetically predicted lower birthweight (ORIVW = 0.61, 95%CI, 0.52 to 0.74), Childhood BMI ( ORIVW = 1.37, 95%CI, 1.12 to 1.64), and adult BMI (ORIVW = 1.41, 95%CI, 1.27 to 1.57) was significantly associated with subsequent risk of MASLD after Bonferroni correction. The MVMR analysis demonstrated compelling proof that birthweight and adult BMI had a direct causal relationship with MASLD. However, after adjusting for birthweight and adult BMI, the direct causal relationship between childhood BMI and MASLD disappeared. CONCLUSION: For the first time, this MR elucidated new evidence for the effect of life course adiposity on MASLD risk, providing lower birthweight and duration of obesity are independent risk factors for MASLD. Our findings indicated that weight management during distinct time periods plays a significant role in the prevention and treatment of MASLD.
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Adiposidad , Peso al Nacer , Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Humanos , Adulto , Adiposidad/genética , Niño , Factores de Riesgo , Hígado Graso/genética , Femenino , Masculino , Circunferencia de la CinturaRESUMEN
Perinatal nutrition exerts a profound influence on adult metabolic health. This study aimed to investigate whether increased maternal vitamin A (VA) supply can lead to beneficial metabolic phenotypes in the offspring. The researchers utilized mice deficient in the intestine-specific homeobox (ISX) transcription factor, which exhibits increased intestinal VA retinoid production from dietary ß-carotene (BC). ISX-deficient dams were fed a VA-sufficient or a BC-enriched diet during the last week of gestation and the whole lactation period. Total retinol levels in milk and weanling livers were 2- to 2.5-fold higher in the offspring of BC-fed dams (BC offspring), indicating increased VA supplies during late gestation and lactation. The corresponding VA-sufficient and BC offspring (males and females) were compared at weaning and adulthood after being fed either a standard or high-fat diet (HFD) with regular VA content for 13 weeks from weaning. HFD-induced increases in adiposity metrics, such as fat depot mass and adipocyte diameter, were more pronounced in males than females and were attenuated or suppressed in the BC offspring. Notably, the BC offspring were protected from HFD-induced increases in circulating triacylglycerol levels and hepatic steatosis. These protective effects were associated with reduced food efficiency, enhanced capacity for thermogenesis and mitochondrial oxidative metabolism in adipose tissues, and increased adipocyte hyperplasia rather than hypertrophy in the BC offspring. In conclusion, maternal VA nutrition influenced by genetics may confer metabolic benefits to the offspring, with mild increases in late gestation and lactation protecting against obesity and metabolic dysregulation in adulthood.NEW & NOTEWORTHY A genetic mouse model, deficient in intestine-specific homeobox (ISX) transcription factor, is used to show that a mildly increased maternal vitamin A supply from ß-carotene feeding during late gestation and lactation programs energy and lipid metabolism in tissues and protects the offspring from diet-induced hypertrophic obesity and hepatic steatosis. This knowledge may have implications for human populations where polymorphisms in ISX and ISX target genes involved in vitamin A homeostasis are prevalent.
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Dieta Alta en Grasa , Homeostasis , Obesidad , Vitamina A , Animales , Femenino , Ratones , Vitamina A/metabolismo , Masculino , Embarazo , Obesidad/metabolismo , Obesidad/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/genética , beta Caroteno/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Ratones Endogámicos C57BL , Lactancia , Ratones Noqueados , Herencia Materna , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Dieta , Hígado/metabolismo , Adiposidad/genéticaRESUMEN
Importance: Low childhood socioeconomic status (SES) is a social hallmark of aging that contributes to adult health disparities and earlier morbidity and mortality. Childhood perceptions of stress are associated with child health outcomes and may contribute to premature biological aging into adulthood. Objective: To describe the association of childhood SES and perceived stress with midlife insulin resistance and epigenetic age and to explore whether late adolescent adiposity mediates the observed associations. Design, Setting, and Participants: The longitudinal cohort National Heart, Lung, and Blood Institute Growth and Health Study enrolled girls aged 10 years from January 1987 to May 1988, and followed them up to 19 years of age. Participants from Richmond, California, were recruited again at midlife in 2016 to assess insulin resistance and epigenetic age. Analyses were conducted from August 2, 2023, to March 18, 2024. A total of 433 participants were eligible and included in the analyses (specific sample sizes ranged across analyses from 303 to 391). Exposures: Childhood levels of SES at 10 years of age (parental educational level and income) and perceived stress at 11 years of age. Main Outcomes and Measures: The hypotheses tested were formulated after data collection. Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and the GrimAge and DunedinPACE epigenetic clocks. Waist circumference in late adolescence was tested as a mediator. Results: Among the 433 participants, the mean (SD) age was 39.4 (1.2) years; 218 (50.3%) were Black and 215 (49.7%) were White; and 135 (31.2%) had parents with a college degree or higher. Higher parental educational level was associated with lower HOMA-IR (B = -0.22 [95% CI, -0.41 to -0.02]; P = .03), lower midlife GrimAge (B = -1.76 [95% CI, -2.85 to -0.66] years; P = .002), and slower midlife DunedinPACE (B = -0.03 [95% CI, -6.29 to -0.002]; P = .04). Childhood perceived stress was indirectly associated through late adolescent adiposity with midlife HOMA-IR (B = 0.01 [95% CI, 0.001-0.01]; P = .02) and midlife GrimAge (B = 0.02 [95% CI, 0.003-0.04] years; P = .01). Conclusions and Relevance: In this longitudinal cohort study of midlife health and aging, childhood social hallmarks of aging were associated with midlife insulin resistance and epigenetic age (GrimAge and DunedinPACE). Future studies should identify malleable factors that may slow the impact of social hallmarks of aging.
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Estrés Psicológico , Humanos , Femenino , Niño , Estudios Longitudinales , Resistencia a la Insulina/genética , Adolescente , Adulto , Clase Social , Epigenómica/métodos , Persona de Mediana Edad , Adulto Joven , Estados Unidos , Adiposidad/genética , MasculinoRESUMEN
Objectives: The relationship between adiposity and sepsis has received increasing attention. This study aims to explore the causal relationship between life course adiposity and the sepsis incidence. Methods: Mendelian randomization (MR) method was employed in this study. Instrumental variants were obtained from genome-wide association studies for life course adiposity, including birth weight, childhood body mass index (BMI), childhood obesity, adult BMI, waist circumference, visceral adiposity, and body fat percentage. A meta-analysis of genome-wide association studies for sepsis including 10,154 cases and 454,764 controls was used in this study. MR analyses were performed using inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. Instrumental variables were identified as significant single nucleotide polymorphisms at the genome-wide significance level (P < 5×10-8). The sensitivity analysis was conducted to assess the reliability of the MR estimates. Results: Analysis using the MR analysis of inverse variance weighted method revealed that genetic predisposition to increased childhood BMI (OR = 1.29, P = 0.003), childhood obesity (OR = 1.07, P = 0.034), adult BMI (OR = 1.38, P < 0.001), adult waist circumference (OR = 1.01, P = 0.028), and adult visceral adiposity (OR = 1.53, P < 0.001) predicted a higher risk of sepsis. Sensitivity analysis did not identify any bias in the MR results. Conclusion: The results demonstrated that adiposity in childhood and adults had causal effects on sepsis incidence. However, more well-designed studies are still needed to validate their association.
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Adiposidad , Índice de Masa Corporal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Sepsis , Humanos , Adiposidad/genética , Sepsis/genética , Sepsis/epidemiología , Predisposición Genética a la Enfermedad , Obesidad Infantil/genética , Obesidad Infantil/epidemiología , Obesidad Infantil/complicaciones , Adulto , Circunferencia de la Cintura , Niño , Masculino , FemeninoRESUMEN
BACKGROUND: The causal relationship between childhood adiposity and adult risk of heart diseases has not been clearly demonstrated. This study aims to ascertain whether genetically predicted childhood body mass index (BMI) and childhood obesity are causally associated with adult coronary heart disease, myocardial infarction, heart failure, atrial fibrillation, hypertrophic cardiomyopathy, and pulmonary heart disease. METHODS AND RESULTS: To investigate the causative relationships and underlying mechanisms between childhood adiposity and adult heart diseases, 3 main methods of Mendelian randomization were used: 2-sample Mendelian randomization, multivariable Mendelian randomization with controlling for several cardiometabolic risk variables, and mediation analysis. Every 1-SD rise in genetically predicted childhood body mass index was associated with 24% (odds ratio [OR], 1.24 [95% CI, 1.12-1.37]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), and 27% (OR, 1.27 [95% CI, 1.04-1.49]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. Every 1-unit increase in log-odds in childhood obesity was associated with 11% (OR, 1.11 [95% CI, 1.06-1.16]), 14% (OR, 1.14 [95% CI, 1.04-1.23]), 10% (OR, 1.10 [95% CI, 1.03-1.18]), and 20% (OR, 1.20 [95% CI, 1.08-1.32]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. The link between childhood adiposity and adult heart diseases was found to be mediated by high-density lipoprotein cholesterol, triglyceride, hypertension, and type 2 diabetes. CONCLUSIONS: Our findings support the causal relationships between childhood adiposity and risk of adult coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation. Blood lipids, hypertension, and type 2 diabetes are factors that mediate the aforementioned associations.
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Adiposidad , Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Obesidad Infantil , Humanos , Adiposidad/genética , Obesidad Infantil/genética , Obesidad Infantil/epidemiología , Obesidad Infantil/diagnóstico , Niño , Adulto , Cardiopatías/epidemiología , Cardiopatías/genética , Medición de Riesgo , Masculino , Femenino , Factores de Riesgo , Predisposición Genética a la Enfermedad , Factores de Riesgo de Enfermedad Cardiaca , Factores de EdadRESUMEN
Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 24.5 million primary-care health records in over 740,000 individuals in the UK Biobank, Million Veteran Program USA, and Estonian Biobank, to discover and validate the genetic architecture of adiposity trajectories. Using multiple BMI measurements over time increases power to identify genetic factors affecting baseline BMI by 14%. In the largest reported genome-wide study of adiposity-change in adulthood, we identify novel associations with BMI-change at six independent loci, including rs429358 (APOE missense variant). The SNP-based heritability of BMI-change (1.98%) is 9-fold lower than that of BMI. The modest genetic correlation between BMI-change and BMI (45.2%) indicates that genetic studies of longitudinal trajectories could uncover novel biology of quantitative traits in adulthood.
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Adiposidad , Índice de Masa Corporal , Registros Electrónicos de Salud , Estudio de Asociación del Genoma Completo , Obesidad , Polimorfismo de Nucleótido Simple , Humanos , Adiposidad/genética , Masculino , Femenino , Obesidad/genética , Persona de Mediana Edad , Adulto , Anciano , Reino Unido , Fenotipo , Estonia , Estados Unidos , Predisposición Genética a la EnfermedadRESUMEN
AIM: The relationship between the gut microbiota, metabolites and body fat percentage (BFP) remains unexplored. We systematically assessed the causal relationships between gut microbiota, metabolites and BFP using Mendelian randomization analysis. MATERIALS AND METHODS: Single nucleotide polymorphisms associated with gut microbiota, blood metabolites and BFP were screened via a genome-wide association study enrolling individuals of European descent. Summary data from genome-wide association studies were extracted from the MiBioGen consortium and the UK Biobank. The inverse variance-weighted model was the primary method used to estimate these causal relationships. Sensitivity analyses were performed using pleiotropy, Mendelian randomization-Egger regression, heterogeneity tests and leave-one-out tests. RESULTS: In the aspect of phyla, classes, orders, families and genera, we observed that o_Bifidobacteriales [ß = -0.05; 95% confidence interval (CI): -0.07 to -0.03; false discovery rate (FDR) = 2.76 × 10-3], f_Bifidobacteriaceae (ß = -0.05; 95% CI: -0.07 to -0.07; FDR = 2.76 × 10-3), p_Actinobacteria (ß = -0.06; 95% CI: -0.09 to -0.03; FDR = 6.36 × 10-3), c_Actinobacteria (ß = -0.05; 95% CI: -0.08 to -0.02; FDR = 1.06 × 10-2), g_Bifidobacterium (ß = -0.05; 95% CI: -0.07 to -0.02; FDR = 1.85 × 10-2), g_Ruminiclostridium9 (ß = -0.03; 95% CI: -0.06 to -0.01; FDR = 4.81 × 10-2) were negatively associated with BFP. G_Olsenella (ß = 0.02; 95% CI: 0.01-0.03; FDR = 2.16 × 10-2) was positively associated with BFP. Among the gut microbiotas, f_Bifidobacteriales, o_Bifidobacteriales, c_Actinobacteria and p_Actinobacteria were shown to be significantly associated with BFP in the validated dataset. In the aspect of metabolites, we only observed that valine (ß = 0.77; 95% CI: 0.5-1.04; FDR = 8.65 × 10-6) was associated with BFP. CONCLUSIONS: Multiple gut microbiota and metabolites were strongly associated with an increased BFP. Further studies are required to elucidate the mechanisms underlying this putative causality. In addition, BFP, a key indicator of obesity, suggests that obesity-related interventions can be developed from gut microbiota and metabolite perspectives.
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Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Microbioma Gastrointestinal/genética , Causalidad , Femenino , Obesidad/microbiología , Obesidad/genética , Masculino , Tejido Adiposo/metabolismo , Adiposidad/genéticaRESUMEN
The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.
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Adiposidad , Densidad de la Mama , Neoplasias de la Mama , Mamografía , Menarquia , Análisis de la Aleatorización Mendeliana , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Adiposidad/genética , Factores de Riesgo , Niño , Tamaño Corporal , Adulto , Polimorfismo de Nucleótido Simple , Persona de Mediana EdadRESUMEN
Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11ß-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11ß-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11ß-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11ß-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11ß-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Adiposidad , Médula Ósea , Restricción Calórica , Ratones Noqueados , Animales , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Femenino , Masculino , Adiposidad/genética , Médula Ósea/metabolismo , Ratones , Humanos , Tejido Adiposo/metabolismo , Ratones Endogámicos C57BL , Glucocorticoides/metabolismo , Factores SexualesRESUMEN
We previously reported that solute carrier family 22 member 18 (Slc22a18) regulates lipid accumulation in 3T3-L1 adipocytes. Here, we provide additional evidence derived from experiments with adenoviral vector expression and genetic manipulation of mice. In primary cultured rat hepatocytes, adenoviral overexpression of mouse Slc22a18 increased triglyceride accumulation and triglyceride synthetic activity, which was decreased in an adenoviral knockdown experiment. Adenoviral overexpression of mouse Slc22a18 in vivo caused massive fatty liver in mice, even under normal dietary conditions. Conversely, adenoviral knockdown of mouse Slc22a18 reduced hepatic lipid accumulation induced by a high-glucose and high-sucrose diet. We created Slc22a18 knockout mice, which grew normally and showed no obvious spontaneous phenotypes. However, compared with control littermates, the knockout mice exhibited decreased hepatic triglyceride content under refeeding conditions, significantly reduced epididymal fat mass, and tended to have lower liver weight in conjunction with leptin deficiency. Finally, we created transgenic mice overexpressing rat Slc22a18 in an adipose-specific manner, which had increased body weight and epididymal fat mass primarily because of increased adipocyte cell volume. In these transgenic mice, a positive correlation was observed between adiposity and the expression levels of the rat Slc22a18 transgene. Taken together, these results indicate that Slc22a18 has positive effects on lipid accumulation in vivo.
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Proteínas de Transporte de Catión Orgánico , Animales , Ratones , Ratas , Masculino , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Ratones Noqueados , Hepatocitos/metabolismo , Triglicéridos/metabolismo , Ratones Transgénicos , Metabolismo de los Lípidos/genética , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/patología , Ratones Endogámicos C57BL , Hígado/metabolismo , Adiposidad/genética , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Células Cultivadas , Ratas Sprague-DawleyRESUMEN
Hypertension is a leading risk factor for cardiovascular disease and is modulated by genetic variants. This study aimed to assess the effect of obesity genetic liability and physical activity on hypertension among European and African ancestry individuals within the UK Biobank (UKB). Participants were 230 115 individuals of European ancestry and 3239 individuals of African ancestry from UKB. Genetic liability for obesity were estimated using previously published data including genetic variants and effect sizes for body mass index (BMI), waist-hip ratio (WHR) and waist circumference (WC) using Plink software. The outcome was defined as stage 2 hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of anti-hypertensive medications). The association between obesity genetic liability and the outcome was assessed across categories of self-reported physical activity using logistic regression. Among European ancestry participants, there was up to a 1.2 greater odds of hypertension in individuals with high genetic liability and low physical activity compared to individuals with low genetic liability and high physical activity (p < 0.001). In individuals engaging in low levels of physical activity compared with moderate/high physical activity, the effect of BMI genetic liability on hypertension was greater (p interaction = 0.04). There was no evidence of an association between obesity genetic liability and hypertension in individuals of African ancestry in the whole sample or within separate physical activity groups (p > 0.05). This study suggests that higher physical activity levels are associated with lower odds of stage 2 hypertension among European ancestry individuals who carry high genetic liability for obesity. This cannot be inferred for individuals of African ancestry, possibly due to the low African ancestry sample size within the UKB.
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Adiposidad , Población Negra , Ejercicio Físico , Hipertensión , Obesidad , Población Blanca , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adiposidad/genética , Población Negra/genética , Presión Sanguínea/genética , Índice de Masa Corporal , Predisposición Genética a la Enfermedad , Hipertensión/genética , Obesidad/genética , Factores de Riesgo , Reino Unido , Circunferencia de la Cintura , Relación Cintura-Cadera , Población Blanca/genética , África/etnología , Europa (Continente)/etnologíaRESUMEN
BACKGROUND: The accumulation of visceral and ectopic fat comprise a major cause of cardiometabolic diseases. However, novel drug targets for reducing unnecessary visceral and ectopic fat are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on visceral and ectopic fat using Mendelian randomization (MR) approach. METHODS: We performed two-sample MR analyses based on five large genome-wide association study (GWAS) summary statistics of 2656 plasma proteins, to screen for causal associations of these proteins with traits of visceral and ectopic fat in over 30,000 participants of European ancestry, as well as to assess mediation effects by risk factors of outcomes. The colocalization analysis was conducted to examine whether the identified proteins and outcomes shared casual variants. RESULTS: Genetically predicted levels of 14 circulating proteins were associated with visceral and ectopic fat (P < 4.99 × 10- 5, at a Bonferroni-corrected threshold). Colocalization analysis prioritized ten protein targets that showed effect on outcomes, including FST, SIRT2, DNAJB9, IL6R, CTSA, RGMB, PNLIPRP1, FLT4, PPY and IL6ST. MR analyses revealed seven risk factors for visceral and ectopic fat (P < 0.0024). Furthermore, the associations of CTSA, DNAJB9 and IGFBP1 with primary outcomes were mediated by HDL-C and SHBG. Sensitivity analyses showed little evidence of pleiotropy. CONCLUSIONS: Our study identified candidate proteins showing putative causal effects as potential therapeutic targets for visceral and ectopic fat accumulation and outlined causal pathways for further prevention of downstream cardiometabolic diseases.
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Adiposidad , Enfermedades Cardiovasculares , Humanos , Adiposidad/genética , Proteoma , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Obesidad , Proteínas de la Membrana , Chaperonas Moleculares , Proteínas del Choque Térmico HSP40RESUMEN
We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.
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Adiposidad , Diabetes Mellitus Tipo 2 , Medicina de Precisión , Adiposidad/genética , Diabetes Mellitus Tipo 2/genética , Humanos , Estudio de Asociación del Genoma Completo , Variación Genética , Masculino , Femenino , Alelos , Sitios de Carácter Cuantitativo , Análisis por ConglomeradosRESUMEN
OBJECTIVE: The objective of this study was to examine associations between umbilical cord mitochondrial DNA copy number (mtDNAcn) and adiposity across childhood. METHODS: In a prospective birth cohort of Dominican and African American children from New York City, New York (1998-2006), mtDNAcn was measured in cord blood. Children (N = 336) were evaluated for their height, weight, and bioimpedance at age 5, 7, 9, and 11 years. We used linear mixed-effects models to assess associations of mtDNAcn tertiles in cord blood with child BMI, BMI z scores, fat mass index, and body fat percentage. Latent class growth models and interactions between mtDNAcn and child age or child age2 were used to assess associations between age and adiposity trajectories. RESULTS: BMI was, on average, 1.5 kg/m2 higher (95% CI: 0.58, 2.5) in individuals with mtDNAcn in the low- compared with the middle-mtDNAcn tertile. Results were similar for BMI z score, fat mass index, and body fat percentage. Moreover, children in the low-mtDNAcn group had increased odds of being in an "increasing" or "high-stable" adiposity class. CONCLUSIONS: Lower mtDNAcn at birth may predict greater childhood adiposity, highlighting the potential key role of perinatal mitochondrial function in adiposity during development.
Asunto(s)
Adiposidad , Índice de Masa Corporal , Variaciones en el Número de Copia de ADN , ADN Mitocondrial , Sangre Fetal , Obesidad Infantil , Humanos , ADN Mitocondrial/sangre , ADN Mitocondrial/genética , Sangre Fetal/metabolismo , Sangre Fetal/química , Adiposidad/genética , Femenino , Masculino , Niño , Preescolar , Estudios Prospectivos , Obesidad Infantil/genética , Obesidad Infantil/sangre , Ciudad de Nueva York , Negro o Afroamericano/genética , Cohorte de Nacimiento , República DominicanaRESUMEN
Importance: Epicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects. Objective: To evaluate the association of EPAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of EPAT in a large population cohort. Design, Setting, and Participants: A deep learning model was trained to quantify EPAT area from 4-chamber magnetic resonance images using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. Prospective associations were additionally controlled for abdominal visceral adipose tissue (VAT) volumes. A genome-wide association study was performed, and a polygenic score (PGS) for EPAT was examined in independent FinnGen cohort study participants. Data analyses were conducted from March 2022 to December 2023. Exposures: The primary exposures were magnetic resonance imaging-derived continuous measurements of epicardial and pericardial adipose tissue area and visceral adipose tissue volume. Main Outcomes and Measures: Prevalent and incident CAD, AF, heart failure (HF), stroke, and type 2 diabetes (T2D). Results: After exclusions, this study included 44â¯475 participants (mean [SD] age, 64.1 [7.7] years; 22â¯972 female [51.7%]) from the UK Biobank. Cross-sectional and prospective cardiovascular disease associations were evaluated for a mean (SD) of 3.2 (1.5) years of follow-up. Prospective associations were additionally controlled for abdominal VAT volumes for 38â¯527 participants. A PGS for EPAT was examined in 453â¯733 independent FinnGen cohort study participants. EPAT was positively associated with male sex (ß = +0.78 SD in EPAT; P < 3 × 10-324), age (Pearson r = 0.15; P = 9.3 × 10-229), body mass index (Pearson r = 0.47; P < 3 × 10-324), and VAT (Pearson r = 0.72; P < 3 × 10-324). EPAT was more elevated in prevalent HF (ß = +0.46 SD units) and T2D (ß = +0.56) than in CAD (ß = +0.23) or AF (ß = +0.18). EPAT was associated with incident HF (hazard ratio [HR], 1.29 per +1 SD in EPAT; 95% CI, 1.17-1.43), T2D (HR, 1.63; 95% CI, 1.51-1.76), and CAD (HR, 1.19; 95% CI, 1.11-1.28). However, the associations were no longer significant when controlling for VAT. Seven genetic loci were identified for EPAT, implicating transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2, and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The EPAT PGS was associated with T2D (odds ratio [OR], 1.06; 95% CI, 1.05-1.07; P =3.6 × 10-44), HF (OR, 1.05; 95% CI, 1.04-1.06; P =4.8 × 10-15), CAD (OR, 1.04; 95% CI, 1.03-1.05; P =1.4 × 10-17), AF (OR, 1.04; 95% CI, 1.03-1.06; P =7.6 × 10-12), and stroke in FinnGen (OR, 1.02; 95% CI, 1.01-1.03; P =3.5 × 10-3) per 1 SD in PGS. Conclusions and Relevance: Results of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.
Asunto(s)
Adiposidad , Enfermedades Cardiovasculares , Pericardio , Humanos , Pericardio/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Adiposidad/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Anciano , Tejido Adiposo/diagnóstico por imagen , Estudios Prospectivos , Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética , Grasa Intraabdominal/diagnóstico por imagenRESUMEN
BACKGROUND AND AIMS: Hepatic steatosis is known to be heritable, but its genetic basis is mostly uncharacterized. Steatosis is associated with metabolic and adiposity features; recent studies hypothesize that shared genetic effects between these traits could account for some of the unexplained heritability. This study aimed to quantify these genetic associations in a family-based sample of non-Hispanic white adults. METHODS AND RESULTS: 704 participants (18-95 years, 55.8% female) from the Fels Longitudinal Study with an MRI assessment of liver fat were included. Quantitative genetic analyses estimated the age- and sex-adjusted heritability of individual traits and the genetic correlations within trait pairs. Mean liver fat was 5.95% (SE = 0.23) and steatosis (liver fat >5.56%) was present in 29.8% of participants. Heritability (h2± SE) of steatosis was 0.72 ± 0.17 (p = 6.80e-6). All other traits including liver enzymes, fasting glucose, HOMA-IR, visceral and subcutaneous adipose tissue (VAT, SAT), body mass index, body fat percent, waist circumference, lipids and blood pressure were also heritable. Significant genetic correlations were found between liver fat and all traits except aspartate aminotransferase (AST), and among most trait pairs. Highest genetic correlations were between liver fat and HOMA-IR (0.85 ± 0.08, p = 1.73e-8), fasting glucose and ALT (0.89 ± 0.26, p = 6.68e-5), and HOMA-IR with: waist circumference (0.81 ± 0.12, p = 3.76e-6), body fat percent (0.78 ± 0.12 p = 2.42e-5) and VAT (0.73 ± 0.07, p = 6.37e-8). CONCLUSIONS: Common genes may exist between liver fat accumulation, metabolic features and adiposity phenotypes.
Asunto(s)
Adiposidad , Predisposición Genética a la Enfermedad , Fenotipo , Humanos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Adiposidad/genética , Anciano , Estudios Longitudinales , Adolescente , Adulto Joven , Anciano de 80 o más Años , Hígado/patología , Hígado/metabolismo , Herencia , Estados Unidos/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Hígado Graso/genética , Imagen por Resonancia Magnética , Medición de Riesgo , Estudios de Asociación GenéticaRESUMEN
Background: General obesity is a well-established risk factor for gallstone disease (GSD), but whether central obesity contributes additional independent risk remains controversial. We aimed to comprehensively clarify the effect of body fat distribution on GSD. Methods: We first investigated the observational association of central adiposity, characterized by waist-to-hip ratio (WHR), with GSD risk using data from UK Biobank (N=472,050). We then explored the genetic relationship using summary statistics from the largest genome-wide association study of GSD (ncase=43,639, ncontrol=506,798) as well as WHR, with and without adjusting for body mass index (BMI) (WHR: n=697,734; WHRadjBMI: n=694,649). Results: Observational analysis demonstrated an increased risk of GSD with one unit increase in WHR (HR=1.18, 95%CI=1.14-1.21). A positive WHR-GSD genetic correlation (rg =0.41, P=1.42×10-52) was observed, driven by yet independent of BMI (WHRadjBMI: rg =0.19, P=6.89×10-16). Cross-trait meta-analysis identified four novel pleiotropic loci underlying WHR and GSD with biological mechanisms outside of BMI. Mendelian randomization confirmed a robust WHR-GSD causal relationship (OR=1.50, 95%CI=1.35-1.65) which attenuated yet remained significant after adjusting for BMI (OR=1.17, 95%CI=1.09-1.26). Furthermore, observational analysis confirmed a positive association between general obesity and GSD, corroborated by a shared genetic basis (rg =0.40, P=2.16×10-43), multiple novel pleiotropic loci (N=11) and a causal relationship (OR=1.67, 95%CI=1.56-1.78). Conclusion: Both observational and genetic analyses consistently provide evidence on an association of central obesity with an increased risk of GSD, independent of general obesity. Our work highlights the need of considering both general and central obesity in the clinical management of GSD.
Asunto(s)
Colelitiasis , Obesidad Abdominal , Humanos , Adiposidad/genética , Estudio de Asociación del Genoma Completo , Obesidad/complicaciones , Obesidad/genética , Obesidad Abdominal/complicaciones , Obesidad Abdominal/genéticaRESUMEN
BACKGROUND: Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging. METHODS AND RESULTS: In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end-diastolic volume: ß=0.24 [95% CI, 0.15-0.33]; P=3×10-7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat-free mass and childhood height, respectively. CONCLUSIONS: Our findings suggest that, although childhood body size has a long-term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse.
Asunto(s)
Adiposidad , Obesidad Infantil , Humanos , Adiposidad/genética , Sobrepeso/complicaciones , Análisis de la Aleatorización Mendeliana/métodos , Circulación Pulmonar , Índice de Masa Corporal , Obesidad Infantil/diagnóstico , Obesidad Infantil/epidemiología , Obesidad Infantil/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND AND AIM: The relationship between appendicular lean mass (ALM) and most cardiovascular events has been established, but the direct association between ALM and atrial fibrillation (AF) remains uncertain. METHODS AND RESULTS: Herein, we identified 494 single-nucleotide polymorphisms (SNPs) strongly associated with ALM as instrumental variables (P < 5E-8) based on a genome-wide association study (GWAS) with 450,243 European participants. Then, we employed five Mendelian randomization (MR) analysis methods to investigate the causal relationship between ALM and AF. All results indicated a causal relationship between ALM and AF, among Inverse variance weighted (P = 8.44E-15, odds ratio [OR]: 1.16, 95 % confidence interval [CI]: 1.114-1.198). Furthermore, we performed a sensitivity analysis, which revealed no evidence of pleiotropy (egger_intercept = 0.000089, P = 0.965) or heterogeneity (MR Egger, Q Value = 0.980; Inverse variance weighted, Q Value = 0.927). The leave-one-out method demonstrates that individual SNPs have no driven impact on the whole causal relationship. Multivariable MR analysis indicates that, after excluding the influence of hypertension and coronary heart disease, a causal relationship between ALM and AF still exists (P = 7.74E-40, OR 95 %CI: 1.389 (1.323-1.458)). Importantly, the Radial MR framework analysis and Robust Adjusted Profile Score (RAPS) further exhibit the robustness of this causal relationship. CONCLUSION: A strong association between ALM and AF was confirmed, and high ALM is a risk factor for AF.