Adiposity Distribution Research Articles

IMPACT OF BODY FAT DISTRIBUTION, ADIPOCYTOKINES AND VARIABILITY IN ASSOCIATED GENES ON KIDNEY TRANSPLANT OUTCOMES

Objective: Adiposity distribution contributes to a number of pathologies. We aimed to assess whether this distribution was associated with clinical outcomes and to identify its relationship with leptin and adiponectin gene variants and plasma concentrations in renal transplant recipients (RTR). Design and method: Anthropometric parameters were measured in 236 RTR by bioelectrical impedance analysis, allograft function and post-transplant complications were retrieved from records. Blood samples were drawn to measure plasma leptin/adiponectin levels and to seek for polymorphisms in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes. Logistic regression models were applied to identify associations. Results: The waist-to-height ratio (WHr) displayed a significant association with delayed graft function (DGF), acute rejection (AR) and post-transplant diabetes mellitus, with OR values of 2.04 (1.02–4.08) p = 0.045; 3.08 (1.22–7.79) p = 0.017 and 2.79 (1.16–6.74) p = 0.022, respectively. Waist circumference was linked to DGF [OR = 1.03 (1.01 – 1.053), p = 0.025] and AR [OR = 1.041 (1.01 – 1.073), p = 0.009]. Leptin levels were significantly higher in patients who experienced AR [19.91 ± 23.72 vs. 11.22 ± 16.42 ng/ml; OR = 1.021 (1.01–1.04), p = 0.017]. The ADIPOQ rs1501299TT genotype showed a significant association with higher WHr (0.63 ± 0.11 vs. 0.59 ± 0.87 for GG/GT genotypes; p = 0.015) and WC values (102.3 ± 14.12 vs. 96.38 ± 14.65 for GG/GT genotypes; p = 0.021). Conclusions: We have shown that WC, and especially WHr, are associated with adverse outcomes in renal transplant and hence may be useful parameters in RTR monitoring. In turn, these anthropometric parameters were affected by variability in the ADIPOQ gene, suggesting this polymorphism could be a useful marker of transplanted patients at risk.

Coronary Endothelial Dysfunction in People Living With HIV Is Related to Body Fat Distribution.

People living with HIV (PLWH) on antiretroviral therapy (ART) are at increased risk of atherosclerotic disease. Abnormal adipose distribution is common in PLWH and may contribute to atherosclerosis. Because coronary artery endothelial function (CEF) is impaired in early atherosclerosis, predicts future cardiovascular events, and is reduced in PLWH, we investigated associations between body fat distribution and CEF in PLWH. Prospective cohort study. PLWH on stable ART underwent MRI to quantify CEF, measured as change in coronary cross-sectional area from rest to that during isometric handgrip exercise, an endothelial-dependent stressor. Abdominal visceral and subcutaneous fat area (axial L4 level) and liver fat fraction were quantified using MRI. Linear regression was used to determine associations between CEF and independent variables. Among 84 PLWH (52 ± 11 years; 33% women), mean cross-sectional area change was 0.74 ± 11.7%, indicating impaired CEF. On univariable regression analysis, CEF was inversely related to waist circumference (R = -0.31, P = 0.014), hip circumference (R = -0.27, P = 0.037), and subcutaneous fat area (R = -0.25, P = 0.031). We did not observe significant relationships between CEF and liver fat fraction, waist/hip ratio, or visceral fat area. On multivariable regression adjusted for age, sex, and race, CEF was associated with waist circumference, hip circumference, subcutaneous fat, and liver fat fraction. Waist and hip circumference and subcutaneous fat area are associated with impaired CEF, an established metric of abnormal vascular health in PLWH on stable ART, and may contribute to the increased rate of heart disease in this population.

Relative Body Fat Distribution in Preadolescent Indian Children Exposed to a Natural Disaster during Early Development.

Fetal life and infancy are critical periods when adverse environmental conditions, such as natural disasters, may alter a developing organism, leading to life-lasting unfavorable health outcomes, such as central body fat distribution. Therefore, the aim of this study was to assess the effect of the exposure to cyclone Aila in utero or during infancy on the relative subcutaneous adiposity distribution in preadolescent Indian children. The study included children prenatally (N = 336) or postnatally (during infancy, N = 212) exposed to Aila and a non-affected group (N = 284). Anthropometric indices involved, i.e., subscapular, suprailiac, triceps, and biceps skinfolds. The relative adiposity distribution (PC1) and socioeconomic status (SES) were assessed using principal component analysis. An analysis of covariance and Tukey’s post hoc test for unequal samples were performed to assess the effect of exposure to a natural disaster on the PC1, controlling for age, sex, Z-BMI, and SES. Prenatally and postnatally Aila-exposed children revealed a significantly more central-oriented pattern of relative subcutaneous fat distribution compared to the controls (p < 0.05). Early-life exposure to a natural disaster was related to an adverse pattern of relative adipose tissue distribution in preadolescent children.

B-Cell Activating Factor Increases Related to Adiposity, Insulin Resistance, and Endothelial Dysfunction in Overweight and Obese Subjects.

Obesity (OB) is a major healthcare problem that results from long-term energy imbalance. Adipokines and pro-inflammatory cytokines facilitate adipose tissue (AT) remodeling to safely store excess nutrients. B-cell activating factor (BAFF) is a newly described adipokine whose role in enhancing adipogenesis has been reported. The present study aimed to evaluate serum BAFF association with adiposity distribution, serum adipokines, pro-inflammatory cytokines, and metabolic and endothelial dysfunction markers. The study included 124 young Mexican adults with no diagnosed comorbidities, divided according to their BMI. Anthropometric measurements, blood counts, and serum molecules (i.e., glucose, lipid profile, insulin, leptin, pro- and anti-inflammatory cytokines, von Willebrand factor (vWF), and BAFF) were assessed. The analysis showed positive correlation between BAFF and increased fat mass in all anthropometric measurements (p < 0.0001). BAFF augmentation was related to systemic inflammatory environment (p < 0.05), and linked with insulin resistance status (p < 0.05). BAFF increment was also correlated with early endothelial damage markers such as vWF (p < 0.0001). Linear regression analysis showed a role for BAFF in predicting serum vWF concentrations (p < 0.01). In conclusion, our data show that BAFF is an adipokine dynamically related to OB progression, insulin resistance status, and systemic inflammatory environment, and is a predictor of soluble vWF augmentation, in young overweight and obese Mexican subjects.

Serum Follicle-Stimulating Hormone and 5-Year Change in Adiposity in Healthy Postmenopausal Women.

Evidence from animal studies suggests that the gradual rise in follicle-stimulating hormone (FSH) during reproductive senescence may contribute to the change in adiposity distribution characteristic of menopause. The potential independent role the interrelationships of FSH and estradiol (E2) may play in postmenopausal adiposity changes are not well studied. Our objective was to evaluate the associations of FSH and dual x-ray absorptiometry (DXA)-derived adiposity measures, with consideration of estradiol and postmenopausal hormone therapy use. In a sample of 667 postmenopausal women from the Women's Health Initiative Buffalo OsteoPerio Ancillary Study, we studied the associations of serum FSH and E2 levels with dual x-ray absorptiometry (DXA)-derived adiposity measures via cross-sectional and longitudinal analyses (5-year follow-up). In cross-sectional analyses, FSH levels were inversely associated with all measures of adiposity in models adjusted for age, years since menopause, smoking status, pack-years, and hormone therapy (HT) use; these associations were not influenced by adjustment for serum E2. In longitudinal analyses, the subset of women who discontinued HT over follow-up (n = 242) experienced the largest increase in FSH (+33.9 mIU/mL) and decrease in E2 (-44.3 pg/mL) and gains in all adiposity measures in unadjusted analyses. In adjusted analyses, an increase in FSH was associated with a gain in percentage of total body fat, total body fat mass, and subcutaneous adipose tissue (SAT). While cross-sectional findings suggest that FSH is inversely associated with adiposity, our longitudinal findings suggest that greater increases in FSH were associated with greater increases in percentage of total body fat, total body fat mass, and SAT. Future studies are needed to provide additional insight into FSH-adiposity mechanisms in larger samples.

Distinct causal effects of body fat distribution on cardiometabolic traits among children: Findings from the BCAMS study

Background and aimsObservational studies reveal that different body fat measures are associated with cardiometabolic disease with different effects. However, causality is not reflected by such observations. To explore and compare the causal relationships of general obesity (measured by body mass index (BMI)), adipose obesity (measured by fat mass percentage (FMP)) and central obesity (measured by waist-to-height ratio (WHtR)) with cardiometabolic traits among children. Methods and resultsWe conducted one sample Mendelian randomization (MR) analysis in 3266 children from Beijing Children and Adolescents Metabolic Syndrome Study. Genetic instruments based on 28 SNPs were performed to explore and compare the causal associations of genetically BMI, FMP and WHtR with cardiometabolic traits. The genetic instruments were robustly correlated with observed BMI, FMP and WHtR. Each genetically 1-SD increment in BMI, FMP and WHtR were causally associated with increment in systolic blood pressure (SBP), diastolic blood pressure (DBP), log-transformed fasting plasma glucose (FPG), log-transformed HOMA-β, and decrease in log-transformed high-density lipoprotein cholesterol (HDL), respectively (all P < 0.05 after Bonferroni correction). The receiver operating characteristic curve indicated that BMI and FMP showed stronger effects on SBP, DBP, HOMA-β and HDL than WHtR (all P < 0.05). We also observed causal associations of BMI and FMP with log-transformed fasting insulin and HOMA-IR. ConclusionsThe MR analysis based on population-based cohort indicated a causal relationship of adiposity and body fat distribution with cardiometabolic traits. When compared with central obesity, general obesity and adipose obesity might own stronger effects on blood pressure and blood lipids among children.

Non-linear Associations Between Visceral Adipose Tissue Distribution and Anthropometry-Based Estimates of Visceral Adiposity.

BackgroundRecent evidence suggests that excess visceral adipose tissue (VAT) is associated with future loss of subcutaneous adipose tissue (SAT) and skeletal muscle (SM) with aging. In clinical settings (abdominal) circumferences are commonly used to estimate body composition (BC). We aimed to study the linearity of VAT distribution ratios (i.e., VAT/SAT ratio and VAT/SM ratio), waist-to-hip ratio (WHR) and waist circumference (WC) with age and the relationship of VAT distribution ratios with anthropometry (i.e., WHR and WC).Materials and MethodsBC was determined using whole body magnetic resonance imaging in a large multi-ethnic group of 419 adults (42% white, 30% black, 15% Hispanic, 13% Asian, 1% other) with a BMI ranging from 15.9 to 40.8kg/m2. Linear and non-linear regression analysis was used to examine the linearity of VAT distribution ratios and anthropometry from 18 to 88 years. The relation between VAT distribution ratios and anthropometry was assessed separately.ResultsIn both sexes non-linear relationships were found between BC estimates and age, and between BC measures mutually. The ratios of VAT/SAT and VAT/SM showed quadratic relationships with age. VAT distribution ratios showed exponential or quadratic relationships with anthropometry with coefficients of determination ranging between 18 and 55%.ConclusionIn both sexes, VAT distribution ratios showed curvilinear relationships with age and with anthropometry. Given the sex differences in VAT distribution ratios, WHR and WC represent different BC proportions in men and women. These results emphasize the challenge when interpreting changes in BC based upon linear extrapolations in clinical practice.

Body mass index and adipose distribution have opposing genetic impacts on human blood traits.

Body mass index (BMI), hyperlipidemia, and truncal adipose distribution concordantly elevate cardiovascular disease risks, but have unknown genetic effects on blood trait variation. Using Mendelian randomization, we define unexpectedly opposing roles for increased BMI and truncal adipose distribution on blood traits. Elevated genetically determined BMI and lipid levels decreased hemoglobin and hematocrit levels, consistent with clinical observations associating obesity and anemia. We found that lipid-related effects were confined to erythroid traits. In contrast, BMI affected multiple blood lineages, indicating broad effects on hematopoiesis. Increased truncal adipose distribution opposed BMI effects, increasing hemoglobin and blood cell counts across lineages. Conditional analyses indicated genes, pathways, and cell types responsible for these effects, including Leptin Receptor and other blood cell-extrinsic factors in adipocytes and endothelium that regulate hematopoietic stem and progenitor cell biology. Our findings identify novel roles for obesity on hematopoiesis, including a previously underappreciated role for genetically determined adipose distribution in determining blood cell formation and function.

Abstract TMP76: Association Of Adiposity With Intracranial Atherosclerosis

Introduction: Adiposity, as measured by Body Mass Index (BMI) and Waist-to-Hip Ratio (WHR), is associated with ischemic stroke. However, association with Intercranial Atherosclerosis has not been well-established in the United States. We assessed the hypothesis that adiposity is associated with asymptomatic intracranial atherosclerosis (ICAS). Methods: BMI was calculated as weight (kg)/height (m) 2 . The ratio of waist (umbilical level) to hip (maximum buttocks) circumference (WHR) was calculated as a measure of fat distribution. In the ARIC cohort, a stratified subset (N=1145) underwent 3D time-of-flight MR angiogram and 3D high-isotropic resolution black blood MRI. ICAS was graded according to the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease trial. In this study, we evaluated the relationship between BMI as well as WHR, and significant asymptomatic ICAS, defined as ≥50% stenosis. Student t-tests were performed to test continuous variables, and X 2 test was used to compare categorical variables. Analysis of covariance (ANCOVA) was used for multivariate testing. Results: Among subjects who underwent vascular imaging, 1033 (90%) had &lt;50% ICAS and 112 (10%) had ≥50% ICAS. At the time of assessment, those with ≥50% ICAS were older (age 79±5 vs. 76±5, p&lt;0.001), and had higher systolic blood pressure or SBP (134±19 vs. 130±18, p=0.02), compared with those with &lt;50% ICAS. The BMI was higher (29.1±6.7 vs. 28.1±5.2), although the difference was statistically borderline significant (p=0.06). The WHR was higher (0.95±0.07 vs. 0.93±0,08), the difference being statistically significant (p=0.01). The difference remained significant after adjustment for age and SBP (p=0.02). Conclusion: We report a significant association between WHR, a measure of central adiposity, and ≥50% ICAS. This may be one of the first reported associations between central adiposity and ICAS. These results emphasize the importance of adiposity distribution in addition to overall adiposity, as a risk factor for significant asymptomatic ICAS.

Associations between body composition, fat distribution and metabolic consequences of excess adiposity with severe COVID-19 outcomes: observational study and Mendelian randomisation analysis

BackgroundHigher body mass index (BMI) and metabolic consequences of excess weight are associated with increased risk of severe COVID-19, though their mediating pathway is unclear.MethodsA prospective cohort study included 435,504 UK Biobank participants. A two-sample Mendelian randomisation (MR) study used the COVID-19 Host Genetics Initiative in 1.6 million participants. We examined associations of total adiposity, body composition, fat distribution and metabolic consequences of excess weight, particularly type 2 diabetes, with incidence and severity of COVID-19, assessed by test positivity, hospital admission, intensive care unit (ICU) admission and death.ResultsBMI and body fat were associated with COVID-19 in the observational and MR analyses but muscle mass was not. The observational study suggested the association with central fat distribution was stronger than for BMI, but there was little evidence from the MR analyses than this was causal. There was evidence that strong associations of metabolic consequences with COVID-19 outcomes in observational but not MR analyses. Type 2 diabetes was strongly associated with COVID-19 in observational but not MR analyses. In adjusted models, the observational analysis showed that the association of BMI with COVID-19 diminished, while central fat distribution and metabolic consequences of excess weight remained strongly associated. In contrast, MR showed the reverse, with only BMI retaining a direct effect on COVID-19.ConclusionsExcess total adiposity is probably casually associated with severe COVID-19. Mendelian randomisation data do not support causality for the observed associations of central fat distribution or metabolic consequences of excess adiposity with COVID-19.

Relationships between adiposity distribution and metabolic health in preconception women in South Africa.

ObjectiveAdipose tissue is a central regulator of metabolic health and a contributor to systemic inflammation. Patterns of adiposity deposition are important to understand for optimizing health. This study aimed to asses relationships between adiposity deposition and metabolic and inflammatory biomarkers in South African women prior to conception.MethodsNon‐pregnant, healthy women (n = 298) were recruited for this cross‐sectional study via home visits. Body composition was measured by Dual X‐ray Absorptiometry. Inflammation markers C‐reactive protein (CRP), alpha1‐acid glycoprotein (AGP), hemoglobin A1c (HbA1c), and blood pressure were scored according to risk. A summative metabolic health risk score was created for women with obesity. Generalized regression models assessed relationships between adiposity deposition and outcomes with adjustment for potential confounders.ResultsObesity was present in 22% of women (mean age = 20.93 years). Fat mass index was associated with inflammation and metabolic health risk (β = 0.58; p < 0.01). Visceral fat, trunk:limb ratio, android:gynoid ratio, body mass index, weight, and waist circumference were positively associated with CRP, AGP, and metabolic health risk (p < 0.01). Weight was associated with Hba1c (β < 0.01; p < 0.05). Participants with obesity and low metabolic health risk had lower fat mass index and visceral fat than participants with obesity and higher metabolic health risk.ConclusionsBlack South African women accumulated excess adipose tissue in abdominal regions. While fat mass and body mass were associated with inflammation and metabolic health risk, women with obesity and with lower fat mass index and lower visceral adipose tissue were metabolically protected. Identification of women at risk for metabolic disease preconception could help ensure future healthy pregnancies and prevent transference of risk to offspring.

Adiposity increases weight-bearing exercise-induced dyspnea despite favoring resting lung hyperinflation in COPD.

ObjectivesOur aim was to study the associations between resting lung hyperinflation, weight-bearing exercise-induced dyspnea and adipose distribution in obese and normal-weight COPD patients.MethodsWe performed a comparison between 80 obese COPD patients (COPDOB) with 80 age- and FEV1 matched normal-weight COPD patients (COPDNW). Dyspnea was assessed by the mMRC scale and the Borg dyspnea score before and after a 6 min walk test. Further characterization included spirometry, body plethysmography and metronome paced tachypnea (MPT) to estimate dynamic hyperinflation. Body composition was assessed with bioelectrical impedance analysis. Associations between dyspnea scores and BMI and body composition groups were studied using logistic regression models.ResultsCOPDOB patients had attenuated increases in TLC, FRC and RV compared to COPDNW patients (p < 0.01). The groups had comparable 6 min walking distance and ΔFRC upon MPT (p > 0.05). Compared to COPDNW, COPDOB patients reported more often a mMRC ≥ 2 (65 vs 46%; p = 0.02; OR 3.0, 95% CI 1.4–6.2, p < 0.01) and had higher ΔBorg upon 6MWT: 2.0 (SEM 0.20) vs. 1.4 (SEM 0.16), p = 0.01; OR for ΔBorg ≥ 2: 2.4, 95% CI 1.1–5.2, p = 0.03. Additional logistic regression analyses on the associations between body composition and dyspnea indicated that increased body fat percentage, fat mass index and waist-to-hip ratio were associated with higher ORs for mMRC ≥ 2 and ΔBorg upon 6MWT ≥ 2.ConclusionDespite its beneficial effect on resting lung hyperinflation, adiposity is associated with increased weight-bearing exercise-induced dyspnea in COPD.

Visceral adiposity index in kidney stone patients who have undergone surgery.

IntroductionThe visceral adiposity index (VAI) is a gender-specific metabolic index that indirectly measures visceral adipose function and distribution using waist circumference, body mass index (BMI), and triglyceride and high-density lipoprotein (HDL) cholesterol values. To assess visceral fat in the diagnostic pathway of urinary stone patients, we investigated the relationship between the VAI and nephrolithiasis as well as the relationship between the VAI and stone and surgery-related parameters.Material and methodsPatients who underwent percutaneous nephrolithotomy and retrograde intrarenal surgery for kidney stones were included in the study. The control group comprised of healthy individuals who volunteered to take part in study and did not have urolithiasis as confirmed by abdominal computed tomography imaging. A total of 148 patients were divided into the nephrolithiasis (n = 103) and the control (n = 45) groups. Weight, height, BMI, waist circumference measurements, and VAI were among the metabolic parameters measured. Stone and surgical parameters were evaluated.ResultsVAI (4.57 vs 2.76), waist circumference (92.1 vs 87.1), and BMI (28.31 vs 26.51) values were higher in the nephrolithiasis group(p = 0.02,p = 0.04, p <0.001,respectively). The VAI was statistically significant in the multivariate analysis for the presence of nephrolithiasis (p <0.001). The VAI negatively correlated with the stone Hounsfield unit (HU) and positively correlated with very-low-density lipoprotein (VLDL), blood creatinine, and calcium levels. The relationship between VAI and surgical parameters was not significant.ConclusionsA significant relationship was detected between nephrolithiasis and VAI, a new gender-specific metabolic index that distinguishes between subcutaneous and visceral adipose mass and demonstrates metabolic syndrome. No significant effect of this relationship on surgical parameters was demonstrated in the present study.

Determinants of cord blood adipokines and association with neonatal abdominal adipose tissue distribution

BackgroundCord blood leptin and adiponectin are adipokines known to be associated with birth weight and overall infant adiposity. However, few studies have investigated their associations with abdominal adiposity in neonates. We examined maternal factors associated with cord blood leptin and adiponectin, and the association of these adipokines with neonatal adiposity and abdominal fat distribution measured by magnetic resonance imaging (MRI) in an Asian mother–offspring cohort.MethodsGrowing Up in Singapore Towards healthy Outcomes (GUSTO), is a prospective mother–offspring birth cohort study in Singapore. Cord blood plasma leptin and adiponectin concentrations were measured using Luminex and Enzyme-Linked Immunosorbent Assay respectively in 816 infants. A total of 271 neonates underwent MRI within the first 2-weeks after delivery. Abdominal superficial (sSAT), deep subcutaneous (dSAT), and intra-abdominal (IAT) adipose tissue compartment volumes were quantified from MRI images. Multivariable regression analyses were performed.ResultsIndian or Malay ethnicity, female sex, and gestational age were positively associated with cord blood leptin and adiponectin concentrations. Maternal gestational diabetes (GDM) positively associated with cord blood leptin concentrations but inversely associated with cord blood adiponectin concentrations. Maternal pre-pregnancy body mass index (BMI) showed a positive relationship with cord blood leptin but not with adiponectin concentrations. Each SD increase in cord blood leptin was associated with higher neonatal sSAT, dSAT and IAT; differences in SD (95% CI): 0.258 (0.142, 0.374), 0.386 (0.254, 0.517) and 0.250 (0.118, 0.383), respectively. Similarly, each SD increase in cord blood adiponectin was associated with higher neonatal sSAT and dSAT; differences in SD (95% CI): 0.185 (0.096, 0.274) and 0.173 (0.067, 0.278), respectively. The association between cord blood adiponectin and neonatal adiposity was observed in neonates of obese mothers only.ConclusionsCord blood leptin and adiponectin concentrations were associated with ethnicity, maternal BMI and GDM, sex and gestational age. Both adipokines showed positive association with neonatal abdominal adiposity.

Dispersal of Abdominal Visceral; Subcutaneous, Visceral to Subcutaneous Adiposity Ratio and Metabolic Syndrome in A Sample of Obese Egyptians

Background: Visceral to subcutaneous adiposity ratio (VSR) may be more crucial than visceral and subcutaneous adipose tissue per se. It reflects relative distribution of abdominal adiposity which is a better indicator of cardio-meta­bolic risk.&#x0D; Aim: to examine if the VSR has diagnostic value in identifying metabolic syndrome (MS) compared with VAT and SAT among sample of obese Egyptians.&#x0D; Subjects and Methods: The over here study included 456 obese Egyptian adults (106 male and 350 female), ageing across 25- 55 years. All participants subjected to blood pressure and anthropometric assessment, abdominal ultrasound, and laboratory tests.&#x0D; Results: Males had quite high level of triglycerides and low HDL than females, who had significantly higher frequency of wide WC than men. There was insignificant sex difference in the frequency of MS. VAT and SAT were significantly higher in presence of wide WC and hypertension among both sexes. Also, VSR was significantly higher in presence of wide WC and hypertension among women only. While presence of MS led to significantly higher value of SAT among men, and VAT among women. Area under the curves (AUCs) for VAT, SAT and VSR; to predict MS; were 0.59, 0.63 and 0.46 among men and 0.63, 0.56 and 0.55 among women.&#x0D; Conclusion: Visceral and subcutaneous adipose tissue; not visceral/subcutaneous ratio; were significantly affected by the presence of MS in both sexes. SAT was significantly superior among men, while VAT was superior among women. VSR cannot be used as a predictor of MS.

Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: A Multicohort Nontargeted Metabolomics Observational and Mendelian Randomization Study.

Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity and circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data were generated with nontargeted ultraperformance liquid chromatography coupled to time-of-flight mass spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N = 1,135), PIVUS (N = 970), and TwinGene (N = 2,059). We assessed associations of general adiposity measured as BMI and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We used MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N = 7,373), the CHARGE Consortium (N = 8,631), the Framingham Heart Study (N = 2,076), and the DIRECT Consortium (N = 3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (P value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid, and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The results of the replication effort provided support for a causal association of adiposity with reduced levels of arachidonic acid (P value = 0.03). Adiposity is associated with variation of large parts of the circulating metabolome; however, further investigation of causality is required in well-powered cohorts.

Genetically Determined Obesity and Adipose Distribution Impact Human Blood Trait Variation across Cell Lineages

IntroductionGenome wide association studies (GWAS) have catalogued thousands of loci that influence blood traits, but genetic mechanisms and impacted cell types are often unknown. While some regulatory factors are blood cell-autonomous, other extrinsic regulatory factors respond to systemic physiology. Epidemiologic studies have correlated generalized obesity (increased body mass index, BMI) and high cholesterol with anemia, but cell types and mechanisms that mediate these effects are incompletely understood, and these studies do not provide evidence for causality. Thus, we wanted to use genetic effects of BMI and cholesterol on hemoglobin level (HGB) and other blood traits to infer causal relationships, identify relevant cell types, and propose genetic mechanisms.MethodsMendelian randomization (MR), akin to a “genetic randomized controlled trial”, uses variants linked to an exposure trait to estimate causal effects of that exposure on a given outcome. 1 Random variant allele allocation at meiosis enables this approach to address confounding and reverse causality that can otherwise preclude causal inference from epidemiologic and cohort studies. Further, effects of multiple factors can be parsed using multivariable MR and causal mediation analyses to help explain genetic associations. 2 Our study used gender- and age-adjusted GWAS summary statistics from European individuals.ResultsWe hypothesized that increased genetically determined BMI would decrease HGB. Using a MR framework, we found that a 5 kg/m 2 (1 standard deviation unit) increase in BMI decreased hemoglobin by 0.06±0.01 g/dL (p=1x10 -5, Fig). Increased BMI also decreased erythrocyte count, and unexpectedly also decreased platelet and white blood cell counts (all with p<5x10 -3). These data showed that obesity-related mechanisms extended beyond the erythroid lineage, perhaps impacting multipotent hematopoietic progenitor cells (HPCs).Similar to BMI, a 1 SD unit increase in total cholesterol decreased HGB (0.10±0.03 g/dL, p=2x10 -3, Fig). However, genetic effects of cholesterol were restricted to erythroid traits (HGB and hematocrit). Multivariable and mediation analyses confirmed that effects of BMI and cholesterol functioned through distinct genetic mechanisms.We speculated that multilineage effects from BMI could reflect a genetic predisposition to accumulate bone marrow adipose tissue, which can impact HPCs and hematopoiesis. 3 A tendency for ‘central’ adiposity increases one's waist-hip ratio (WHR), and increases cardiovascular disease risk concordant with BMI. Unexpectedly, we found that increased WHR, in contrast to BMI, increased HGB (0.08±0.02 g/dL, p=9x10 -6) as well as erythrocyte, platelet, and white blood cell counts (all with p<4x10 -3, Fig). In multivariable experiments, the effects of WHR were exacerbated after accounting for BMI at the individual or population level. Thus, obesity impacts blood traits through genetically determined adipose distribution.ConclusionsOur results confirm that BMI and cholesterol negatively impact HGB at a genetic level, consistent with clinical observations. The unexpected multilineage effects of genetically determined BMI most likely reflects a tendency to accumulate bone marrow adipose tissue, which in turn impacts HPCs and downstream blood cell production. Our findings suggest that adjustment for BMI and adiposity traits may be considered in blood trait GWAS analyses and illuminate opportunities to functionally dissect related genes and molecular pathways.

Cardiometabolic risk: New chronic care models.

Cardiometabolic risk factors, and the chronic cardiovascular diseases (CVDs) that result from them, are highly prevalent in the US and amenable to clinical nutrition interventions. This creates an urgency to develop comprehensive care models that incorporate prevention-based actions by improving lifestyle routines. Such care models should account for social determinants of health, ethnocultural variables, and challenges to sustainability. The relevance of these newly designed chronic care models is to inform and facilitate early intervention, primarily consisting of lifestyle changes and healthy nutrition, which mitigates progression from one stage to subsequent, higher morbidity stages to a greater extent than late intervention. In this article, the mechanistic drivers and ethnocultural validation of the Cardiometabolic-Based Chronic Disease (CMBCD) model are reviewed. Main findings are that in CMBCD, primary (genetics, environment, and behavior) and metabolic (obesity as Adiposity-Based Chronic Disease [ABCD], type 2 diabetes as Dysglycemia-Based Chronic Disease [DBCD], hypertension, and dyslipidemia) drivers initiate and perpetuate the progression of CVD. Epidemiological findings and molecular mechanisms support intra-ABCD/DBCD, as well as ABCD to DBCD stage progression culminating in CVD. The ABCD definition overcomes weight stigma and body mass index underperformance by considering adiposity amount, distribution, and function; and the DBCD definition overcomes criticisms of prediabetes and an exclusive glucocentric approach by considering insulin resistance and residual vascular risk along a clinical spectrum. In conclusion, clinicians should approach patients using the CMBCD model to incorporate lifestyle changes as early as possible to optimally mitigate the burden of CVD.

Impact of Adiposity and Fat Distribution, Rather Than Obesity, on Antibodies as an Illustration of Weight-Loss-Independent Exercise Benefits.

Obesity represents a risk factor for a variety of diseases because of its inflammatory component, among other biological patterns. Recently, with the ongoing COVID-19 crisis, a special focus has been put on obesity as a status in which antibody production, among other immune functions, is impaired, which would impact both disease pathogenesis and vaccine efficacy. Within this piece of writing, we illustrate that such patterns would be due to the increased adiposity and fat distribution pattern rather than obesity (as defined by the body mass index) itself. Within this context, we also highlight the importance of the weight-loss-independent effects of exercise.

Changes in Tissue Composition and Load Response After Transtibial Amputation Indicate Biomechanical Adaptation

Despite the potential for biomechanical conditioning with prosthetic use, the soft tissues of residual limbs following lower-limb amputation are vulnerable to damage. Imaging studies revealing morphological changes in these soft tissues have not distinguished between superficial and intramuscular adipose distribution, despite the recognition that intramuscular fat levels indicate reduced tolerance to mechanical loading. Furthermore, it is unclear how these changes may alter tissue tone and stiffness, which are key features in prosthetic socket design. This study was designed to compare the morphology and biomechanical response of limb tissues to mechanical loading in individuals with and without transtibial amputation, using magnetic resonance imaging in combination with tissue structural stiffness. The results revealed higher adipose infiltrating muscle in residual limbs than in intact limbs (residual: median 2.5% (range 0.2–8.9%); contralateral: 1.7% (0.1–5.1%); control: 0.9% (0.4–1.3%)), indicating muscle atrophy and adaptation post-amputation. The intramuscular adipose content correlated negatively with daily socket use, although there was no association with time post-amputation. Residual limbs were significantly stiffer than intact limbs at the patellar tendon site, which plays a key role in load transfer across the limb-prosthesis interface. The tissue changes following amputation have relevance in the clinical understanding of prosthetic socket design variables and soft tissue damage risk in this vulnerable group.