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Aims: To describe the overall fat distribution patterns independent of body mass index (BMI) in participants with type 2 diabetes (T2D) in the SURPASS‐3 MRI substudy by comparison with sex‐ and BMI‐matched virtual control groups (VCGs) derived from the UK Biobank imaging study at baseline and Week 52. Methods: For each study participant at baseline and Week 52 (N = 296), a VCG of ≥150 participants with the same sex and similar BMI was identified from the UK Biobank imaging study (N = 40 172). Average visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT) and liver fat (LF) levels and the observed standard deviations (SDs; standardized normal z‐scores: z‐VAT, z‐aSAT and z‐LF) were calculated based on the matched VCGs. Differences in z‐scores between baseline and Week 52 were calculated to describe potential shifts in fat distribution pattern independent of weight change. Results: Baseline fat distribution patterns were similar across pooled tirzepatide (5, 10 and 15 mg) and insulin degludec (IDeg) arms. Compared with matched VCGs, SURPASS‐3 participants had higher baseline VAT (mean [SD] z‐VAT +0.42 [1.23]; p < 0.001) and LF (z‐LF +1.24 [0.92]; p < 0.001) but similar aSAT (z‐aSAT −0.13 [1.11]; p = 0.083). Tirzepatide‐treated participants had significant decreases in z‐VAT (−0.18 [0.58]; p < 0.001) and z‐LF (−0.54 [0.84]; p < 0.001) but increased z‐aSAT (+0.11 [0.50]; p = 0.012). Participants treated with IDeg had a significant change in z‐LF only (−0.46 [0.90]; p = 0.001), while no significant changes were observed for z‐VAT (+0.13 [0.52]; p = 0.096) and z‐aSAT (+0.09 [0.61]; p = 0.303). Conclusion: In this exploratory analysis, treatment with tirzepatide in people with T2D resulted in a significant reduction of z‐VAT and z‐LF, while z‐aSAT was increased from an initially negative value, suggesting a possible treatment‐related shift towards a more balanced fat distribution pattern with prominent VAT and LF loss. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the associations between liver fat content and cardiometabolic parameters to explore potential threshold values that define metabolically healthy liver fat content, and to examine the association of liver fat content with cardiovascular events as well as its longitudinal progression. Methods: Participants in the Dallas Heart Study underwent clinical evaluation, including laboratory testing, and liver fat quantification by magnetic resonance spectroscopy (MRS) at baseline (N = 2287) and at follow‐up (N = 343) after a mean of 7.3 years. Cardiovascular events were adjudicated (>12 years). Results: The mean age at study entry was 44 years, 47% of participants were men, and 48% were African American. The following cardiometabolic biomarkers worsened across liver fat quintiles (P < 0.0001): body mass index (BMI); waist circumference; prevalence of hypertension; prevalence of diabetes; cholesterol, triglyceride, high‐sensitivity C‐reactive protein (CRP), leptin and fasting glucose levels; homeostatic model assessment of insulin resistance index (HOMA‐IR); coronary artery calcium score; visceral adipose tissue; abdominal subcutaneous adipose tissue; and lower body subcutaneous adipose tissue. Cardiovascular events were comparable across groups defined by tertile of baseline liver fat content. Change in BMI (R = 0.40), waist circumference (R = 0.35), CRP (R = 0.31), alanine aminotransferase (R = 0.27), HOMA‐IR (R = 0.26), aspartate transaminase (R = 0.15) and triglycerides (R = 0.12) significantly correlated with change in liver fat content (P < 0.01 for all). Conclusion: Clinically relevant metabolic abnormalities were higher across quintiles of liver fat, with increases noted well within normal liver fat ranges, but cardiovascular events were not associated with liver fat content. Longitudinal changes in metabolic parameters, especially adiposity‐related parameters, were correlated with change in liver fat content. [ABSTRACT FROM AUTHOR]

Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008–2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R 2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm2 and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R 2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006–2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000–2007). Performance was comparable to the development setting in PIVUS (R 2 = 0.63, RMSE = 42.4 cm2, calibration slope = 0.94) but lower in MESA (R 2 = 0.44, RMSE = 60.7 cm2, calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements. [ABSTRACT FROM AUTHOR]

Background: Low cardiorespiratory fitness (CRF), high body mass index, and excess visceral adiposity are each associated with impairment in left ventricular (LV) peak circumferential strain (Ecc), an intermediate phenotype that precedes the development of clinical heart failure (HF). However, the association of regional fat distribution and CRF with Ecc independent of each other and other potential confounders is not known. Methods: Participants from the Dallas Heart Study Phase 2 who underwent dual energy X-ray absorptiometry assessment of regional fat distribution, CRF assessment by submaximal treadmill test, and Ecc quantification by tissue-tagged cardiovascular magnetic resonance were included in the analysis. The cross-sectional associations of measures of regional adiposity, namely visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and lower-body fat (LBF) with Ecc after adjustment for CRF and other potential confounders (independent variables) were assessed using multivariable linear regression analysis. Results: The study included 1089 participants (55% female, 39% black). In the unadjusted analysis, higher VAT was associated with greater impairment in Ecc. After adjustment for baseline risk factors, CRF, parameters of LV structure and function, and other fat depots such as SAT and LBF, higher VAT remained associated with greater impairment in Ecc (β: 0.19, P = 0.002). SAT and LBF were not significantly associated with Ecc, however, CRF remained associated with Ecc in the fully adjusted model including all fat depots (β: - 0.15, P < 0.001). Conclusions: VAT and CRF are each independently associated with impairment in Ecc, suggesting that higher VAT burden and low CRF mediate pathological cardiac remodeling through distinct mechanisms. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (13 C)-labeled glycerol.Methods: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-13 C3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models.Results: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss.Conclusions: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity. [ABSTRACT FROM AUTHOR]

The prevalence of obesity has increased globally over the last 2 decades. Although the body mass index has been a convenient and simple index of obesity at the population level, studies have shown that obesity defined by body mass index alone is a remarkably heterogeneous condition with varying cardiovascular and metabolic manifestations across individuals. Adipose tissue is an exquisitely active metabolic organ engaged in cross-talk between various systems; perturbation of adipose tissue results in a pathological response to positive caloric balance in susceptible individuals that directly and indirectly contributes to cardiovascular and metabolic disease. Inadequate subcutaneous adipose tissue expansion in the face of dietary triglycerides leads to visceral and ectopic fat deposition, inflammatory/adipokine dysregulation, and insulin resistance. Conversely, preferential fat storage in the lower body depot may act as a metabolic buffer and protect other tissues from lipotoxicity caused by lipid overflow and ectopic fat. Translational, epidemiological, and clinical studies over the past 30 years have clearly demonstrated a strong link between visceral and ectopic fat and the development of a clinical syndrome characterized by atherogenic dyslipidemia, hyperinsulinemia/glucose intolerance, hypertension, atherosclerosis, and adverse cardiac remodeling/heart failure. This relationship is even more nuanced when clinical entities such as metabolically healthy obesity phenotype and the obesity paradox are considered. Although it is clear that the accumulation of visceral/ectopic fat is a major contributor to cardiovascular and metabolic risk above and beyond the body mass index, implementation of fat distribution assessment into clinical practice remains a challenge. Anthropometric indexes of obesity are easily implemented, but newer imaging-based methods offer improved sensitivity and specificity for measuring specific depots. Lifestyle, pharmacological, and surgical interventions allow a multidisciplinary approach to overweight/obesity that may improve outcomes and align with a public health message to combat the growing epidemic of obesity worldwide and to build healthier lives free of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population.Methods: Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot.Results: Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68-0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model.Conclusion: Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution. [ABSTRACT FROM AUTHOR]

Background Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear. Objectives This study sought to determine the relationship between adipose tissue distribution and incident hypertension. Methods Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI). Results Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m 2 ), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase). Conclusions Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association. [ABSTRACT FROM AUTHOR]

Background: Previous studies that reported an association of dietary Na+ intake with metabolic syndrome were limited by the use of imprecise measures of obesity, Na+ intake, or exclusion of multiethnic populations. The effect of dietary K+ intake on obesity is less well described. Objective: We hypothesized that high dietary Na+ and low K+, based on the ratio of urinary Na+ to K+ (U[Na+]/[K+]) in a first-void morning urinary sample, is independently associated with total body fat. Design: In a prospective population-based cohort, 2782 participants in the community-dwelling, probability-sampled, multiethnic Dallas Heart Study were analyzed. The primary outcome established a priori was total-body percentage fat (TBPF) measured by dual-energy X-ray absorptiometry. The main predictor was U[Na+]/[K+]. Robust linear regression was used to explore an independent association between U[Na+]/[K+] and TBPF. The analyses were stratified by sex and race after their effect modifications were analyzed. Results: Of the cohort, 55.4% were female, 49.8% African American, 30.8% white, 17.2% Hispanic, and 2.2% other races. The mean (6SD) age was 44 6 10 y, BMI (in kg/m2) was 30 6 7, TBPF was 32 6 10%, and U[Na+]/[K+] was 4.2 6 2.6; 12% had diabetes. In the unadjusted and adjusted models, TBPF increased by 0.75 (95% CI: 0.25, 1.25) and 0.43 (0.15, 0.72), respectively (P = 0.003 for both), for every 3-unit increase in U[Na+]/[K+]. A statistically significant interaction was found between race and U[Na+] /[K+], so that the non-African American races had a higher TBPF than did the African Americans per unit increase in U[Na+]/[K+] (P-interaction, 0.0001 for both). No interaction was found between sex and U[Na+]/[K+]. Conclusions: The ratio of dietary Na+ to K+ intake may be independently associated with TBPF, and this association may be more pronounced in non-African Americans. Future studies should explore whether easily measured spot U[Na+]/[K+] can be used to monitor dietary patterns and guide strategies for obesity management. [ABSTRACT FROM AUTHOR]

Objective: Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population-based cohort of obese adults. Design and Methods: Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation ( n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography ( n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. Results: In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number ( p < 0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque ( p < 0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment. Conclusion: VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort. Background: Natriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models, but data are lacking in humans. Methods: A total of 2,619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP); and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index. Results: Median BNP and NT-proBNP levels in the study cohort (mean age 44 years; 56% women, 48% African Americans, 32% obese) were 3.0 and 28.1 pg/ml, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance, including lower visceral fat, liver fat, and homeostasis model assessment of insulin resistance index, and increased lower body fat and higher adiponectin (p < 0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral fat (beta coefficient = −0.08; p < 0.0001) and liver fat (beta coefficient = −0.14; p < 0.0001) and positively associated with lower body fat (beta coefficient = 0.07; p < 0.0001) independent of age, sex, race, and obesity status; findings were similar with BNP. Adjustment for body composition, homeostasis model assessment of insulin resistance index, circulating androgens, and adipocytokines did not attenuate the associations. Conclusions: Higher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides. [Copyright &y& Elsevier]

In the original publication, disclosure statement for the author Ian J. Neeland was published incorrectly. The correct statement should read as “Ian J. Neeland received financial assistance for publishing/article processing fees from Boehringer Ingelheim”. [ABSTRACT FROM AUTHOR]

Background: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established.Methods: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m2), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes.Results: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (R2=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI (P interaction=0.04) and WC (P interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each).Conclusions: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes. [ABSTRACT FROM AUTHOR]

Obesity contributes to reduced life expectancy because of its link with type 2 diabetes and cardiovascular disease. Yet, targeting this poorly diagnosed, ill-defined, and underaddressed modifiable risk factor remains a challenge. In this review, we emphasize that the tendency among health care professionals to amalgam all forms of obesity altogether as a single entity may contribute to such difficulties and discrepancies. Obesity is a heterogeneous condition both in terms of causes and health consequences. Attention should be given to 2 prevalent subgroups of individuals: 1) patients who are overweight or moderately obese with excess visceral adipose tissue; and 2) patients with severe obesity, the latter group having distinct additional health issues related to their large body fat mass. The challenge of tackling high-cardiovascular-risk forms of obesity through a combination of personalized clinical approaches and population-based solutions is compounded by the current obesogenic environment and economy. [ABSTRACT FROM AUTHOR]

Aim: To investigate the reliability of multicompartmental volumetric mesenchymal segmentations on MRI and their correlations with anthropomorphic and clinical parameters.Materials and Methods: A consecutive series of middle-age (35-50 year old) female volunteers with variable body mass index (BMI) and MRI scans performed as a part of the Dallas Heart Study were included. A semi-automatic segmentation tool was used to partition different mesenchymal tissues- fat, muscle, and bone on MRI of pelvis. Total volumes of each compartment were calculated and compared between overweight/obese (BMI> = 25 kg/m2) and non-obese (BMI < 25 kg/m2) groups, and with physical performance measurements, i.e. mean activity counts per minute (MVPA) and cardiorespiratory fitness (CRF) estimated by submaximal treadmill test (TT). Kruskal Wallis, Mann-Whitney U test, intraclass correlation coefficient (ICC) and Spearman correlations were used. P value <0.05 was considered statistically significant.Results: There were statistically significant positive correlations between fat volume and BMI (p < 0.0001), muscle volume and height (p = 0.03), and bone volume and height (p < 0.0001). Significant inverse correlations were found between bone volume and BMI (p = 0.002). Fair to good interobserver reliability was seen with muscle and fat volumes (ICC = 0.43-0.64) and excellent reliability was seen with bone volumes (ICC = 0.78-0.79). Statistically significant inverse correlations were found between MVPA and age (p = 0.01), and TT with BMI and weight (p = 0.01, 0.03).Conclusion: Multi-compartment mesenchymal tissue volume quantification on pelvic MRI is reliable in females. Inverse correlation of bone volume with BMI has potential implications for future risk of fracture. [ABSTRACT FROM AUTHOR]