Obesity-related Cardiometabolic Diseases Research Articles

INFLA score: a novel inflammatory marker for assessing cardiometabolic disease risk in obese individuals

BackgroundThe low-grade inflammation score (INFLA-score) is a composite index that assesses chronic inflammatory status using multiple inflammatory markers. However, its correlation with cardiometabolic diseases (CMDs) in obese populations remains unclear.MethodsWe conducted a prospective cohort study involving 79,160 participants with obesity (BMI ≥ 30 kg/m2) from the UK Biobank. The INFLA-score was calculated based on high-sensitivity C-reactive protein, leukocyte count, platelet count and granulocyte/lymphocyte ratio. We employed Kaplan–Meier survival curves, multivariable Cox regression, restricted cubic splines and accelerated time-to-failure models to analyse the association between the INFLA-score and CMDs risk, including coronary heart disease (CAD), stroke and type 2 diabetes mellitus (T2DM).ResultsOver a median follow-up of 161.41 months, we recorded 14,903 CMDs events, comprising 7184 CAD cases, 1914 strokes and 7924 T2DM cases. Cox regression analysis revealed that each unit increase in the INFLA-score corresponded to a 1.5%, 1.1%, 1.2% and 2.4% increase CMDs risk (HR: 1.015, 95% CI 1.013–1.018), CAD risk (HR: 1.011, 95% CI 1.007–1.015), stroke risk (HR: 1.012, 95% CI 1.004–1.020) and T2DM risk (HR: 1.024, 95% CI 1.020–1.028), respectively. Restricted cubic spline analysis indicated a non-linear relationship between cumulative INFLA-score and CMDs risk (P = 0.044). Subgroup analysis revealed interactions between sex, age, history of lipid-lowering drug use, and INFLA-score regarding CMDs risk. Sensitivity analysis corroborated the main findings.ConclusionOur findings strongly support the close association between INFLA-score and CMDs risk, particularly notable in women, those aged < 55, and individuals with a history of lipid-lowering drug use. These findings offer new insights into the role of inflammation in obesity-related CMDs, suggesting potential applications for prevention and identification of high-risk populations.

INFLA score: a novel inflammatory marker for assessing cardiometabolic disease risk in obese individuals

BackgroundThe low-grade inflammation score (INFLA-score) is a composite index that assesses chronic inflammatory status using multiple inflammatory markers. However, its correlation with cardiometabolic diseases (CMDs) in obese populations remains unclear.MethodsWe conducted a prospective cohort study involving 79,160 participants with obesity (BMI ≥ 30 kg/m2) from the UK Biobank. The INFLA-score was calculated based on high-sensitivity C-reactive protein, leukocyte count, platelet count and granulocyte/lymphocyte ratio. We employed Kaplan–Meier survival curves, multivariable Cox regression, restricted cubic splines and accelerated time-to-failure models to analyse the association between the INFLA-score and CMDs risk, including coronary heart disease (CAD), stroke and type 2 diabetes mellitus (T2DM).ResultsOver a median follow-up of 161.41 months, we recorded 14,903 CMDs events, comprising 7184 CAD cases, 1914 strokes and 7924 T2DM cases. Cox regression analysis revealed that each unit increase in the INFLA-score corresponded to a 1.5%, 1.1%, 1.2% and 2.4% increase CMDs risk (HR: 1.015, 95% CI 1.013–1.018), CAD risk (HR: 1.011, 95% CI 1.007–1.015), stroke risk (HR: 1.012, 95% CI 1.004–1.020) and T2DM risk (HR: 1.024, 95% CI 1.020–1.028), respectively. Restricted cubic spline analysis indicated a non-linear relationship between cumulative INFLA-score and CMDs risk (P = 0.044). Subgroup analysis revealed interactions between sex, age, history of lipid-lowering drug use, and INFLA-score regarding CMDs risk. Sensitivity analysis corroborated the main findings.ConclusionOur findings strongly support the close association between INFLA-score and CMDs risk, particularly notable in women, those aged < 55, and individuals with a history of lipid-lowering drug use. These findings offer new insights into the role of inflammation in obesity-related CMDs, suggesting potential applications for prevention and identification of high-risk populations.

Accelerometer-Based Estimates of Physical Activity and Sedentary Time Among Samoan Adults.

The prevalence of obesity-related cardiometabolic disease in Samoa is among the highest globally. While physical activity is a modifiable risk factor for obesity-related disease, little is known about physical activity levels among adult Samoans. Using wrist-worn accelerometer-based devices, this study aimed to characterize physical activity among Samoan adults. Samoan adults (n = 385; 55% female, mean [SD] age 52 [10] y) wore Actigraph GT3X+ devices for 7 to 10days. General linear models were used to examine mean daily minutes of sedentary time, light physical activity, and moderate to vigorous physical activity by various participant characteristics. Time spent in moderate to vigorous physical activity did not differ statistically between men (88 [5]min; 95% confidence interval [CI], 80-97) and women (78 [4]min; 95% CI, 70-86; P = .08). Women, however, spent more time than men in light physical activity: 380 (7)minutes (95% CI, 367-393) versus 344 (7)minutes (95% CI, 329-358; P < .001). While there were no differences in physical activity by census region, education, or occupation among women, men in urban areas spent significantly less time in moderate to vigorous physical activity than those in peri-urban and rural areas (P = .015). Women with class II/III obesity spent more time in sedentary activities than those with healthy weight or overweight/class I obesity (P = .048). This study characterizes physical activity among Samoan adults and highlights variation by sex, urbanicity, and weight status. In providing initial device-measured estimates of physical activity in Samoa, this analysis establishes a baseline from which the success of future attempts to intervene on physical activity may be assessed.

Inhibition of activin receptor 2 signalling ameliorates metabolic dysfunction–associated steatotic liver disease in western diet/L-NAME induced cardiometabolic disease

ObjectiveBlockade of activin 2 receptor (ACVR2) signaling has been shown to improve insulin sensitivity and aid in weight loss. Inhibition of ACVR2 signaling restores cardiac function in multiple heart failure models. However, its potential in the treatment of obesity-related cardiometabolic disease remains unknown. Here, we investigated targeting ACVR2 signaling in cardiometabolic disease manifested with metabolic dysfunction–associated steatotic liver disease (MASLD). MethodsMice were fed a high-fat, high-sugar diet combined with the administration of nitric oxide synthase inhibitor L-NAME in drinking water, which causes hypertensive stress. For the last eight weeks, the mice were treated with the soluble ACVR2B decoy receptor (sACVR2B-Fc). ResultssACVR2B-Fc protected against the development of comorbidities associated with cardiometabolic disease. This was most pronounced in the liver where ACVR2 blockade attenuated the development of MASLD including cessation of pro-fibrotic activation. It also significantly reduced total plasma cholesterol levels, impeded brown adipose tissue whitening, and improved cardiac diastolic function. In vitro, ACVR2 ligands activin A, activin B and GDF11 induced profibrotic signaling and the proliferation of human cardiac fibroblasts. ConclusionsBlockade of ACVR2B exerts broad beneficial effects for therapy of cardiometabolic disease. By reducing obesity, ameliorating cardiovascular deterioration and restraining MASLD, blockade of ACVR2B signaling proves a potential target in MASLD and its comorbidities.

The timing of energy intake.

The aim of the paper is to review the current evidence on the impact of 'the timing of energy intake' on the risk of developing obesity and obesity-related metabolic diseases. The prevalence of obesity is currently increasing worldwide thus becoming a severe health burden for most countries. Indeed, obesity represents a risk factor for several non-communicable diseases such as cancer, type 2 diabetes, dyslipidaemia, CVD and overall mortality. In order to treat obesity, several pharmacological approaches have been developed and are indicated for subjects with obesity with a BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 and obesity-related comorbidities. For severe obesity (BMI ≥ 40 kg/m2), bariatric surgery represents a promising approach. The most common bariatric surgical procedures are represented by the Roux-en-Y gastric bypass, laparoscopic adjustable band, laparoscopic gastric sleeve and biliopancreatic diversion with duodenal switch. Both anti-obesity pharmacological and surgical treatments require change in lifestyle. When a nutritional plan is established, attention is usually paid to macronutrient composition and energy intake, while 'the time of food' is not taken into account. Chronotype, which is the attitude of a subject to carry out most of their daily activities in the first (morning chronotype) or second half (evening chronotype) of the day, has been reported to have a role in the pathogenesis of obesity and obesity-related cardiometabolic diseases as well as eating speed. Thus, adopting a physiological timing of energy intake could be an additional strategy to potentiate the current anti-obesity approaches.

Abstract 14613: Sex Differences in Protein Biomarkers and Measures of Fat Distribution

Background: Sex differences in obesity and fat distribution have been well described and may explain differences in subsequent cardiovascular risk in men vs women. Underlying mechanisms are not fully elucidated and warrant further investigation. Objective: This study aims to examine sex differences in the associations of obesity and fat distribution measures with cardiovascular disease (CVD) protein biomarkers reflecting key pathways including inflammation, adiposity, fibrosis, and neurohormonal regulation. Methods: We measured 71 circulating protein biomarkers in 3,143 participants with available computed tomography measures of adiposity in the Framingham Heart Study. We examined whether sex modified the association of obesity (body mass index [BMI] and waist circumference [WC]) and fat distribution measures (visceral adipose tissue [VAT]) with protein biomarkers using multiplicative interaction terms in multivariable linear regression models. Sex-stratified analyses were performed as appropriate. Results: Among 3,143 participants (mean age 50 years, 48.7% women), we found that sex modified the association of BMI with 8 protein biomarkers including AGP-1, adipsin, IGFBP-1, IGFBP-2, ADM, KLKB1, MCP-1, and ucMGP (FDR-q int &lt; 0.05 for all, Figure 1 ). For example, BMI was associated with higher MCP-1 levels in women, but not in men (ß 0.132, SE 0.025, p &lt; 0.0001 in women vs ß 0.036, SE 0.028, p = 0.20 in men, FDR-q int 0.03). We found that sex also modified the association of WC and VAT with key CVD protein biomarkers including AGP-1 and A1M. Conclusions: We found that sex modified the association of obesity and adipose traits with cardiovascular risk as ascertained using biomarkers of CVD. These findings highlight potential biological pathways that may contribute to obesity-related cardiometabolic disease uniquely in men versus women.

FRI025 Succinate Receptor Activation Increases Respiration In Human But Not Murine Brown Adipocytes

Abstract Disclosure: B.T. McNeill: None. A. Kelman: None. L.E. Ramage: None. K.J. Suchacki: None. S.J. Wakelin: None. N.M. Morton: None. R.H. Stimson: None. Brown adipose tissue (BAT) is a thermogenic tissue that generates heat to maintain body temperature. BAT activation is a potential therapeutic target for treating obesity-related cardiometabolic disease. We performed RNA sequencing of human primary brown and white adipocytes and identified SUCNR1, which encodes the succinate receptor, as highly differentially expressed (20-fold) in brown versus white adipocytes. Succinate is known to increase BAT thermogenesis, while SUCNR1 activation inhibits lipolysis in white adipose tissue (WAT). We hypothesized that SUCNR1 activation increases BAT thermogenesis in humans and in mice. To test this, we investigated the effect of succinate and the selective SUCNR1 agonist cis-epoxysuccinic acid (C-ESA) in human and murine primary brown/ beige adipocytes. In addition, we determined the metabolic effects of disruption of Sucnr1 in mice either fed control or a high fat (HFD) for 12 weeks and measured energy expenditure when housed at standard room temperature (21°C) and during cold exposure (4°C). In human brown and white adipocytes, succinate increased basal and noradrenaline-stimulated respiration, while C-ESA increased basal respiration only in human brown adipocytes without altering UCP1 mRNA levels. SUCNR1 activation reduced glycerol release only in human white adipocytes. Male (but not female) Sucnr1-/- mice exhibited impaired glucose tolerance versus Sucnr1+/+ littermates after 2 weeks of HFD, and greater fat mass was also observed in the Sucnr1-/- mice following chronic HFD. However, energy expenditure, locomotor activity and tail vein temperature were unchanged in male Sucnr1-/- mice either at 21°C or 4°C. In addition, expression of Ucp1 and Pgc1α in BAT and inguinal WAT were similar between genotypes. Sucnr1 deletion had no effect on fat mass or glucose tolerance in mice fed a control diet. In vitro, differentiated brown adipocytes from Sucnr1-/- mice demonstrated comparable cellular respiration and Ucp1 mRNA levels both basally and during noradrenaline stimulation to Sucnr1+/+ adipocytes. Succinate and C-ESA did not stimulate respiration in murine brown or white adipocytes. These data reveal that SUCNR1 activation enhances brown adipocyte respiration in human but not murine brown adipocytes, highlighting a novel pathway regulating BAT function in addition to differences between species. These data also reveal novel sex-specific differences in the metabolic effects of SUCNR1, although the mechanisms through which female mice are protected from the adverse metabolic effects of Sucnr1 deletion are unclear. SUCNR1 activation may be a novel therapeutic target to treat obesity and associated metabolic disease, but requires further research in humans to determine the specific mechanisms through which SUCNR1 regulates BAT thermogenesis. Presentation: Friday, June 16, 2023

Distinct inflammatory signatures of upper and lower body adipose tissue and adipocytes in women with normal weight or obesity.

Upper and lower body fat accumulation poses an opposing obesity-related cardiometabolic disease risk. Depot-differences in subcutaneous adipose tissue (SAT) function may underlie these associations. We aimed to investigate the inflammatory signatures of abdominal (ABD) and femoral (FEM) SAT in postmenopausal women with normal weight or obesity. We included 23 postmenopausal women with normal weight (n = 13) or obesity (n = 10). In vivo secretion of adipokines from ABD and FEM SAT was measured using the arterio-venous balance technique. Adipokine gene expression and adipocyte morphology were examined in ABD and FEM SAT. Furthermore, adipokine expression and secretion were investigated in vitro using differentiated human primary ABD and FEM subcutaneous adipocytes derived from the study participants. Plasma leptin and plasminogen activator inhibitor (PAI)-1 concentrations were higher, and ABD and FEM adipocytes were larger in women with obesity than normal weight. No differences in adipocyte size and blood flow were apparent between ABD and FEM SAT. We found significant release of leptin and monocyte chemoattractant protein (MCP)-1 from ABD and FEM SAT, with higher fractional release of MCP-1 from ABD than FEM SAT. Gene expression of leptin, PAI-1, and tumor necrosis factor-α was lower in ABD than FEM SAT and higher in women with obesity than normal weight. In ABD adipocytes, interleukin-6, PAI-1, and leptin gene expression were higher, while adiponectin and dipeptidyl-peptidase-4 gene expression were lower than in FEM adipocytes. Finally, ABD adipocytes secreted less MCP-1 compared to FEM adipocytes. These findings demonstrate that upper and lower body SAT and adipocytes are characterized by distinct inflammatory signatures in postmenopausal women, which seem independent of adipocyte size.

Endothelial-Specific Expression of CIDEC Improves High-Fat Diet-Induced Vascular and Metabolic Dysfunction.

Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), originally identified to be a lipid droplet-associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells and regulates vascular function. The current study was designed to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg mice exhibited protection against high-fat diet-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, these mice displayed improved insulin signaling and endothelial nitric oxide synthase activation, enhanced endothelium-dependent vascular relaxation, and improved vascularization of adipose tissue, skeletal muscle, and heart. Mechanistically, we identified a novel interplay of CIDEC-vascular endothelial growth factor A (VEGFA)-vascular endothelial growth factor receptor 2 (VEGFR2) that reduced VEGFA and VEGFR2 degradation, thereby increasing VEGFR2 activation. Overall, our results demonstrate a protective role of endothelial CIDEC against obesity-induced metabolic and vascular dysfunction, in part, by modulation of VEGF signaling. These data suggest that CIDEC may be investigated as a potential future therapeutic target for mitigating obesity-related cardiometabolic disease.

Abstract P3003: Endothelial-Specific Expression Of Cidec Improves High-Fat Diet-induced Vascular And Metabolic Dysfunction

Cell death-inducing DNA fragmentation factor-α-like effector C (CIDEC), originally identified to be a lipid-droplet associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells (ECs) and regulates vascular function in obesity. The present study was designed to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg mice exhibited protection against HFD-impaired glucose intolerance, insulin resistance and dyslipidemia. Moreover, these mice displayed improved insulin signaling and eNOS activation, enhanced endothelium-dependent vascular relaxation and improved vascularization of adipose tissue, skeletal muscle, and heart. Mechanistically, we identified a novel interplay of CIDEC-VEGFA-VEGFR2 that reduced VEGFA and VEGFR2 ubiquitin-mediated degradation thereby increasing VEGFR2 activation. Overall, our results demonstrate a protective role of endothelial CIDEC against obesity-induced metabolic and vascular dysfunction, in part, by modulation of VEGF signaling. These data suggests that CIDEC may be considered as a potential future therapeutic target for mitigating obesity-related cardiometabolic disease.

Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures

SummaryAdipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.

Abstract MP70: Differing Age, Sex, And Ancestry-related Trends In Visceral Fat Between Youth With Healthy Weight, Obesity, And Type 2 Diabetes

Introduction: Excess visceral fat is implicated in obesity-related cardiometabolic disease, but normal age, sex, and ancestry-related trends in visceral fat among youth with varying body size and metabolic health status are unknown. Objective: The objective of this study was to characterize age, sex, and ancestry-related trends in abdominal visceral fat among youth with healthy weight, obesity, and type 2 diabetes. Methods: This cross-sectional sample included youth ages 10 to 23 years (67% female, 56% non-black) with healthy weight (BMI=5 th to 85 th percentile, n=236), obesity (BMI &gt; 95 th percentile, n=224), and type 2 diabetes (BMI &gt; 95 th percentile, n=145). Visceral fat (cm 2 ) was assessed via dual-energy X-ray absorptiometry. Multiple linear regression analyses were performed to examine interaction and main effects of age, sex, and ancestry in relation to visceral fat (log) in the three groups separately. Results: Age was positively associated with visceral fat in the healthy weight (P&lt;0.001), obese (P&lt;0.001), and type 2 diabetes groups (P=0.051), such that visceral fat was greater in later adolescents and young adults compared to younger children. Non-blacks had significantly greater visceral fat compared to blacks in the healthy weight (P=0.003), obesity (P&lt;0.001), and type 2 diabetes groups (P&lt;0.001). Sex differences in visceral fat differed by group. In the healthy weight group, males had significantly greater visceral fat than females, but in the obesity group, females had greater visceral fat than males (both P&lt;0.001). In the type 2 diabetes group, females tended to have greater visceral fat, but this difference did not reach statistical significance (P=0.060). When accounting for BMI, significant sex and ancestry differences were maintained, but age associations were nullified. Conclusions: This study reports novel findings with respect to demographic determinants of visceral fat assessed via DXA in children, adolescents, and young adults. Our findings that sex differences in visceral fat in youth with obesity and type 2 diabetes persisted following control for BMI are novel and of clinical interest. Specifically, that females may accrue greater visceral adiposity with weight gain when compared to their male counterparts might help to explain differing risk for obesity-related chronic disease. Prospective studies of youth during critical periods of growth are needed to define the consequences of excess visceral fat accrual with respect to future cardiometabolic risk.

Adipsin Serum Concentrations and Adipose Tissue Expression in People with Obesity and Type 2 Diabetes.

(1) Adipsin is an adipokine that may link increased fat mass and adipose tissue dysfunction to obesity-related cardiometabolic diseases. Here, we investigated whether adipsin serum concentrations and adipose tissue (AT) adipsin mRNA expression are related to parameters of AT function, obesity and type 2 diabetes (T2D). (2) Methods: A cohort of 637 individuals with a wide range of age and body weight (Age: 18–85 years; BMI: 19–70 kg/m2) with (n = 237) or without (n = 400) T2D was analyzed for serum adipsin concentrations by ELISA and visceral (VAT) and subcutaneous (SAT) adipsin mRNA expression by RT-PCR. (3) Results: Adipsin serum concentrations were significantly higher in patients with T2D compared to normoglycemic individuals. We found significant positive univariate relationships of adipsin serum concentrations with age (r = 0.282, p < 0.001), body weight (r = 0.264, p < 0.001), fasting plasma glucose (r = 0.136, p = 0.006) and leptin serum concentrations (r = 0.362, p < 0.001). Neither VAT nor SAT adipsin mRNA expression correlated with adipsin serum concentrations after adjusting for age, sex and BMI. Independent of T2D status, we found significantly higher adipsin expression in SAT compared to VAT (4) Conclusions: Our data suggest that adipsin serum concentrations are strongly related to obesity and age. However, neither circulating adipsin nor adipsin AT expression reflects parameters of impaired glucose or lipid metabolism in patients with obesity with or without T2D.

Nutrition knowledge is associated with greater weight loss in obese patients following a multidisciplinary rehabilitation program.

A major objective of the metabolic-nutritional-psychological multidisciplinary rehabilitation of obese subjects is providing a nutritional education aimed at achieving a weight loss and the improvement of obesity-related cardio-metabolic diseases. The impact of nutrition knowledge in healthy eating patterns and weight loss is still debated. The aim of this study was to identify whether the increase in nutrition knowledge is associated with weight loss. Two hundred fifty-six obese patients (80% women, mean age 57.5±12.4 years) were consecutively recruited among those referred for a three-month metabolic-nutritional-psychologic rehabilitation program. Education level and time of the onset of obesity were collected. Before and at the end of the intervention, anthropometric measures and body composition were assessed and the Moynihan Questionnaire (MQ) and the International Physical Activity Questionnaire administered. The weight loss maintenance was evaluated in patients who attended the 6-month follow-up visit. Nutrition knowledge was poor/sufficient in 97 out of 256 obese patients. The MQ Score was associated with the education level but not with age, gender and Body Mass Index. After rehabilitation, there was an increase in nutrition knowledge (mean score change -12±10.5%, P<0.0001) in the whole group of patients as well as in those with poor knowledge, 77% of whom reached a good/high level of knowledge on healthy diet. The improvement in knowledge was greater in patients with a weight loss ≥5% (P<0.05 vs. patients with a lower weight loss). Weight maintenance at follow-up, was associated with a better improvement in the nutritional knowledge during the previous rehabilitation. Weight-management programs should include a strong component of nutrition education to alleviate knowledge inequalities and promote more effective weight loss and control. The MQ may be a useful tool to verify the nutritional education carried out during the rehabilitation of obese subjects.

Roux-en-y gastric bypass improves in short term the clinical-anthropometric parameters and reduces risk for obesity-related cardiometabolic diseases / Bypass gástrico roux-en-y melhora a curto prazo os parâmetros clínico-antropométricos e reduz o risco de doenças cardiometabólicas relacionadas à obesidade

Roux-en-Y gastric bypass surgery (RYGB) is the most applied technique in the treatment of severe obesity worldwide. However, its impact on anthropometric parameters and the risk for cardiometabolic diseases in obese patients is uncertain. To evaluate anthropometric clinical parameters and the evolution of risk factors for obesity-related diseases in individuals of both sexes undergoing RYGB. Sixty-nine adults subjects from both sexes submitted to RYGB surgery treatment were divided into 3 groups: G1(13 months, n=24); G2 (13 and 25 months, n=21), and G3 (25 and 37 months, n=24). Sociodemographic and anthropometric information before and after surgery were collected. The abdominal perimeter was used in the classification of cardiometabolic risk and the BMI was used for the risk of obesity-related diseases. Hypotheses were tested by Student's t-test and ANOVA, and the significance level adopted was 5%. The average age was 36.0±10.0 years, with 69.6% being male and 30.4% female. Anthropometric parameters (weight, BMI, and abdominal circumference) were higher among women, except for weight loss and percentage of weight loss. There was a difference in weight loss between the sexes in the moments before and after RYGB. There was a decrease in the risk of disease due to obesity and cardiovascular diseases after RYGB. Weight loss and %WL were greater years by year in the short term of 3 years after surgery. RYGB proved to be an effective strategy for both sexes in combating obesity, providing in the short term a significant improvement in clinical-anthropometric parameters and reduction of risk factors for obesity-related cardiometabolic diseases.

Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis.

BackgroundEpidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses.Methods and findingsWe selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null.ConclusionsIn this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

Impact of Obesity-Related Inflammation on Cardiac Metabolism and Function.

This review focuses on the role of adipose tissue in obese individuals in the development of metabolic diseases, and their consequences for metabolic and functional derangements in the heart. The general idea is that the expansion of adipocytes during the development of obesity gives rise to unhealthy adipose tissue, characterized by low-grade inflammation and the release of proinflammatory adipokines and fatty acids (FAs). This condition, in turn, causes systemic inflammation and elevated FA concentrations in the circulation, which links obesity to several pathologies, including impaired insulin signaling in cardiac muscle and a subsequent shift in myocardial substrate oxidation in favor of FAs and reduced cardiac efficiency. This review also argues that efforts to prevent obesity-related cardiometabolic disease should focus on anti-obesogenic strategies to restore normal adipose tissue metabolism.

Nutrition knowledge is associated with greater weight loss in obese patients following a multidisciplinary rehabilitaiton program

A major objective of the metabolic-nutritional-psychological multidisciplinary rehabilitation of obese subjects is providing a nutritional education aimed at achieving a weight loss and the improvement of obesity-related cardio-metabolic diseases. The impact of nutrition knowledge in healthy eating patterns and weight loss is still debated. The aim of this study was to identify whether the increase in nutrition knowledge is associated with weight loss. Two hundred fifty-six obese patients (80% women, mean age 57.5±12.4 years) were consecutively recruited among those referred for a three-month metabolic-nutritional-psychologic rehabilitation program. Education level and time of the onset of obesity were collected. Before and at the end of the intervention, anthropometric measures and body composition were assessed and the Moynihan Questionnaire (MQ) and the International Physical Activity Questionnaire administered. The weight loss maintenance was evaluated in patients who attended the 6-month follow-up visit. Nutrition knowledge was poor/sufficient in 97 out of 256 obese patients. The MQ Score was associated with the education level but not with age, gender and Body Mass Index. After rehabilitation, there was an increase in nutrition knowledge (mean score change -12±10.5%, P<0.0001) in the whole group of patients as well as in those with poor knowledge, 77% of whom reached a good/high level of knowledge on healthy diet. The improvement in knowledge was greater in patients with a weight loss ≥5% (P<0.05 vs. patients with a lower weight loss). Weight maintenance at follow-up, was associated with a better improvement in the nutritional knowledge during the previous rehabilitation. Weight-management programs should include a strong component of nutrition education to alleviate knowledge inequalities and promote more effective weight loss and control. The MQ may be a useful tool to verify the nutritional education carried out during the rehabilitation of obese subjects.

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity

SummaryThe melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing β-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.

Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk.

Components of the adipose tissue (AT) extracellular matrix (ECM) are recently discovered contributors to obesity-related cardiometabolic disease. We identified increased adipocyte expression of ECM-related clusterin (apolipoprotein J) in obese versus lean women by microarray. Our objective was to determine 1) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and 2) how clusterin may contribute to increased risk. We validated increased clusterin expression in adipocytes from a separate group of 18 lean and 54 obese individuals. The relationship of clusterin gene expression and plasma clusterin with IR, cardiovascular biomarkers, and risk of cardiovascular disease (CVD) was then determined. Further investigations in human cultured cells and in aged LDLR-/- mice prone to development of obesity-associated complications were performed. SAd clusterin correlated with IR, multiple CVD biomarkers, and CVD risk, independent of traditional risk factors. Circulating human clusterin exhibited similar associations. In human adipocytes, palmitate enhanced clusterin secretion, and in human hepatocytes, clusterin attenuated insulin signaling and APOA1 expression and stimulated hepatic gluconeogenesis. LRP2 (megalin), a clusterin receptor, highly expressed in liver, mediated these effects, which were inhibited by LRP2 siRNA. In response to Western diet feeding, an increase in adipocyte clusterin expression was associated with a progressive increase in liver fat, steatohepatitis, and fibrosis in aged LDLR-/- mice. Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.