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Highest Obesity Category Associated With Largest Decrease in N-Terminal Pro-B-Type Natriuretic Peptide in Patients Hospitalized With Heart Failure With Preserved Ejection Fraction.
Vaishnav J, Chasler JE, Lee YJ, Ndumele CE, Hu JR, Schulman SP, Russell SD, Sharma K
(2020) J Am Heart Assoc 9: e015738
MeSH Terms: Aged, Heart Failure, Hospitalization, Humans, Male, Middle Aged, Natriuretic Peptide, Brain, Obesity, Peptide Fragments, Stroke Volume
Show Abstract · Added August 13, 2020
Background Heart failure with preserved ejection fraction (HFpEF) constitutes half of hospitalized heart failure cases and is commonly associated with obesity. The role of natriuretic peptide levels in hospitalized obese patients with HFpEF, however, is not well defined. We sought to evaluate change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels by obesity category and related clinical outcomes in patients with HFpEF hospitalized for acute heart failure. Methods and Results A total of 89 patients with HFpEF hospitalized with acute decompensated heart failure were stratified into 3 obesity categories: nonobese (body mass index [BMI] <30.0 kg/m, 19%), obese (BMI 30.0-39.9 kg/m, 29%), and severely obese (BMI ≥40.0 kg/m, 52%), and compared for percent change in NT-proBNP during hospitalization and clinical outcomes. Clinical characteristics were compared between patients with normal NT-proBNP (≤125 pg/mL) and elevated NT-proBNP. Admission NT-proBNP was inversely related to BMI category (nonobese, 2607 pg/mL [interquartile range, IQR: 2112-5703]; obese, 1725 pg/mL [IQR: 889-3900]; and severely obese, 770.5 pg/mL [IQR: 128-1268]; <0.01). Severely obese patients had the largest percent change in NT-proBNP with diuresis (-64.8% [95% CI, -85.4 to -38.9] versus obese -40.4% [95% CI, -74.3 to -12.0] versus nonobese -46.9% [95% CI, -57.8 to -37.4]; =0.03). Nonobese and obese patients had significantly worse 1-year survival compared with severely obese patients (63% versus 76% versus 95%, respectively; <0.01). Patients with normal NT-proBNP (13%) were younger, with higher BMI, less atrial fibrillation, and less structural heart disease than those with elevated NT-proBNP. Conclusions In hospitalized patients with HFpEF, NT-proBNP was inversely related to BMI with the largest decrease in NT-proBNP seen in the highest obesity category. These findings have implications for the role of NT-proBNP in the diagnosis and assessment of treatment response in obese patients with HFpEF.
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10 MeSH Terms
Association of smoking with abdominal adipose deposition and muscle composition in Coronary Artery Risk Development in Young Adults (CARDIA) participants at mid-life: A population-based cohort study.
Terry JG, Hartley KG, Steffen LM, Nair S, Alman AC, Wellons MF, Jacobs DR, Tindle HA, Carr JJ
(2020) PLoS Med 17: e1003223
MeSH Terms: Abdominal Fat, Adiposity, Adult, Blood Pressure, Body Mass Index, Cohort Studies, Female, Humans, Intra-Abdominal Fat, Life Style, Male, Middle Aged, Muscle, Skeletal, Obesity, Abdominal, Risk Factors, Smoking, Tomography, X-Ray Computed
Show Abstract · Added July 28, 2020
BACKGROUND - Smokers have lower risk of obesity, which some consider a "beneficial" side effect of smoking. However, some studies suggest that smoking is simultaneously associated with higher central adiposity and, more specifically, ectopic adipose deposition. Little is known about the association of smoking with intermuscular adipose tissue (IMAT), an ectopic adipose depot associated with cardiovascular disease (CVD) risk and a key determinant of muscle quality and function. We tested the hypothesis that smokers have higher abdominal IMAT and lower lean muscle quality than never smokers.
METHODS AND FINDINGS - We measured abdominal muscle total, lean, and adipose volumes (in cubic centimeters) and attenuation (in Hounsfield units [HU]) along with subcutaneous (SAT) and visceral adipose tissue (VAT) volumes using computed tomography (CT) in 3,020 middle-aged Coronary Artery Risk Development in Young Adults (CARDIA) participants (age 42-58, 56.3% women, 52.6% white race) at the year 25 (Y25) visit. The longitudinal CARDIA study was initiated in 1985 with the recruitment of young adult participants (aged 18-30 years) equally balanced by female and male sex and black and white race at 4 field centers located in Birmingham, AL, Chicago, IL, Minneapolis, MN, and Oakland, CA. Multivariable linear models included potential confounders such as physical activity and dietary habits along with traditional CVD risk factors. Current smokers had lower BMI than never smokers. Nevertheless, in the fully adjusted multivariable model with potential confounders, including BMI and CVD risk factors, adjusted mean (95% CI) IMAT volume was 2.66 (2.55-2.76) cm3 in current smokers (n = 524), 2.36 (2.29-2.43) cm3 in former smokers (n = 944), and 2.23 (2.18-2.29) cm3 in never smokers (n = 1,552) (p = 0.007 for comparison of former versus never smoker, and p < 0.001 for comparison of current smoker versus never and former smoker). Moreover, compared to participants who never smoked throughout life (41.6 [41.3-41.9] HU), current smokers (40.4 [39.9-40.9] HU) and former smokers (40.8 [40.5-41.2] HU) had lower lean muscle attenuation suggesting lower muscle quality in the fully adjusted model (p < 0.001 for comparison of never smokers with either of the other two strata). Among participants who had ever smoked, pack-years of smoking exposure were directly associated with IMAT volume (β [95% CI]: 0.017 [0.010-0.025]) (p < 0.001). Despite having less SAT, current smokers also had higher VAT/SAT ratio than never smokers. These findings must be viewed with caution as residual confounding and/or reverse causation may contribute to these associations.
CONCLUSIONS - We found that, compared to those who never smoked, current and former smokers had abdominal muscle composition that was higher in adipose tissue volume, a finding consistent with higher CVD risk and age-related physical deconditioning. These findings challenge the belief that smoking-associated weight loss or maintenance confers a health benefit.
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17 MeSH Terms
The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.
Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Brüning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschöp MH, Müller TD
(2020) Nat Commun 11: 2306
MeSH Terms: Activating Transcription Factor 2, Adipogenesis, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Nucleus, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Positron Emission Tomography Computed Tomography, Protein Binding, Sequestosome-1 Protein, Uncoupling Protein 1, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 22, 2020
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62 mice, global p62 and Ucp1-Cre p62 mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.
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18 MeSH Terms
Gut Epithelial Metabolism as a Key Driver of Intestinal Dysbiosis Associated with Noncommunicable Diseases.
Shelton CD, Byndloss MX
(2020) Infect Immun 88:
MeSH Terms: Animals, Colon, Disease Susceptibility, Dysbiosis, Energy Metabolism, Enterobacteriaceae, Gastrointestinal Microbiome, Humans, Intestinal Mucosa, Noncommunicable Diseases, Obesity, Oxidation-Reduction, Risk Assessment, Risk Factors
Show Abstract · Added March 30, 2020
In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent β-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic , regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.
Copyright © 2020 American Society for Microbiology.
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14 MeSH Terms
Maternal microbial molecules affect offspring health.
Ferguson J
(2020) Science 367: 978-979
MeSH Terms: Animals, Child, Child Health, Diet, High-Fat, Female, Gastrointestinal Microbiome, Mice, Obesity, Phenotype, Pregnancy
Added March 3, 2020
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10 MeSH Terms
Transendothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice.
Williams IM, McClatchey PM, Bracy DP, Bonner JS, Valenzuela FA, Wasserman DH
(2020) Obesity (Silver Spring) 28: 303-314
MeSH Terms: Animals, Capillaries, Endothelium, Vascular, Insulin, Male, Mice, Mice, Obese, Muscle, Skeletal, Obesity
Show Abstract · Added March 30, 2020
OBJECTIVE - The continuous endothelium of skeletal muscle (SkM) capillaries regulates insulin's access to skeletal myocytes. Whether impaired transendothelial insulin transport (EIT) contributes to SkM insulin resistance (IR), however, is unknown.
METHODS - Male and female C57/Bl6 mice were fed either chow or a high-fat diet for 16 weeks. Intravital microscopy was used to measure EIT in SkM capillaries, electron microscopy to assess endothelial ultrastructure, and glucose tracers to measure indices of glucose metabolism.
RESULTS - Diet-induced obesity (DIO) male mice were found to have a ~15% reduction in EIT compared with lean mice. Impaired EIT was associated with a 45% reduction in endothelial vesicles. Despite impaired EIT, hyperinsulinemia sustained delivery of insulin to the interstitial space in DIO male mice. Even with sustained interstitial insulin delivery, DIO male mice still showed SkM IR indicating severe myocellular IR in this model. Interestingly, there was no difference in EIT, endothelial ultrastructure, or SkM insulin sensitivity between lean female mice and female mice fed a high-fat diet.
CONCLUSIONS - These results suggest that, in male mice, obesity results in ultrastructural alterations to the capillary endothelium that delay EIT. Nonetheless, the myocyte appears to exceed the endothelium as a contributor to SkM IR in DIO male mice.
© 2020 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).
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9 MeSH Terms
Associations of Thigh and Abdominal Adipose Tissue Radiodensity with Glucose and Insulin in Nondiabetic African-Ancestry Men.
Tilves C, Zmuda JM, Kuipers AL, Carr JJ, Terry JG, Wheeler V, Peddada SD, Nair S, Miljkovic I
(2020) Obesity (Silver Spring) 28: 404-411
MeSH Terms: Adipose Tissue, Adiposity, Adult, African Continental Ancestry Group, Aged, Blood Glucose, Body Composition, Cross-Sectional Studies, Glucose, Humans, Insulin, Intra-Abdominal Fat, Male, Middle Aged, Obesity, Overweight, Subcutaneous Fat, Thigh, West Indies
Show Abstract · Added January 10, 2020
OBJECTIVE - Decreased radiodensity of adipose tissue (AT) located in the visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) abdominal depots is associated with hyperglycemia, hyperinsulinemia, and insulin resistance independent of AT volumes. These associations were sought in African-ancestry men, who have higher risk for type 2 diabetes and have been underrepresented in previous studies.
METHODS - This cross-sectional analysis included 505 nondiabetic men of African-Caribbean ancestry (median age: 61 years; median BMI: 26.8 kg/m ) from the Tobago Health Study. AT volumes and radiodensities were assessed using computed tomography, including abdominal (VAT and SAT) and thigh (IMAT) depots. Associations between AT radiodensities were assessed with fasting serum glucose and insulin and with insulin resistance (updated homeostatic model assessment of insulin resistance, HOMA2-IR).
RESULTS - Higher radiodensity in any AT depot was associated with lower log-insulin and log-HOMA2-IR (β range: -0.16 to -0.18 for each; all P < 0.0001). No AT radiodensity was associated with glucose. Thigh IMAT radiodensity associations were independent of, and similar in magnitude to, VAT radiodensities. Model fit statistics suggested that AT radiodensities were a better predictor for insulin and insulin resistance compared with AT volumes in individuals with overweight and obesity.
CONCLUSIONS - AT radiodensities at multiple depots are significantly associated with insulin and insulin resistance in African-ancestry men.
© 2019 The Obesity Society.
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19 MeSH Terms
The effects of intensive dietary weight loss and exercise on gait in overweight and obese adults with knee osteoarthritis. The Intensive Diet and Exercise for Arthritis (IDEA) trial.
Messier SP, Beavers DP, Mihalko SL, Miller GD, Lyles MF, Hunter DJ, Carr JJ, Eckstein F, Guermazi A, Loeser RF, DeVita P
(2020) J Biomech 98: 109477
MeSH Terms: Aged, Exercise Therapy, Female, Gait, Humans, Knee Joint, Male, Middle Aged, Obesity, Osteoarthritis, Knee, Quality of Life, Treatment Outcome, Weight Loss
Show Abstract · Added January 10, 2020
The Intensive Diet and Exercise for Arthritis (IDEA) trial was an 18-month randomized controlled trial that enrolled 454 overweight and obese older adults with symptomatic and radiographic knee osteoarthritis (OA). Participants were randomized to either exercise (E), intensive diet-induced weight loss (D), or intensive diet-induced weight loss plus exercise (D + E) interventions. We previously reported that the clinical benefits of D + E were significantly greater than with either intervention alone (e.g., greater pain reduction, and better function, mobility, and health-related quality of life). We now test the hypothesis that D + E has greater overall benefit on gait mechanics compared to either intervention alone. Knee joint loading was analyzed using inverse dynamics and musculoskeletal modeling. Analysis of covariance determined the interventions' effects on gait. The D + E group walked significantly faster at 18-month follow-up (1.35 m s) than E (1.29 m s, p = 0.0004) and D (1.31 m s, p = 0.0007). Tibiofemoral compressive impulse was significantly lower (p = 0.0007) in D (1069 N s) and D + E (1054 N s) compared to E (1130 N s). D had significantly lower peak hip external rotation moment (p = 0.01), hip abduction moment (p = 0.0003), and peak hip power production (p = 0.016) compared with E. Peak ankle plantar flexion moment was significantly less (p < 0.0001) in the two diet groups compared with E. There also was a significant dose-response to weight loss; participants that lost >10% of baseline body weight had significantly (p = 0.0001) lower resultant knee forces and lower muscle (quadriceps, hamstring, and gastrocnemius) forces than participants that had less weight loss. Compared to E, D produces significant load reductions at the hip, knee, and ankle; combining D with E attenuates these reductions, but most remain significantly better than with E alone.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Roux-en-Y gastric bypass surgery improves hepatic glucose metabolism and reduces plasma kisspeptin levels in morbidly obese patients with type 2 diabetes.
Flynn CR, Albaugh VL, Tamboli RA, Gregory JM, Bosompem A, Sidani RM, Winnick JJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G370-G374
MeSH Terms: Adolescent, Adult, Anastomosis, Roux-en-Y, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucagon, Glucose, Humans, Insulin, Kisspeptins, Liver, Male, Middle Aged, Obesity, Morbid, Treatment Outcome, Young Adult
Show Abstract · Added November 12, 2019
Roux-en-Y gastric bypass surgery (RYGB) is known to improve whole-body glucose metabolism in patients with type 2 diabetes (T2D), although the mechanisms are not entirely clear and are likely multifactorial. The aim of this study was to assess fasting hepatic glucose metabolism and other markers of metabolic activity before and after RYGB in patients with and without T2D. Methods: Metabolic characteristics of patients who are obese with T2D were compared with those without the disease (non-T2D) before and 1 and 6 mo after RYGB. Fasting plasma insulin and the insulin:glucagon ratio were markedly reduced as early as 1 mo after RYGB in both patients with T2D and without T2D. Despite this reduction, endogenous glucose production and fasting plasma glucose levels were lower in both groups after RYGB, with the reductions being much larger in T2D. Plasma kisspeptin, an inhibitor of insulin secretion, was reduced only in T2D after surgery. Improved hepatic glucose metabolism and lower plasma kisspeptin in T2D after RYGB may link improved hepatic function with enhanced insulin responsiveness after surgery. Our manuscript is the first, to the best of our knowledge, to present data showing that Roux-en-Y gastric bypass surgery (RYGB) lowers fasting kisspeptin levels in patients who are obese with type 2 diabetes. This lowering of kisspeptin is important because it could link improvements in liver glucose metabolism after RYGB with increased insulin responsiveness also seen after surgery.
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17 MeSH Terms
CD8 T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease.
Breuer DA, Pacheco MC, Washington MK, Montgomery SA, Hasty AH, Kennedy AJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G211-G224
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Hepatic Stellate Cells, Hepatitis, Humans, Hyperlipidemias, Interleukin-10, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease, Obesity, Receptors, LDL
Show Abstract · Added March 3, 2020
Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8 T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8 T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8 T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8 T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8 T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8 T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8 T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8 T cells may be a novel approach for treatment of obesity-associated NASH. Our study demonstrates that CD8 T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8 T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8 T cells are key players in obesity-associated NASH.
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15 MeSH Terms