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Aim: To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double-blind placebo-controlled trial in abdominally obese individuals. Materials and methods: Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m 2) were randomized to an 8-week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, β-cell function, insulin-mediated microvascular recruitment, skin microvascular function, flow-mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra-performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one-way ANCOVA. Results: In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule-1 (sVCAM-1) in the low and high PM dose group and of soluble intercellular adhesion molecule-1 (sICAM-1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. Conclusions: This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM-1 and sICAM-1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis.

BACKGROUND: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. PATIENTS AND METHODS: This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Programmed death-ligand 1 (PD-L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). RESULTS: Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02-1.08] p = 0.003), and weight loss 2% early weight loss remained a predictor of OS, independent of PD-L1 expression (HR 2.09 [1.11-3.92] p = 0.02, HR 2.18 [1.13-4.21] p = 0.02). CONCLUSION: We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD-L1 expression. ispartof: CANCER MEDICINE vol:12 issue:7 pages:7699-7712 ispartof: location:United States status: published

OBJECTIVE: Complement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight-loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction.METHODS: The study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8-week dietary weight-loss intervention.RESULTS: The intervention significantly reduced C3 (-0.15 g/L [95% CI: -0.23 to -0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight-loss-induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule.CONCLUSIONS: Diet-induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet-induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic cardiac condition whose prevalence continues to rise, with high social and economic burden, but with no specific approved treatment. Patients diagnosed with HFpEF have a high prevalence of comorbidities and exhibit a high misdiagnosis rate. True HFpEF is likely to have multiple pathophysiological causes - with these causes being clinically ill-defined due to limitations of current measurement techniques. Myocyte, interstitium, microvascular, and metabolic abnormalities have been regarded as key components of the pathophysiology and potential therapeutic targets. Cardiac magnetic resonance (CMR) has the capability to look deeper with a number of tissue characterization techniques which are closer to the underlying specific abnormalities and which could be linked to personalized medicine for HFpEF. This review aims to discuss the potential role of CMR to better define HFpEF phenotypes and to infer measurable therapeutic targets.

Inflammasomes are multi‐protein complexes that regulate the cleavage of cysteine protease caspase‐1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod‐like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.

Cardiometabolic risk factors (CMRs) are associated with accelerated brain aging and increased risk for sex-dimorphic illnesses such as Alzheimer’s Disease (AD). Yet, it is unknown how CMRs interact with sex and apolipoprotein E-ε4 (APOE4), a known genetic risk factor for AD, to influence brain age across different life stages. Using age prediction based on multi-shell diffusion-weighted imaging data in 21,308 UK Biobank participants, we investigated whether associations between white matter Brain Age Gap (BAG) and body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage (BF%), and APOE4 status varied i) between males and females, ii) according to age at menopause in females, and iii) across different age groups in males and females. We report sex differences in associations between BAG and all three CMRs, with stronger positive associations among males com- pared to females. Higher BAG (older brain age relative to chronological age) was associated with greater BMI, WHR, and BF% in males, whereas in females, higher BAG was associated with greater WHR, but not BMI and BF%. These divergent associations were most prominent within the oldest group of females (66-81yrs), where higher BF% was linked to lower BAG (younger brain age relative to chronological age). Earlier menopause transition was associated with higher BAG, but no interactions were found with CMRs. APOE4 status was not significantly associated with BAG, and no significant interactions with CMRs were found. In conclusion, the findings point to sex- and age-specific associations between body fat composition and brain age. Incorporating sex as a factor of interest in studies addressing cardiometabolic risk may promote sex-specific precision medicine, consequently improving health care for both males and females.

Background Macrophages are associated with metabolic complications to obesity including fatty liver disease and impaired hepatic and muscle insulin sensitivity (IS). Bariatric surgery induces weight loss and improves IS. We investigated associations between the macrophage activation marker soluble (s)CD163, alanine‐aminotransferase (ALT), and IS before and after Roux‐en‐Y Gastric Bypass (RYGB). Methods We analyzed sCD163 from 10 type 2 diabetes (T2D) and 10 obese patients with normal glucose tolerance (NGT) undergoing RYGB for associations with hepatic, adipose tissue, and muscle IS and ALT after 1‐week, 3, and 12 months postoperatively. IS was evaluated by hyperinsulinemic‐euglycemic clamp in combination with glucose tracer technique. Results Preoperative sCD163 correlated with ALT (r = 0.58, p = 0.007) and tended to associate inversely with hepatic (r = −0.39, p = 0.1) and adipose tissue (r = −0.39, p = 0.09), but not muscle IS. Following RYGB, sCD163 decreased significantly in all patients. The decrease in sCD163 during the first 3 months correlated inversely with the improvement of hepatic IS (r = −0.65, p = 0.01) and tended to be associated with changes in muscle IS (r = −0.45, p = 0.09). After 3 months sCD163 remained associated with ALT (r = 0.75, p, Macrophage activation assessed by soluble CD163 is associated with hepatic insulin resistance in patients with severe obesity and its improvement after Roux‐en‐Y gastric bypass and weight loss.

The growing number of patients with obstructive sleep apnea is challenging healthcare systems worldwide. Obstructive sleep apnea is characterized by chronic intermittent hypoxaemia, episodes of apnea and hypopnea, and fragmented sleep. Cardiovascular and metabolic diseases are common in obstructive sleep apnea, also in lean patients. Further, comorbidity burden is not unambiguously linked to the severity of obstructive sleep apnea. There is a growing body of evidence revealing diverse functions beyond the conventional tasks of different organs such as carotid body and gut microbiota. Chronic intermittent hypoxia and sleep loss due to sleep fragmentation are associated with insulin resistance. Indeed, carotid body is a multi-sensor organ not sensoring only hypoxia and hypercapnia but also acting as a metabolic sensor. The emerging evidence shows that obstructive sleep apnea and particularly chronic intermittent hypoxia is associated with non-alcoholic fatty liver disease. Gut dysbiosis seems to be an important factor in the pathophysiology of obstructive sleep apnea and its consequences. The impact of sleep fragmentation and intermittent hypoxia on the development of metabolic syndrome may be mediated via altered gut microbiota. Circadian misalignment seems to have an impact on the cardiometabolic risk in obstructive sleep apnea. Dysfunction of cerebral metabolism is also related to hypoxia and sleep fragmentation. Therefore, obstructive sleep apnea may alter cerebral metabolism and predispose to neurocognitive impairment. Moreover, recent data show that obstructive sleep apnea independently predicts impaired lipid levels. This mini-review will provide novel insights into the mechanisms of metabolic dysfunction in obstructive sleep apnea combining recent evidence from basic, translational and clinical research, and discuss the impact of positive airway pressure treatment on metabolic disorders.

Summary Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low‐grade inflammation via altered secretion of adipokines and cytokines. Furthermore, an increased flux of fatty acids from the adipose tissue may contribute to increased fat storage in the liver and in skeletal muscle, resulting in an altered secretion of hepatokines, mitochondrial dysfunction, and impaired insulin signalling in skeletal muscle. Recent studies suggest that obesity and lipid derangements in adipose tissue can also lead to the development of muscle atrophy, which would make insulin resistance and muscle atrophy two sides of the same coin. Unfortunately, the exact relationship between lipid accumulation, type 2 diabetes, and muscle atrophy remains largely unexplored. The aim of this review is to discuss the relationship between type 2 diabetes and muscle loss and to discuss some of the joint pathways through which lipid accumulation in organs may affect peripheral insulin sensitivity and muscle mass.

The circadian clock and metabolism are tightly intertwined. Hence, the specific timing of interventions that target metabolic changes may affect their efficacy. Here we retrospectively compared the metabolic health effects of morning versus afternoon exercise training in metabolically compromised subjects enrolled in a 12‐week exercise training program. Thirty‐two adult males (58 ± 7 yrs) at risk for or diagnosed with type 2 diabetes performed 12 weeks of supervised exercise training either in the morning (8.00–10.00 a.m., N = 12) or in the afternoon (3.00–6.00 p.m., N = 20). Compared to participants who trained in the morning, participants who trained in the afternoon experienced superior beneficial effects of exercise training on peripheral insulin sensitivity (+5.2 ± 6.4 vs. −0.5 ± 5.4 μmol/min/kgFFM, p = .03), insulin‐mediated suppression of adipose tissue lipolysis (−4.5 ± 13.7% vs. +5.9 ± 11%, p = .04), fasting plasma glucose levels (−0.3 ± 1.0 vs. +0.5 ± 0.8 mmol/l, p = .02), exercise performance (+0.40 ± 0.2 vs. +0.2 ± 0.1 W/kg, p = .05) and fat mass (−1.2 ± 1.3 vs. −0.2 ± 1.0 kg, p = .03). In addition, exercise training in the afternoon also tended to elicit superior effects on basal hepatic glucose output (p = .057). Our findings suggest that metabolically compromised subjects may reap more pronounced metabolic benefits from exercise training when this training is performed in the afternoon versus morning. ClinicalTrials.gov ID NCT01317576., Afternoon exercise is more optimal than morning to improve insulin sensitivity, body composition, and exercise performance in metabolically compromised individuals.

BACKGROUND: Non-alcoholic fatty liver (NAFL) disease (NAFLD) is the most common chronic liver disease in the world. While most subjects have 'inert' NAFL, a subset will progress to non-alcoholic steatohepatitis (NASH) and its life-threatening complications. A substantial body of literature supports that a low muscle mass, low strength, and/or muscle fatty infiltration (myosteatosis) are associated with NAFLD severity. Here, we evaluated the muscle compartment in NASH preclinical models to decipher the kinetics of muscle alterations in relation with liver disease progression. METHODS: We developed and validated a micro-computed tomography-based methodology to prospectively study skeletal muscle mass and density in muscle and liver (i.e. reflecting fatty infiltration) in a high-throughput and non-invasive manner in three preclinical NAFLD/NASH rodent models: fat aussie (FOZ) mice fed a high-fat diet (FOZ HF), wild-type (WT) mice fed a high-fat high-fructose diet (WT HFF), and WT mice fed a high-fat diet (WT HF). We compared them with WT mice fed a normal diet (WT ND) used as controls. RESULTS: -FOZ HF with fibrosing NASH had sarcopenia characterized by a reduced muscle strength when compared with WT HF and WT HFF with early NASH and WT ND controls (165.2 ± 5.2 g vs. 237.4 ± 11.7 g, 256 ± 5.7 g, and 242.9 ± 9.3 g, respectively, P 60; 0.001). Muscle mass or strength was not lower in FOZ HF, WT HF, and WT HFF with early NASH than in controls. Myosteatosis was present in FOZ HF with fibrosing NASH, but also in FOZ HF, WT HF, and WT HFF with early NASH (muscle density = 0.50 ± 0.02, 0.62 ± 0.02, 0.70 ± 0.05, and 0.75 ± 0.03, respectively, with P 60; 0.001 when compared with respective controls). Myosteatosis degree was strongly correlated with NAFLD activity score (r = -0.87, n = 67, P 60; 0.001). In multivariate analysis, the association between myosteatosis and NASH was independent from homeostatic model assessment of insulin resistance and visceral fat area (P 60; 0.05). Myosteatosis degree powerfully discriminated NASH from benign NAFL and normal liver (area under the receiver operating characteristic = 0.96, n = 67, P 60; 0.001). CONCLUSIONS: Taken together, our data support that there is no sarcopenia in obese mice with early NASH. In contrast, the severity of myosteatosis reflects on hepatocellular damage and inflammation during early NASH development. This observation prompts us to exploit myosteatosis as a novel non-invasive marker of NASH. ispartof: JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE vol:12 issue:1 pages:144-158 ispartof: location:Germany status: published

AIMS: Adipose tissue and inflammation may play a role in the pathophysiology of patients with heart failure (HF) with mildly reduced or preserved ejection fraction. We therefore investigated epicardial fat in patients with HF with preserved (HFpEF) and mid-range ejection fraction (HFmrEF), and related this to co-morbidities, plasma biomarkers and cardiac structure.METHODS AND RESULTS: A total of 64 HF patients with left ventricular ejection fraction >40% and 20 controls underwent routine cardiac magnetic resonance examination. Epicardial fat volume was quantified on short-axis cine stacks covering the entire epicardium and was related to clinical correlates, biomarkers associated with inflammation and myocardial injury, and cardiac function and contractility on cardiac magnetic resonance. HF patients and controls were of comparable age, sex and body mass index. Total epicardial fat volume was significantly higher in HF patients compared to controls (107 mL/m2 vs. 77 mL/m2 , P CONCLUSION: Heart failure patients had more epicardial fat compared to controls, despite similar body mass index. Epicardial fat volume was associated with the presence of atrial fibrillation and type 2 diabetes mellitus and with biomarkers related to myocardial injury. The clinical implications of these findings are unclear, but warrant further investigation.

Background: Vitamin D may modulate adipogenesis. However, limited studies have investigated the effect of maternal vitamin D during pregnancy on offspring adiposity or cardiometabolic parameters with inconclusive results. Objectives: The objective of this study is to examine the association of maternal 25(OH)-vitamin D [25(OH)D] status with offspring obesity and cardiometabolic characteristics in 532 mother-child pairs from the prospective pregnancy cohort Rhea in Crete, Greece. Methods: Maternal 25(OH)D concentrations were measured at the first prenatal visit (mean: 14 weeks, SD: 4). Child outcomes included body mass index standard deviation score, waist circumference, skin-fold thickness, blood pressure and serum lipids at ages 4 and 6 years. Body fat percentage was also measured at 6 years. Body mass index growth trajectories from birth to 6 years were estimated by mixed effects models with fractional polynomials of age. Adjusted associations were obtained via multivariable linear regression analyses. Results: About two-thirds of participating mothers had 25(OH)D concentrations = 37.7 nmol L-1), on covariate-adjusted analyses. The observed relationships persisted at age 6 years. We found no association between maternal 25(OH)D concentrations and offspring blood pressure or serum lipids at both time points. Conclusions: Exposure to very low 25(OH)D concentrations in utero may increase childhood adiposity indices. Given that vitamin D is a modifiable risk factor, our findings may have important public health implications.

Background Obese subjects have lower natriuretic peptide levels, but males and females have different anthropometric characteristics and fat distribution. Whether obesity-associated lowering of natriuretic peptides differs among males and females is unknown. Therefore, we investigated sex-specific associations of obesity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels among adults in the general population. Methods and result Using 8260 participants (50.1% females) from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, we evaluated the relationship of NT-proBNP levels with obesity-associated parameters, i.e. waist circumference (WC), body mass index (BMI) and body weight in the overall population, and in males and females separately. NT-proBNP levels were higher in females (median, interquartile range: 50.5, 28.2-87.0 ng/L) than in males (24.3, 10.1-54.6 ng/L; P < 0.001). In the overall population, NT-proBNP levels were significantly lower in heavier individuals and displayed a 'U-shaped' relationship with increasing WC, but were not associated with BMI. After sex stratification, there was no significant association between NT-proBNP concentrations and anthropometric measures in females. However, in males increasing WC and BMI were associated with higher NT-proBNP levels (P < 0.05) while increasing body weight was associated with slightly lower NT-proBNP levels (P < 0.05). Age strongly confounded the association of NT-proBNP levels with obesity, and age-associated increases in NT-proBNP were significantly higher in males than in females (P < 0.001). In multivariable adjusted analyses, the inverse association of obesity and NT-proBNP levels was also significantly modified by sex: NT-proBNP levels were lower with increasing WC, BMI and body weight among females compared with males (P-interaction

Prior investigation has suggested a positive association between increased colonic propionate production and circulating odd-chain fatty acids [(OCFAs; pentadecanoic acid (C15:0), heptadecanoic acid (C17:0)]. As the major source of propionate in humans is the microbial fermentation of dietary fiber, OCFAs have been proposed as candidate biomarkers of dietary fiber. The objective of this study is to critically assess the plausibility, robustness, reliability, dose-response, time-response aspects of OCFAs as potential biomarkers of fermentable fibers in two independent studies using a validated analytical method. OCFAs were first assessed in a fiber supplementation study, where 21 participants received 10g dietary fiber supplementation for 7 days with blood samples collected on the final day at a 420 minute study visit. OCFAs were then assessed in a highly controlled inpatient setting, which 19 participants consumed a high fiber (45.1g/day) and a low fiber diet (13.6g/day) for 4 days. Collectively in both studies, dietary intakes of fiber as fiber supplementations or having consumed a high fiber diet did not increase circulating levels of OCFAs. The dose and temporal relations were not observed. Current study has generated new insight on the utility of OCFAs as fiber biomarkers and highlighted the importance of critical assessment of candidate dietary biomarkers before application.

The infrapatellar fat pad (IFP) is an extrasynovial, intracapsular, adipose body occupying the space in the knee joint between the inferior border of the patella, the femoral condyles, tibial plateau and patellar tendon. Little is known about the anatomy and normal function of the IFP, but it has been suggested to play a role in the aetiology of Anterior knee pain syndrome, including that associated with osteoarthritis. Forty-three knees from 11 male and 15 female embalmed cadavers (mean age 84 years; range 55-97 years) were investigated. The cadavers were donated and the study performed in compliance with the provisions of the UK Human Tissue Act (2004). The quadriceps tendon and the medial and lateral patellar retinacula were dissected from the patella, which was then reflected antero-distally. The IFP was carefully excised and details of its morphology and attachments to components of the knee joint were recorded, together with the presence of articular surface pathology on the patella and femoral condyles. The principal novel findings of the current study were that 81% of IFPs were attached to the superior border of the patella by supero-medial extensions and 65% were attached by supero-lateral extensions; the supero-medial extensions were larger than the supero-lateral extensions. The superior extensions of the IFP were always attached anteriorly to the patellar retinacula and in four individuals the extensions formed a full loop around the superior border of the patella. The volume of IFPs with attachments to the superior border of the patella was significantly greater (p = .007) than those without, and the IFP was attached to the medial meniscus in significantly (p = .009) more knees with IFP attachment to the superior border of the patella than those without. All IFPs were attached to the medial anterior horn of the meniscus and the medial Kaplan's ligament. Ninety-seven per cent were attached to the lateral anterior horn of the meniscus and 97% to the lateral Kaplan's ligament. The length of IFP attachment to the lateral meniscus was significantly longer (p = .004) than that to the medial meniscus. Ninety-seven per cent of IFPs were attached to the superior portion of the patellar tendon with the mean tendon attachment being 60%. Ninety-one per cent of IFPs were attached to the inferior border of the patella. Significantly fewer knees with patellar (p = .001) and femoral (p = .002) articular surface osteophytes exhibited superior IFP extensions and these extensions were significantly shorter in knees with patellar (p = .000) and femoral (p = .006) osteophytes, compared with those without. The IFP was attached to the medial meniscus in significantly fewer knees with femoral (p = .050) and patellar (p = .023) osteophytes than those without. All IFPs not attached to the anterior horn of the lateral menisci, medial Kaplan's ligament, superior patella or inferior border of the patella, were in knees with articular surface osteophytes. This relationship between IFP morphology and knee joint pathology suggests a functional role for the IFP that requires further investigation.

Scope Obesity causes DNA damage, which is causally related to several disorders including cancer, infertility, and cognitive dysfunctions. The aim of this study is to investigate whether weight loss improves the integrity of the genetic material. Methods and Results Overweight mice are fed ad libitum either with a Western diet (WD), with a 40% caloric restricted WD, or with a high carbohydrate low protein (HCLP) diet. Caloric restriction and also the HCLP diet lead to ca. 30% weight loss, which is paralleled by decreased DNA damage ("comet" formation) and oxidative damage of purines in inner organs, additionally the activity of nucleotide excision repair increased. The effects are more pronounced in animals that have received the HCLP chow. Results of biochemical analyses indicate that the reduction of DNA damage is associated with a decrease of pro-inflammatory cytokines and lower insulin levels. Conclusion The study indicates that weight loss may prevent obesity-associated adverse health effects due to reduction of overall DNA damage.

The obese insulin-resistant state is often associated with low circulating concentration of vitamin D 25-hydroxyvitamin D3 [25(OH)D3]. Fat sequestration of vitamin D in the expanded obese adipose tissue mass has been pointed out as a plausible explanation for this circulating vitamin D deficiency. However, the putative mechanisms behind this hypovitaminosis D remain to be elucidated. The presence of vitamin D receptor and vitamin D-metabolizing enzymes in insulin-sensitive organs suggests that vitamin D may be involved in glucose and lipid metabolism and may be related to insulin sensitivity. Indeed, mainly in vitro studies support a role of vitamin D in regulating glucose and lipid metabolism in several insulin-sensitive tissues including adipose tissue, skeletal muscle, liver, as well as pancreatic insulin secretion. A potential role of vitamin D in gut barrier function and metabolism has also been suggested. This review summarizes recent knowledge on vitamin D deficiency in the aetiology of obesity-related insulin resistance and discusses potential underlying mechanisms. Finally, the role of vitamin D supplementation on insulin sensitivity and glycaemic control is discussed.

The aggrecanase ADAMTS5 (A Disintegrin and Metalloproteinase with ThromboSpondin type 1 motifs, member 5) and the cleavage of its substrate versican have been implicated in the development of heart valves. Furthermore, ADAMTS5 deficiency was shown to protect against diet-induced obesity, a known risk factor for cardiovascular disease. Therefore, in this study, we investigated the potential role of ADAMTS5 in cardiac function using ADAMTS5-deficient (Adamts5-/- ) mice and their wild-type (Adamts5+/+ ) counterparts exposed to a standard-fat or a high-fat diet (HFD). Eight-weeks-old Adamts5-/- and Adamts5+/+ mice were exposed to each diet for 15 weeks. Cardiac function and electrophysiology were analyzed by transthoracic echocardiogram and electrocardiogram at the end of the study. Cleavage of versican, as detected by the appearance of the DPEEAE neo-epitope on western blotting with protein extracts, was defective in the heart of HFD-treated Adamts5-/- as compared with Adamts5+/+ mice. ADAMTS5 deficiency led to statistically significant increases in diastolic posterior wall thickness (0.94 ± 0.023 vs. 0.82 ± 0.036 mm; P = 0.0056) and left ventricle volume (47 ± 4.5 vs. 31 ± 2.5 μL; P = 0.0043) in comparison to Adamts5+/+ mice, but only in animals on a HFD. Cardiac function parameters such as ejection fraction, fractional shortening, and stroke volume were unaffected by ADAMTS5 deficiency or diet. Electrocardiogram analysis revealed no ADAMTS5-specific changes in either diet group. Thus, in the absence of ADAMTS5, cleavage of versican in the cardiac extracellular matrix is impaired, but cardiac function, even upon exposure to a HFD, is not markedly affected. ispartof: CELL BIOLOGY INTERNATIONAL vol:43 issue:6 pages:593-604 ispartof: location:England status: published

Scope Obesity causes DNA damage, which is causally related to several disorders including cancer, infertility, and cognitive dysfunctions. The aim of this study is to investigate whether weight loss improves the integrity of the genetic material. Methods and Results Overweight mice are fed ad libitum either with a Western diet (WD), with a 40% caloric restricted WD, or with a high carbohydrate low protein (HCLP) diet. Caloric restriction and also the HCLP diet lead to ca. 30% weight loss, which is paralleled by decreased DNA damage ("comet" formation) and oxidative damage of purines in inner organs, additionally the activity of nucleotide excision repair increased. The effects are more pronounced in animals that have received the HCLP chow. Results of biochemical analyses indicate that the reduction of DNA damage is associated with a decrease of pro-inflammatory cytokines and lower insulin levels. Conclusion The study indicates that weight loss may prevent obesity-associated adverse health effects due to reduction of overall DNA damage. Austrian Science FundAustrian Science Fund (FWF) [AP2658721]; European Cooperation in Science and TechnologyEuropean Cooperation in Science and Technology (COST) [CA15132]; Fonds Wetenschappelijk OnderzoekFWO [12L5216N]; Vlaamse Instelling voor Technologisch Onderzoek

ObjectiveThis study examined associations of regional fat depots with all-cause mortality over 11 years of follow-up.MethodsData were from 2,187 men and 2,900 women, aged 66-96 years in the AGES-Reykjavik Study. Abdominal visceral fat and subcutaneous fat and thigh intermuscular fat and subcutaneous fat were measured by CT.ResultsIn men, every standard deviation (SD) increment in thigh intermuscular fat was related to a significantly greater mortality risk (HR: 1.17, 95% CI: 1.08-1.26) after adjustment for age, education, smoking, physical activity, alcohol, BMI, type 2 diabetes, and coronary heart disease. In women, visceral fat (per SD increment) significantly increased mortality risk (HR: 1.13, 95% CI: 1.03-1.25) while abdominal subcutaneous fat (per SD increment) was associated with a lower mortality risk (HR: 0.70, 95% CI: 0.61-0.80). Significant interactions with BMI were found in women, indicating that visceral fat was a strong predictor of mortality in obese women while abdominal and thigh subcutaneous fat were associated with a lower mortality risk in normal-weight and overweight women.ConclusionsFat distribution is associated with mortality over 11 years of follow-up independent of overall fatness. The divergent mortality risks for visceral fat and subcutaneous fat in women suggest complex relationships between overall fatness and mortality.

Source at https://doi.org/10.1002/ijc.31172. Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C‐reactive protein, interleukin (IL)‐6, IL‐10 and tumor necrosis factor (TNF)‐α and the risk of TC. A case‐control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer‐free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (ORT3vs.T1 = 0.69, 95% CI: 0.49–0.98, Ptrend = 0.04) but not among men (ORT3vs.T1 = 1.36, 95% CI: 0.67–2.76, Ptrend = 0.37). Increasing levels of IL‐10 were positively associated with TC risk in both genders and significantly so in women (ORT3vs.T1 = 1.59, 95% CI: 1.13–2.25, Ptrend = 0.01) but not in men (ORT3vs.T1 = 1.78, 95% CI: 0.80–3.98, Ptrend = 0.17). Leptin, CRP, IL‐6 and TNF‐α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL‐10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight.

cope Previous work highlighted the potential of odd-chain length saturated fatty acids as potential markers of dairy intake. The aim of this study was to assess the reproducibility of these biomarkers and their sensitivity to changes in dairy intake. Methods and results Fatty acid profiles and dietary intakes from food frequency questionnaires (FFQs) were measured three times over six months in the Food4Me Study. Reproducibility was explored through intra-class correlation coefficients (ICCs) and within-subject coefficients of variation (WCV). Sensitivity to changes in diet was examined using regression analysis. C15:0 blood levels showed high correlation over time (ICC: 0.62, 95% CI: 0.57, 0.68), however, the ICC for C17:0 was much lower (ICC: 0.32, 95% CI: 0.28, 0.46). The WCV for C15:0 was 16.6% and that for C17:0 was 14.6%. There were significant associations between changes in intakes of total dairy, high-fat dairy, cheese and butter and C15:0; and change in intakes of high-fat dairy and cream and C17:0. Conclusions Results provide evidence of reproducibility of C15:0 levels over time and sensitivity to change in intake of high-fat dairy products with results comparable to the well-established biomarker of fish intake (EPA+DHA). This article is protected by copyright. All rights reserved

Aims:\ud An excessive production of aldosterone influences outcome in patients with heart failure (HF) and in obese patients. Findings from laboratory studies suggest that chronic aldosterone blockade maybe more beneficial in abdominally obese HF-prone rats. In the current study, we investigated if the clinical response to a mineralocorticoid receptor antagonist in mildly symptomatic HF patients varied by abdominal obesity.\ud \ud Methods and results:\ud A total of 2587 NYHA class II, reduced ejection fraction HF (HFrEF) patients enrolled in the EMPHASIS-HF trial were randomly assigned to eplerenone and placebo. In this post hoc analysis, patients were categorized according to waist circumference (WC) (normal if WC < 102 cm in men and

BACKGROUND: Malnutrition, weight loss, and muscle wasting (sarcopenia) are common among women with advanced ovarian cancer and have been associated with adverse clinical outcomes and survival. Our objective is to investigate overall survival (OS) related to changes in skeletal muscle (SM) for patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking. METHODS: Ovarian cancer patients (n = 123) treated with neoadjuvant chemotherapy and interval debulking in the area of Maastricht (the Netherlands) between 2000 and 2014 were included retrospectively. Surface areas of SM and adipose tissue were defined on computed tomography at the level of the third lumbar vertebra. Low SM at baseline and SM changes during chemotherapy were compared with Kaplan Meier curves, and Cox-regression models were applied to test predictors of OS. RESULTS: Median OS for patients who lost SM (n = 83) was 916 ± 99 days, which was significantly different from median OS for patients who maintained or gained SM (n = 40), which was 1431 ± 470 days (P = 0.004). Loss of SM was also a significant predictor of OS in multivariable Cox-regression analysis (hazard ratio 1.773 (95%CI: 1.018-3.088), P = 0.043). Low baseline SM did not influence survival. CONCLUSIONS: Patients with ovarian cancer have a worse survival when they lose SM during neoadjuvant chemotherapy. Evaluation of low SM at a specific time point is not prognostic for OS. External and prospective validation of these findings is imperative. Nutritional, pharmacological, and/or physical intervention studies are necessary to establish whether SM impairment can be prevented to prolong ovarian cancer survival. ispartof: JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE vol:7 issue:4 pages:458-466 ispartof: location:Germany status: published

Excess accumulation of lipids in nonadipose tissues such as skeletal muscle and liver has been implicated in the development of obesity-related disorders, but the cause of this ectopic lipid overload remains unknown. The aim of this study was to determine in vivo postprandial lipid partitioning in rat skeletal muscle and liver, using localized (1) H-[(13) C] magnetic resonance spectroscopy in combination with the oral administration of (13) C-labeled lipids. Six rats were measured at baseline and 5 and 24 h after administration of 400 mg [U-(13) C]-labeled algal lipids. Five hours after administration, fractional (13) C enrichments of the lipid pools in muscle and liver were increased 3.9-fold and 4.6-fold (P < 0.05), respectively, indicating that part of the ingested lipids had been taken up by muscle and liver tissue. At 24 h, fractional (13) C enrichments of muscle and liver lipids were decreased 1.6-fold and 2.2-fold (P < 0.05), respectively, compared with the 5 h values. This can be interpreted as a depletion of (13) C-labeled lipids from the intracellular lipid pools as a consequence of lipid turnover. In conclusion, the novel application of (1) H-[(13) C] magnetic resonance spectroscopy in combination with the oral administration of (13) C-labeled lipids is applicable for the longitudinal assessment of in vivo lipid partitioning between multiple tissues. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc.

Background Systemic inflammation is suggested as a mechanism by which overweight might induce asthma. However, few studies have linked childhood overweight, inflammation and asthma.Objective To study the association between body mass index (BMI), asthma symptoms and pro-inflammatory proteins.Methods High-sensitivity C-reactive protein (hs-CRP), complement factor 3 (C3) and 4 (C4) concentrations, and body weight and height were available for 359 4-year-old children participating in the Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Data on asthma symptoms were obtained by yearly questionnaires. Logistic regression and generalized estimating equations were used to analyse the cross-sectional and prospective associations between BMI, asthma symptoms and pro-inflammatory proteins.Results BMI was associated with asthma symptoms {odds ratio [OR] 1.43 [95% confidence interval (CI): 1.08-1.88] per BMI standard deviation scores [SDS]}. The inclusion of hs-CRP, C3 and C4 in the statistical models did not change this association. C3 was cross-sectionally associated with frequent asthma symptoms [OR per interquartile range of C3: 1.97 (95% CI: 1.20-3.24)] and prospectively with asthma symptoms [OR: 1.48 (95% CI: 1.04-2.09)], independent of BMI SDS.Conclusions and Clinical Relevance We showed no evidence for a role of hs-CRP, C3 and C4 in the association between BMI and asthma symptoms. C3 concentrations were associated with (frequent) asthma symptoms, independent of BMI.

Summary The current obesity and type 2 diabetes pandemics have causes beyond changes in eating and exercise habits against a susceptible genetic background. Gut bacteria seem to additionally contribute to the differences in body weight, fat distribution, insulin sensitivity and glucose- and lipid-metabolism. Data, mostly derived from preclinical studies, suggest that gut microbiota play an important role in conditions such as obesity, diabetes, metabolic syndrome and non-alcoholic fatty liver disease. Regulation of energy uptake from the gut, by digesting otherwise indigestible common polysaccharides in our diet, production or activation of signalling molecules involved in host metabolism, modification of gut permeability, the release of gut hormones and inflammation, are among the mechanisms by which gut microbiota may influence the host cardiometabolic phenotype. Recent evidence suggests that quantitative and qualitative differences in gut microbiota exist between lean and obese, and between diabetic and non-diabetic individuals. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may favourably affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are eagerly awaited.

Recognition of the link between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has boosted research in this area. The main objective of this paper is to review the literature on NAFLD in the context of CVD, focussing on underlying mechanisms and treatment. Besides excessive fatty acid influx, etiologic factors may include components of the metabolic syndrome, cytokines and mitochondrial dysfunction. NAFLD is associated with both hepatic and systemic insulin resistance. In the case of NAFLD, the liver overproduces several atherogenic factors, notably inflammatory cytokines, glucose, lipoproteins and coagulation factors, and factors increasing blood pressure. Intervention studies on diet and laparoscopic surgery revealed improvements of hepatic fat content and CVD risk profile. Pharmacological approaches with potential benefit have been developed as well, but effects are often confounded by weight change. NAFLD is associated with an increased CVD risk profile (and hepatic risk). In order to improve CVD risk profile, prevention and treatment of NAFLD seem advisable. However, well-designed intervention studies, randomized clinical trials and long-term follow-up studies are scarce.

Lipotoxicity in skeletal muscle plays a critical role in the aetiology of insulin resistance and type 2 diabetes mellitus by interference of lipid metabolites with insulin signalling and action. The dynamics of lipid oxidation and fine tuning with fatty acid uptake and intramyocellular triacylglycerol turnover may be very important to limit the accumulation of lipid intermediates. The use of metabolic inflexibility, defined as the impaired capacity to increase fat oxidation upon increased fatty acid availability and to switch between fat and glucose as the primary fuel source after a meal, does more justice to the complexity of changes in fuel oxidation during the day. Fatty acid availability, uptake and oxidation all play a role in metabolic flexibility and insulin resistance. During high fatty acid availability, fatty acid transporters may limit cellular and mitochondrial fatty acid uptake and thus limit fat oxidation. After a meal, when the demand for fatty acids as fuel is low, an increased fractional extraction of lipids from plasma may promote intramyocellular lipid accumulation and insulin resistance. Furthermore, defects in fuel switching cluster together with impaired mitochondrial content and/or function. Lifestyle changes in dietary fat intake, physical activity and weight loss may improve metabolic flexibility in skeletal muscle, and thereby contribute to the prevention of type 2 diabetes.

In type 2 diabetes mellitus, circulating C-reactive protein (CRP) is increased, whereas the high density lipoprotein (HDL)-associated, anti-oxidative and anti-inflammatory enzyme, paraoxonase-I, is decreased. Both high CRP and low paraoxonase-I activity may predict cardiovascular disease. It is unknown whether lower paraoxonase-I activity contributes to higher CRP levels in diabetes. In type 2 diabetic and control subjects, we determined the relationship of CRP with paraoxonase-I when taking account of plasma levels of pro- and anti-inflammatory adipokines.In 81 type 2 diabetic patients and 89 control subjects, plasma high-sensitive CRP, serum paraoxonase-I activity (arylesterase activity, assayed as the rate of hydrolysis of phenyl acetate into phenol), plasma leptin, adiponectin, resistin and lipids were determined.Body mass index (BMI), waist, insulin resistance, triglycerides, CRP, leptin and resistin levels were higher (P 0.20 for all).low paraoxonase-I activity is related to higher CRP, independently of adipokines, as well as of obesity and lipids. Low paraoxonase-I activity in type 2 diabetes mellitus may contribute to increased cardiovascular risk via an effect on enhanced systemic low-grade inflammation.

Aims Slowly digestible starch is associated with beneficial health effects. The glucose-lowering drug acarbose has the potential to retard starch digestion since it inhibits alpha-amylase and alpha-glucosidases. We tested the hypothesis that a low dose of acarbose delays the rate of digestion of rapidly digestible starch without reducing its bioavailability and thereby increasing resistant starch flux into the colon.Methods In a crossover study, seven healthy males ingested corn pasta (50.3 g dry weight), naturally enriched with C-13, with and without 12.5 mg acarbose. Plasma glucose and insulin concentrations, and (CO2)-C-13 and hydrogen excretion in breath were monitored for 6 h after ingestion of the test meals. Using a primed continuous infusion of D-[6,6-H-2(2)] glucose, the rate of appearance of starch-derived glucose was estimated, reflecting intestinal glucose absorption.Results Areas under the 2-h postprandial curves of plasma glucose and insulin concentrations were significantly decreased by acarbose (-58.1 +/- 8.2% and -72.7 +/- 7.4%, respectively). Acarbose reduced the overall 6-h appearance of exogenous glucose (bioavailability) by 22 +/- 7% (mean +/- SE) and the 6-h cumulative (CO2)-C-13 excretion by 30 +/- 6%.Conclusions These data show that in healthy volunteers a low dose of 12.5 mg acarbose decreases the appearance of starch-derived glucose substantially. Reduced bioavailability seems to contribute to this decrease to a greater extent than delay of digestion. This implies that the treatment effect of acarbose could in part be ascribed to the metabolic effects of colonic starch fermentation.

Objectives. Essential hypertension may be associated with abnormalities in free fatty acids (FFA) and triglyceride metabolism, which could lead to alterations in high density lipoproteins (HDL). Lecithin: cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of cholesterol and the subsequent transfer of cholesteryl ester from HDL towards triglyceride-rich lipoproteins. We compared baseline plasma lipids, HDL lipids, plasma LCAT and CETP activity as well as the lowering Of plasma FFA and triglycerides by acute hyperglycaemia-induced hyperinsulinaemia in patients with essential hypertension and control subjects.Setting. University Hospital, Groningen.Subjects and design. Eight patients with essential hypertension and eight control subjects were studied during a 3-h hyperglycaemic glucose clamp (blood glucose, 10 mmol L(-1)).Main outcome measures. Plasma insulin, FFA, triglycerides and HDL lipids, plasma LCAT and CETP.Results. Baseline plasma FFA, total cholesterol and HDL cholesterol were not different between the groups, but plasma triglycerides tended to be higher in the hypertensive patients (PConclusion. The action of insulin on FFA metabolism is impaired which is likely to contribute to higher plasma triglycerides in essential hypertension. In turn, higher triglycerides influence the HDL lipid composition, either directly or via an effect on the plasma LCAT/CETP ratio.

1 Concentrations of etretinate, acitretin and its main metabolite 13-cis-acitretin were measured in plasma and subcutaneous fat samples from 37 women of childbearing age exposed to acitretin before November 1990. Twenty of the women still used acitretin and 17 had stopped therapy for a period ranging from 1 to 29 months.2 The prevalences of detectable etretinate concentrations were 45% and 83% in plasma and subcutaneous tissue, respectively, among current acitretin users and 18% and 86% among those who had stopped acitretin therapy. Thus, inability to detect plasma etretinate is a poor predictor of the absence of etretinate in fat.3 Acitretin and/or etretinate were detectable in fat and in some cases in plasma from women who had ceased acitretin therapy for up to 29 months.4 We suggest that (cis)-acitretin and etretinate should be monitored in subcutaneous tissue when plasma measurements are negative. The recommended contraception period of 2 years after cessation of acitretin therapy should be reconsidered to avoid the risk of teratogenicity.

Protein kinase C theta (PKC-theta) is the PKC isoform predominantly expressed in skeletal muscle, and it is supposed to mediate many signals necessary for muscle histogenesis and homeostasis, such as TGFbeta, nerve-dependent signals and insulin. To study the role of PKC-theta in these mechanisms we generated transgenic mice expressing a "kinase dead" mutant form of PKC-theta (PKC-thetaK/R), working as "dominant negative," specifically in skeletal muscle. These mice are viable and fertile, however, by the 6-7 months of age, they gain weight, mainly due to visceral fat deposition. Before the onset of obesity (4 months of age), they already show increased fasting and fed insulin levels and reduced insulin-sensitivity, as measured by ipITT, but normal glucose tolerance, as measured by ipGTT. After the 6-7 months of age, transgenic mice develop hyperinsulinemia in the fasting and fed state. The ipGTT revealed in the transgenic mice both hyperglycemia and hyperinsulinemia. At the molecular level, impaired activation of the IR/IRS/PI3K pathway and a significant decrease both in the levels and in insulin-stimulated activation of the serine/threonine kinase Akt were observed. Taken together these data demonstrate that over-expression of dominant negative PKC-theta in skeletal muscle causes obesity associated to insulin resistance, as demonstrated by defective receptor and post-receptorial activation of signaling cascade.