Nutrition & Metabolism[JOURNAL]
Sun
200 papers
Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters.
Briand F, Maupoint J, Brousseau E … +11 more , Breyner N, Bouchet M, Costard C, Leste-Lasserre T, Petitjean M, Chen L, Chabrat A, Richard V, Burcelin R, Dubroca C, Sulpice T
Metabolism · 2021 Apr · PMID 33444606 · Publisher ↗
BACKGROUND: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the...
BACKGROUND: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients. METHODS: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks. RESULTS: Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios. CONCLUSION: Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF.
PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation.
Tobón-Cornejo S, Vargas-Castillo A, Leyva-Martínez A … +7 more , Ortíz V, Noriega LG, Velázquez-Villegas LA, Aleman G, Furosawa-Carballeda J, Torres N, Tovar AR
Metabolism · 2021 Mar · PMID 33422545 · Publisher ↗
The preservation of body proteins is essential to guarantee their functions in organisms. Therefore, the utilization of amino acids as energy substrates is regulated by a precise fine-tuned mechanism. Recent evidence sug...
The preservation of body proteins is essential to guarantee their functions in organisms. Therefore, the utilization of amino acids as energy substrates is regulated by a precise fine-tuned mechanism. Recent evidence suggests that the transcription factors peroxisome proliferator-activated receptor alpha (PPARα) and hepatocyte nuclear factor 4 alpha (HNF4α) are involved in this regulatory mechanism. Thus, the aim of this study was to determine how these transcription factors interact to regulate the expression of amino acid catabolism genes. In vivo studies using PPARα-knockout mice (Pparα-null) fed different amounts of dietary protein showed that in the absence of PPARα, there was a significant increase in HNF4α abundance in the liver, which corresponded with an increase in amino acid catabolizing enzyme (AACE) expression and the generation of increased amounts of postprandial urea. Moreover, this effect was proportional to the increase in dietary protein consumed. Chromatin immunoprecipitation assays showed that HNF4α can bind to the promoter of AACE serine dehydratase (SDS), an effect that was potentiated by dietary protein in the Pparα-null mice. The mechanistic studies revealed that the presence of retinoid X receptor alpha (RXRα) is essential to repress HNF4α activity in the presence of PPARα, and this interaction accelerates HNF4α degradation via the proteasome pathway. These results showed that PPARα can downregulate liver amino acid catabolism in the presence of RXRα by inhibiting HNF4α activity.
Maternal high-fat high-sucrose diet and gestational exercise modulate hepatic fat accumulation and liver mitochondrial respiratory capacity in mothers and male offspring.
Stevanović-Silva J, Beleza J, Coxito P … +11 more , Pereira S, Rocha H, Gaspar TB, Gärtner F, Correia R, Martins MJ, Guimarães T, Martins S, Oliveira PJ, Ascensão A, Magalhães J
Metabolism · 2021 Mar · PMID 33421507 · Publisher ↗
BACKGROUND: Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exerci...
BACKGROUND: Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. METHODS: Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. RESULTS: Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p < 0.01) and glucose intolerance (p < 0.01), characteristic of GDM. Their offspring had normal glucose metabolism, but increased early-age body weight, which was reverted by gestational exercise. Gestational exercise also reduced offspring hepatic triglycerides accumulation (p < 0.05) and improved liver mitochondrial respiration capacity (p < 0.05), contributing to the recovery of liver bioenergetics compromised by maternal HFHS diet. Interestingly, liver mitochondrial respiration remained increased by gestational exercise in HFHS-fed dams despite prolonged HFHS consumption and exercise cessation. CONCLUSIONS: Gestational exercise can result in liver mitochondrial adaptations in GDM animals, which can be preserved even after the exercise program cessation. Exposure to maternal GDM programs liver metabolic setting of male offspring, whereas gestational exercise appears as an important preventive tool against maternal diet-induced metabolic alterations.
Excess body weight is an independent risk factor for severe forms of COVID-19.
Pietri L, Giorgi R, Bégu A … +8 more , Lojou M, Koubi M, Cauchois R, Grangeot R, Dubois N, Kaplanski G, Valéro R, Béliard S
Metabolism · 2021 Apr · PMID 33421506 · Full text
BACKGROUND AND AIMS: Few studies distinguished the independent role of overweight/obesity or their associated-comorbidities in the evolution towards severe forms of COVID-19. Obesity as a unifying risk factor for severe...
BACKGROUND AND AIMS: Few studies distinguished the independent role of overweight/obesity or their associated-comorbidities in the evolution towards severe forms of COVID-19. Obesity as a unifying risk factor for severe COVID-19 is an emerging hypothesis. The aim of this study was to evaluate whether excessive body weight per se, was a risk factor for developing a severe form of COVID-19. PATIENTS AND METHODS: We included 131 patients hospitalized for COVID-19 pneumonia in a single center of the internal medicine department in Marseille, France. We recorded anthropometric and metabolic parameters such as fasting glycaemia, insulinemia, HOMA-IR, lipids, and all clinical criteria linked to SARS-CoV-2 infection at the admission. Excess body weight was defined by a BMI ≥ 25 kg/m. The occurrence of a serious event was defined as a high-debit oxygen requirement over 6 L/min, admission into the intensive care unit, or death. RESULTS: Among 113 patients, two thirds (n = 76, 67%) had an excess body weight. The number of serious events was significantly higher in excess body weight patients compared to normal weight patients (respectively 25% vs 8%, p = 0.03) although excess body weight patients were younger (respectively 63.6 vs 70.3 years old, p = 0.01). In multivariate analyses, the excess body weight status was the only predictor for developing a serious event linked to SARS-CoV-2 infection, with an odds ratio at 5.6 (95% CI: 1.30-23.96; p = 0.02), independently of previous obesity associated comorbidities. There was a trend towards a positive association between the BMI (normal weight, overweight and obesity) and the risk of serious events linked to COVID-19, with a marked increase from 8.1% to 20% and 30.6% respectively (p = 0.05). CONCLUSION: Excess body weight was significantly associated with severe forms of the disease, independently of its classical associated comorbidities. Physicians and specialists in Public Health must be sensitized to better protect people with an excess body weight against SARS-CoV-2 infection.
Human adipose tissue-derived stem cell paracrine networks vary according metabolic risk and after TNFα-induced death: An analysis at the single-cell level.
Oliva-Olivera W, Castellano-Castillo D, von Meyenn F … +3 more , Cardona F, Lönnberg T, Tinahones FJ
Metabolism · 2021 Mar · PMID 33333081 · Publisher ↗
OBJECTIVE: Adipose tissue-derived stem cells (ASCs) might play an important role in adipose microenvironment remodelling during tissue expansion through their response to hypoxia. We examined the cytokine profiles of hyp...
OBJECTIVE: Adipose tissue-derived stem cells (ASCs) might play an important role in adipose microenvironment remodelling during tissue expansion through their response to hypoxia. We examined the cytokine profiles of hypoxic visceral ASCs (hypox-visASCs) from subjects with different metabolic risk, the interactions between cytokines as well as the impact of TNFα-induced death in the behavior of surviving hypoxic subcutaneous ASCs (hypox-subASCs) both at bulk population and single-cell level. MATERIALS/METHODS: Visceral adipose tissue was processed to isolate the ASCs from 33 subjects grouped into normal weight, obese with and without metabolic syndrome. Multiplex assay was used to simultaneously measure multiple inflammatory, anti-inflammatory and angiogenic cytokines in hypox-visASCs from these patients and to elucidate cytokine profiles of hypox-subASCs upon stimulation with IL1β or TNFα and after TNFα-induced death. qPCR and single-cell RNA-sequencing were also performed to elucidate transcriptional impact in surviving hypox-subASCs after TNFα-induced apoptosis. RESULTS: Hypox-visASCs from subjects without metabolic syndrome showed greater secretion levels of inflammatory, anti-inflammatory and angiogenic cytokines compared with those from patients with metabolic syndrome. While IL-1β stimulation was sufficient to increase the secretion levels of these cytokines in hypox-subASCs, TNFα-induced apoptosis also increased their levels and impacted on the expression levels of extracellular matrix proteins, acetyl-CoA producing enzymes and redox-balance proteins in surviving hypox-subASCs. TNFα-induced apoptosis under different glucose concentrations caused selective impoverishment of cell clusters and differentially influenced gene expression profiles of surviving hypox-subASCs. CONCLUSIONS: Immunoregulatory and angiogenic functions of hypox-visASCs from patients with metabolic syndrome could be insufficient to promote healthy adipose tissue expansion. TNFα-induced apoptosis may impact on functionality of hypox-subASC populations, whose differential metabolic sensitivity to death could serve to manipulate individual populations selectively in order to elucidate their role in shaping adipose heterogeneity and treating metabolic disorders.
Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester.
Monzo L, Sedlacek K, Hromanikova K … +5 more , Tomanova L, Borlaug BA, Jabor A, Kautzner J, Melenovsky V
Metabolism · 2021 Feb · PMID 33248064 · Publisher ↗
AIMS: Upregulation of ketone body (β-hydroxybutyrate, βHB) utilization has been documented in human end-stage heart failure (HF), but is unclear if this is due to intrinsic cardiac metabolic remodeling or a HF-related ca...
AIMS: Upregulation of ketone body (β-hydroxybutyrate, βHB) utilization has been documented in human end-stage heart failure (HF), but is unclear if this is due to intrinsic cardiac metabolic remodeling or a HF-related catabolic state. This study sought to evaluate the maximal ketone body utilization capacity and its determinants in controls and in patients with moderate HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: 19 HFrEF patients and 9 controls underwent sampling from the arterial circulation (A) and coronary sinus (CS) to measure transmyocardial extraction of energy-providing substrates and oxygen. In a separate experiment, measurements were performed 80-min after oral administration of 25 g of ketone ester (KE, (R)-3-hydroxybutyl(R)-3-hydroxybutyrate) drink in 11 HFrEF and 6 control subjects. There were no statistically significant differences in fasting substrate levels and fractional extractions between HF and controls. Administration of KE increased βHB by 12.9-fold, revealing an increased ability to utilize ketones in HFrEF as compared to controls (fractional extraction, FE%: 52 vs 39%, p = 0.035). βHB FE% correlated directly with βHB myocardial delivery (r = 0.90), LV mass (r = 0.56), LV diameter (r = 0.65) and inversely with LV EF (-0.59) (all p < 0.05). βHB FE% positively correlated with lactate FE% (p < 0.01), but not with FFA or glucose FE%, arguing against substrate competition. CONCLUSIONS: Acute nutritional ketosis enhances βHB extraction in patients with HFrEF compared to controls, and this enhancement correlates with degree of cardiac dysfunction and remodeling. Data suggest that subclinical metabolic remodeling occurs early in HF progression. Further studies are needed to determine whether exogenous ketones may have a potential therapeutic role.
Visceral fat is associated to the severity of COVID-19.
Favre G, Legueult K, Pradier C … +6 more , Raffaelli C, Ichai C, Iannelli A, Redheuil A, Lucidarme O, Esnault V
Metabolism · 2021 Feb · PMID 33246009 · Full text
BACKGROUND: Excess visceral fat (VF) or high body mass index (BMI) is risk factors for severe COVID-19. The receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expressed at higher levels in the V...
BACKGROUND: Excess visceral fat (VF) or high body mass index (BMI) is risk factors for severe COVID-19. The receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expressed at higher levels in the VF than in the subcutaneous fat (SCF) of obese patients. AIM: To show that visceral fat accumulation better predicts severity of COVID-19 outcome compared to either SCF amounts or BMI. METHODS: We selected patients with symptomatic COVID-19 and a computed tomography (CT) scan. Severe COVID-19 was defined as requirement for mechanical ventilation or death. Fat depots were quantified on abdominal CT scan slices and the measurements were correlated with the clinical outcomes. ACE 2 mRNA levels were quantified in fat depots of a separate group of non-COVID-19 subjects using RT-qPCR. RESULTS: Among 165 patients with a mean BMI of 26.1 ± 5.4 kg/m, VF was associated with severe COVID-19 (p = 0.022) and SCF was not (p = 0.640). Subcutaneous fat was not different in patients with mild or severe COVID-19 and the SCF/VF ratio was lower in patients with severe COVID-19 (p = 0.010). The best predictive value for severe COVID-19 was found for a VF area ≥128.5 cm (ROC curve), which was independently associated with COVID-19 severity (p < 0.001). In an exploratory analysis, ACE 2 mRNA positively correlated with BMI in VF but not in SCF of non-COVID-19 patients (r = 0.27 vs 0.0008). CONCLUSION: Severe forms of COVID-19 are associated with high visceral adiposity in European adults. On the basis of an exploratory analysis ACE 2 in the visceral fat may be a trigger for the cytokine storm, and this needs to be clarified by future studies.
MAFLD and risk of CKD.
Sun DQ, Jin Y, Wang TY … +7 more , Zheng KI, Rios RS, Zhang HY, Targher G, Byrne CD, Yuan WJ, Zheng MH
Metabolism · 2021 Feb · PMID 33212070 · Publisher ↗
BACKGROUND/AIMS: Whereas nonalcoholic fatty liver disease (NAFLD) is a multisystem disease, the association between metabolic dysfunction-associated fatty liver disease (MAFLD) and extra-hepatic diseases is not known. Th...
BACKGROUND/AIMS: Whereas nonalcoholic fatty liver disease (NAFLD) is a multisystem disease, the association between metabolic dysfunction-associated fatty liver disease (MAFLD) and extra-hepatic diseases is not known. The aim of this cross-sectional study was to compare the prevalence of chronic kidney disease (CKD) in patients with either MAFLD or NAFLD, and then to examine the association between the presence and severity of MAFLD and CKD and abnormal albuminuria. METHODS: A total of 12,571 individuals with complete biochemical and liver ultrasonography data from the Third National Health and Nutrition Examination Survey (1988-1994) were included in the analysis. Multivariable logistic regression analyses were performed to test the independence of associations between MAFLD or MAFLD severity as the key exposures and CKD (defined as either CKD stage ≥1 or stage ≥3) or abnormal albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol) as the outcomes. RESULTS: The prevalence of MAFLD and NAFLD was 30.2% (n = 3794) and 36.2% (n = 4552), respectively. MAFLD individuals had a lower eGFR (74.96 ± 18.21 vs. 76.46 ± 18.24 ml/min/1.73 m, P < 0.001) and a greater prevalence of CKD (29.60% vs. 26.56%, P < 0.05) than NAFLD individuals. Similarly, there was a higher prevalence CKD in MAFLD than in non-metabolic dysfunction-associated NAFLD (P < 0.05). Notably, after adjustment for sex, age, ethnicity, alcohol intake and diabetes, the severity of MAFLD (i.e. NAFLD fibrosis score ≥ 0.676) was associated with 1.34-fold higher risk of prevalent CKD (P < 0.05). CONCLUSIONS: MAFLD identifies patients with CKD better than NAFLD. MAFLD and MAFLD with increased liver fibrosis score are strongly and independently associated with CKD and abnormal albuminuria.
Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name.
Polyzos SA, Kang ES, Tsochatzis EA … +13 more , Kechagias S, Ekstedt M, Xanthakos S, Lonardo A, Mantovani A, Tilg H, Côté I, Grefhorst A, Greene MW, Araujo-Vilar D, Alisi A, Casanueva F, Mantzoros CS
Metabolism · 2020 Dec · PMID 33164861 · Publisher ↗
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Mediterranean diet as a nutritional approach for COVID-19.
Angelidi AM, Kokkinos A, Katechaki E … +2 more , Ros E, Mantzoros CS
Metabolism · 2021 Jan · PMID 33080270 · Full text
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Commentary: COVID-19 and obesity pandemics converge into a syndemic requiring urgent and multidisciplinary action.
Hill MA, Sowers JR, Mantzoros CS
Metabolism · 2021 Jan · PMID 33080269 · Full text
While substantial evidence points towards obesity and associated cardiometabolic disorders being a major factor for poor outcomes in SARS-CoV2 infections (COVID-19), the complexity of the interplay between these two pand...
While substantial evidence points towards obesity and associated cardiometabolic disorders being a major factor for poor outcomes in SARS-CoV2 infections (COVID-19), the complexity of the interplay between these two pandemics is becoming apparent. Indeed, as previously defined, this interaction between obesity and COVID-19 represents a 'syndemic' that requires both current and ongoing attention. At a mechanistic level the chronic inflammatory environment of obesity predisposes to life threatening events such as cytokine storm and enhanced coagulopathy. Obesity and its management are affected by diverse factors manifested at societal, educational, racial, and nutritional levels. A multidisciplinary approach is required to manage obese and type 2 diabetic patients, not only during the current COVID-19 crisis, but to decrease the growing burden of cardiometabolic disease and associated cardiovascular complications impacting future viral pandemics. Further, this syndemic has highlighted disparities in healthcare which need to be addressed to achieve equality in health outcomes in patients infected with COVID-19.
Fasting status and metabolic health in relation to plasma branched chain amino acid concentrations in women.
Tobias DK, Mora S, Verma S … +3 more , Billia F, Buring JE, Lawler PR
Metabolism · 2021 Apr · PMID 33069808 · Full text
BACKGROUND: Circulating branched chain amino acids (BCAA) are associated with cardiometabolic risk, although the mechanisms leading to their accumulation remain uncertain. Examining the relationship between fasting statu...
BACKGROUND: Circulating branched chain amino acids (BCAA) are associated with cardiometabolic risk, although the mechanisms leading to their accumulation remain uncertain. Examining the relationship between fasting status, metabolic syndrome, and type 2 diabetes (T2D) with circulating BCAA levels may provide insights into their metabolic handling. METHODS: We conducted cross-sectional analyses among 25,740 Women's Health Study participants (mean age 55 years). RESULTS: In multivariable linear regression models, fasting was associated with lower plasma BCAAs vs. non-fasting in women without metabolic syndrome or T2D (% mean difference = -5.1%; 95% CI = -5.8, -4.5) and among women with metabolic syndrome only (-3.7%; -4.9, -2.6), p = 0.002. However, there was no difference in BCAAs by fasting status among women with T2D (0.4%; -3.7, 4.7). CONCLUSIONS: We observed higher BCAAs with worsening metabolic health status. Fasting is modestly associated with lower plasma BCAAs, except among women with T2D. These findings support hypotheses that impaired BCAA catabolism may be a feature of T2D pathophysiology.
UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice.
Okamatsu-Ogura Y, Kuroda M, Tsutsumi R … +4 more , Tsubota A, Saito M, Kimura K, Sakaue H
Metabolism · 2020 Dec · PMID 33065161 · Publisher ↗
BACKGROUND: Brown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates...
BACKGROUND: Brown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood. METHODS: We conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice. RESULTS: Cold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) β oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice. CONCLUSIONS: These results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.
Weight gain during early adulthood, trajectory of body shape and the risk of nonalcoholic fatty liver disease: A prospective cohort study among women.
Kim MN, Lo CH, Corey KE … +7 more , Liu PH, Ma W, Zhang X, Jovani M, Song M, Chan AT, Simon TG
Metabolism · 2020 Dec · PMID 33058854 · Full text
BACKGROUND & AIMS: Obesity is established as a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD). However, the influence of dynamic changes in adiposity over the life course on NAFLD risk...
BACKGROUND & AIMS: Obesity is established as a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD). However, the influence of dynamic changes in adiposity over the life course on NAFLD risk remains poorly understood. METHODS: We collected data from 110,054 women enrolled in the Nurses' Health Study II cohort. Early adulthood weight was ascertained at age 18 years, and weight gain since early adulthood was defined prospectively every 2 years. We used a group-based modeling approach to identify five trajectories of body shape from age 5 years up to age 50 years. NAFLD was defined by physician-confirmed diagnoses of fatty liver, after excluding excess alcohol intake and viral hepatitis, using validated approaches. RESULTS: We documented 3798 NAFLD cases over a total of 20 years of follow-up. Compared to women who maintained stable weight (±2 kg), women with ≥20 kg of adulthood weight gain had the multivariable aHR of 6.96 (95% CI, 5.27-9.18), and this remained significant after further adjusting for early adulthood BMI and updated BMI (both P trend <0.0001). Compared to women with a medium-stable body shape trajectory, the multivariable aHRs for NAFLD were, 2.84 (95% CI, 2.50-3.22) for lean-marked increase, 2.60 (95% CI, 2.27-2.98) for medium-moderate increase, and 3.39 (95% CI, 2.95-3.89) for medium-marked increase. CONCLUSIONS: Both early adulthood weight gain and lifetime body shape trajectory were significantly and independently associated with excess risk of developing NAFLD in mid-life. Maintaining both lean and stable weight throughout life may offer the greatest benefit for the prevention of NAFLD.
Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern.
Olkowicz M, Tomczyk M, Debski J … +10 more , Tyrankiewicz U, Przyborowski K, Borkowski T, Zabielska-Kaczorowska M, Szupryczynska N, Kochan Z, Smeda M, Dadlez M, Chlopicki S, Smolenski RT
Metabolism · 2021 Jan · PMID 33058853 · Publisher ↗
OBJECTIVE: Dyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidae...
OBJECTIVE: Dyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidaemia in cardiomyocytes collectively constitute an alternative pathway that escalates myocardial injury. METHODS: Dyslipidaemic apolipoprotein E and low-density lipoprotein receptor (ApoE/LDLR) double knockout (ApoE/LDLR) and wild-type C57BL/6 (WT) mice aged six months old were studied. Cardiac injury under reduced oxygen supply was evaluated by 5 min exposure to 5% oxygen in the breathing air under electrocardiogram (ECG) recording and with the assessment of troponin I release. To address the mechanisms LC/MS was used to analyse the cardiac proteome pattern or in vivo metabolism of stable isotope-labelled substrates and HPLC was applied to measure concentrations of cardiac high-energy phosphates. Furthermore, the effect of blocking fatty acid use with ranolazine on the substrate preference and cardiac hypoxic damage was studied in ApoE/LDLR mice. RESULTS: Hypoxia induced profound changes in ECG ST-segment and troponin I leakage in ApoE/LDLR mice but not in WT mice. The evaluation of the cardiac proteomic pattern revealed that ApoE/LDLR as compared with WT mice were characterised by coordinated increased expression of mitochondrial proteins, including enzymes of fatty acids' and branched-chain amino acids' oxidation, accompanied by decreased expression levels of glycolytic enzymes. These findings correlated with in vivo analysis, revealing a reduction in the entry of glucose and enhanced entry of leucine into the cardiac Krebs cycle, with the cardiac high-energy phosphates pool maintained. These changes were accompanied by the activation of molecular targets controlling mitochondrial metabolism. Ranolazine reversed the oxidative metabolic shift in ApoE/LDLR mice and reduced cardiac damage induced by hypoxia. CONCLUSIONS: We suggest a novel mechanism for myocardial injury in dyslipidaemia that is consequent to an increased reliance on oxidative metabolism in the heart. The alterations in the metabolic pattern that we identified constitute an adaptive mechanism that facilitates maintenance of metabolic equilibrium and cardiac function under normoxia. However, this adaptation could account for myocardial injury even in a mild reduction of oxygen supply.
Obesity in patients with COVID-19: a systematic review and meta-analysis.
Huang Y, Lu Y, Huang YM … +4 more , Wang M, Ling W, Sui Y, Zhao HL
Metabolism · 2020 Dec · PMID 33002478 · Full text
BACKGROUND: Obesity is common in patients with coronavirus disease 2019 (COVID-19). The effects of obesity on clinical outcomes of COVID-19 warrant systematical investigation. OBJECTIVE: This study explores the effects o...
BACKGROUND: Obesity is common in patients with coronavirus disease 2019 (COVID-19). The effects of obesity on clinical outcomes of COVID-19 warrant systematical investigation. OBJECTIVE: This study explores the effects of obesity with the risk of severe disease among patients with COVID-19. METHODS: Body mass index (BMI) and degree of visceral adipose tissue (VAT) accumulation were used as indicators for obesity status. Publication databases including preprints were searched up to August 10, 2020. Clinical outcomes of severe COVID-19 included hospitalization, a requirement for treatment in an intensive care unit (ICU), invasive mechanical ventilation (IMV), and mortality. Risks for severe COVID-19 outcomes are presented as odds ratios (OR) and 95% confidence interval (95%CI) for cohort studies with BMI-defined obesity, and standardized mean difference (SMD) and 95%CI for controlled studies with VAT-defined excessive adiposity. RESULTS: A total of 45, 650 participants from 30 studies with BMI-defined obesity and 3 controlled studies with VAT-defined adiposity were included for assessing the risk of severe COVID-19. Univariate analyses showed significantly higher ORs of severe COVID-19 with higher BMI: 1.76 (95%: 1.21, 2.56, P = 0.003) for hospitalization, 1.67 (95%CI: 1.26, 2.21, P<0.001) for ICU admission, 2.19 (95%CI: 1.56, 3.07, P<0.001) for IMV requirement, and 1.37 (95%CI: 1.06, 1.75, P = 0.014) for death, giving an overall OR for severe COVID-19 of 1.67 (95%CI: 1.43, 1.96; P<0.001). Multivariate analyses revealed increased ORs of severe COVID-19 associated with higher BMI: 2.36 (95%CI: 1.37, 4.07, P = 0.002) for hospitalization, 2.32 (95%CI: 1.38, 3.90, P = 0.001) for requiring ICU admission, 2.63 (95%CI: 1.32, 5.25, P = 0.006) for IMV support, and 1.49 (95%CI: 1.20, 1.85, P<0.001) for mortality, giving an overall OR for severe COVID-19 of 2.09 (95%CI: 1.67, 2.62; P<0.001). Compared to non-severe COVID-19 patients, severe COVID-19 cases showed significantly higher VAT accumulation with a SMD of 0.49 for hospitalization (95% CI: 0.11, 0.87; P = 0.011), 0.57 (95% CI: 0.33, 0.81; P<0.001) for requiring ICU admission and 0.37 (95% CI: 0.03, 0.71; P = 0.035) for IMV support. The overall SMD for severe COVID-19 was 0.50 (95% CI: 0.33, 0.68; P<0.001). CONCLUSIONS: Obesity increases risk for hospitalization, ICU admission, IMV requirement and death among patients with COVID-19. Further, excessive visceral adiposity appears to be associated with severe COVID-19 outcomes. These findings emphasize the need for effective actions by individuals, the public and governments to increase awareness of the risks resulting from obesity and how these are heightened in the current global pandemic.
Synergistic effects of fructose and glucose on lipoprotein risk factors for cardiovascular disease in young adults.
Hieronimus B, Medici V, Bremer AA … +6 more , Lee V, Nunez MV, Sigala DM, Keim NL, Havel PJ, Stanhope KL
Metabolism · 2020 Nov · PMID 32916151 · Full text
BACKGROUND: Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effec...
BACKGROUND: Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effects of consuming fructose, glucose or their combination, high fructose corn syrup (HFCS), on cardiometabolic risk factors. METHODS: Adults (18-40 years; BMI 18-35 kg/m) participated in a parallel, double-blinded dietary intervention during which beverages sweetened with aspartame, glucose (25% of energy requirements (ereq)), fructose or HFCS (25% and 17.5% ereq) were consumed for two weeks. Groups were matched for sex, baseline BMI and plasma lipid/lipoprotein concentrations. 24-h serial blood samples were collected at baseline and at the end of intervention. Primary outcomes were 24-h triglyceride AUC, LDL-cholesterol (C), and apolipoprotein (apo)B. Interactions between fructose and glucose were assessed post hoc. FINDINGS: 145 subjects (26.0 ± 5.8 years; body mass index 25.0 ± 3.7 kg/m) completed the study. As expected, the increase of 24-h triglycerides compared with aspartame was highest during fructose consumption (25%: 6.66 mmol/Lx24h 95% CI [1.90 to 11.63], P = 0.0013 versus aspartame), intermediate during HFCS consumption (25%: 4.68 mmol/Lx24h 95% CI [-0.18 to 9.55], P = 0.066 versus aspartame) and lowest during glucose consumption. In contrast, the increase of LDL-C was highest during HFCS consumption (25%: 0.46 mmol/L 95% CI [0.16 to 0.77], P = 0.0002 versus aspartame) and intermediate during fructose consumption (25%: 0.33 mmol/L 95% CI [0.03 to 0.63], P = 0.023 versus aspartame), as was the increase of apoB (HFCS-25%: 0.108 g/L 95%CI [0.032 to 0.184], P = 0.001; fructose 25%: 0.072 g/L 95%CI [-0.004 to 0.148], P = 0.074 versus aspartame). The post hoc analyses showed significant interactive effects of fructose*glucose on LDL-C and apoB (both P < 0.01), but not on 24-h triglyceride (P = 0.340). CONCLUSION: A significant interaction between fructose and glucose contributed to increases of lipoprotein risk factors when the two monosaccharides were co-ingested as HFCS. Thus, the effects of HFCS on lipoprotein risks factors are not solely mediated by the fructose content and it cannot be assumed that glucose is a benign component of HFCS. Our findings suggest that HFCS may be as harmful as isocaloric amounts of pure fructose and provide further support for the urgency to implement strategies to limit free sugar consumption.
Interesterified palm oil impairs glucose homeostasis and induces deleterious effects in liver of Swiss mice.
Miyamoto JÉ, Reginato A, Portovedo M … +13 more , Dos Santos RM, Stahl MA, Le Stunff H, Latorraca MQ, de Barros Reis MA, Arantes VC, Doneda DL, Ignacio-Souza LM, Torsoni AS, Grimaldi R, Ribeiro APB, Torsoni MA, Milanski M
Metabolism · 2020 Nov · PMID 32910938 · Publisher ↗
BACKGROUND: Interesterified fats have largely replaced the partially hydrogenated oils which are the main dietary source of trans fat in industrialized food. This process promotes a random rearrangement of the native fat...
BACKGROUND: Interesterified fats have largely replaced the partially hydrogenated oils which are the main dietary source of trans fat in industrialized food. This process promotes a random rearrangement of the native fatty acids and the results are different triacylglycerol (TAG) molecules without generating trans isomers. The role of interesterified fats in metabolism remains unclear. We evaluated metabolic parameters, glucose homeostasis and inflammatory markers in mice fed with normocaloric and normolipidic diets or hypercaloric and high-fat diet enriched with interesterified palm oil. METHODS: Male Swiss mice were randomly divided into four experimental groups and submitted to either normolipidic palm oil diet (PO), normolipidic interesterified palm oil diet (IPO), palm oil high-fat diet (POHF) or interesterified palm oil high-fat diet (IPOHF) during an 8 weeks period. RESULTS: When compared to the PO group, IPO group presented higher body mass, hyperglycemia, impaired glucose tolerance, evidence of insulin resistance and greater production of glucose in basal state during pyruvate in situ assay. We also observed higher protein content of hepatic PEPCK and increased cytokine mRNA expression in the IPO group when compared to PO. Interestingly, IPO group showed similar parameters to POHF and IPOHF groups. CONCLUSION: The results indicate that substitution of palm oil for interesterified palm oil even on normocaloric and normolipidic diet could negatively modulate metabolic parameters and glucose homeostasis as well as cytokine gene expression in the liver and white adipose tissue. This data support concerns about the effects of interesterified fats on health and could promote further discussions about the safety of the utilization of this unnatural fat by food industry.
High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study.
Prats-Uribe A, Sayols-Baixeras S, Fernández-Sanlés A … +8 more , Subirana I, Carreras-Torres R, Vilahur G, Civeira F, Marrugat J, Fitó M, Hernáez Á, Elosua R
Metabolism · 2020 Nov · PMID 32891675 · Publisher ↗
BACKGROUND: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). METHODS: We designed a two-sample multivariate Mende...
BACKGROUND: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). METHODS: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. RESULTS: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. CONCLUSIONS: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.
Effect of long-term testosterone therapy on molecular regulators of skeletal muscle mass and fibre-type distribution in aging men with subnormal testosterone.
Kruse R, Petersson SJ, Christensen LL … +5 more , Kristensen JM, Sabaratnam R, Ørtenblad N, Andersen M, Højlund K
Metabolism · 2020 Nov · PMID 32853647 · Publisher ↗
BACKGROUND: Long-term testosterone replacement therapy (TRT) increases muscle mass in elderly men with subnormal testosterone levels. However, the molecular mechanisms underlying this effect of TRT on protein balance in...
BACKGROUND: Long-term testosterone replacement therapy (TRT) increases muscle mass in elderly men with subnormal testosterone levels. However, the molecular mechanisms underlying this effect of TRT on protein balance in human skeletal muscle in vivo remain to be established. METHODS: Here, we examined skeletal muscle biopsies obtained before and 24-h after the last dose of treatment with either testosterone gel (n = 12) or placebo (n = 13) for 6 months in aging men with subnormal bioavailable testosterone levels. The placebo-controlled, testosterone-induced changes (β-coefficients) in mRNA levels, protein expression and phosphorylation were examined by quantitative real-time PCR and western blotting. RESULTS: Long-term TRT increased muscle mass by β = 1.6 kg (p = 0.01) but had no significant effect on mRNA levels of genes involved in myostatin/activin/SMAD or IGF1/FOXO3 signalling, muscle-specific E3-ubiquitin ligases, upstream transcription factors (MEF2C, PPARGC1A-4) or myogenic factors. However, TRT caused a sustained decrease in protein expression of SMAD2 (β = -36%, p = 0.004) and SMAD3 (β = -32%, p = 0.001), which was accompanied by reduced protein expression of the muscle-specific E3-ubiquitin ligases, MuRF1 (β = -26%, p = 0.004) and Atrogin-1/MAFbx (β = -20%, p = 0.04), but with no changes in FOXO3 signalling. Importantly, TRT did not affect muscle fibre type distribution between slow-oxidative (type 1), fast-oxidative (type 2a) and fast-glycolytic (type 2×) muscle fibres. CONCLUSIONS: Our results indicate that long-term TRT of elderly men with subnormal testosterone levels increases muscle mass, at least in part, by decreasing protein breakdown through the ubiquitin proteasome pathway mediated by a sustained suppression of SMAD-signalling and muscle-specific E3-ubiquitin ligases.
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