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1.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020469

RESUMO

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/metabolismo
2.
Nat Commun ; 11(1): 4982, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020474

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians with biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort is used for external validation. Subjects are classified into three subgroups according to histological spectra of NAFLD or fibrosis severity. Significant alterations in microbiome diversity are observed according to fibrosis severity in non-obese, but not obese, subjects. Ruminococcaceae and Veillonellaceae are the main microbiota associated with fibrosis severity in non-obese subjects. Furthermore, stool bile acids and propionate are elevated, especially in non-obese subjects with significant fibrosis. Fibrosis-related Ruminococcaceae and Veillonellaceae species undergo metagenome sequencing, and four representative species are administered in three mouse NAFLD models to evaluate their effects on liver damage. This study provides the evidence for the role of the microbiome in the liver fibrosis pathogenesis, especially in non-obese subjects.


Assuntos
Bactérias/isolamento & purificação , Microbioma Gastrointestinal/fisiologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Fezes/química , Fezes/microbiologia , Fibrose , Microbioma Gastrointestinal/genética , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/microbiologia , Cirrose Hepática/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/patologia , Propionatos/análise , Propionatos/metabolismo , RNA Ribossômico 16S/genética , Reprodutibilidade dos Testes
3.
PLoS Med ; 17(9): e1003307, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32931494

RESUMO

BACKGROUND: Hypertension, together with obesity, is a leading cause of mortality and disability. Whilst metabolic surgery offers remission of several metabolic comorbidities, the effect for patients with hypertension remains controversial. The objective of the present study was to evaluate the effect of metabolic surgery on cardiovascular events and mortality on patients with morbid obesity (body mass index [BMI] ≥ 35 kg/m2) and hypertension. METHODS AND FINDINGS: We conducted a matched cohort study of 11,863 patients with morbid obesity and pharmacologically treated hypertension operated on with metabolic surgery and a matched non-operated-on control group of 26,199 subjects with hypertension (matched by age, sex, and area of residence) of varied matching ratios from 1:1 to 1:9, using data from the Scandinavian Obesity Surgery Register (SOReg), the Swedish National Patient Registers (NPR) for in-hospital and outpatient care, the Swedish Prescribed Drug Register, and Statistics Sweden. The main outcome was major adverse cardiovascular event (MACE), defined as first occurrence of acute coronary syndrome (ACS) event, cerebrovascular event, fatal cardiovascular event, or unattended sudden cardiac death. The mean age in the study group was 52.1 ± 7.46 years, with 65.8% being women (n = 7,810), and mean BMI was 41.9 ± 5.43 kg/m2. MACEs occurred in 379 operated-on patients (3.2%) and 1,125 subjects in the control group (4.5%). After adjustment for duration of hypertension, comorbidities, and education, a reduction in risk was seen in the metabolic surgery group (adjusted hazard ratio [HR] 0.73, 95% confidence intervals [CIs] 0.64-0.84, P < 0.001). The surgery group had lower risk for ACS events (adjusted HR 0.52, 95% CI 0.41-0.66, P < 0.001) and a tendency towards lower risk for cerebrovascular events (adjusted HR 0.81, 95% CI 0.63-1.01, P = 0.060) compared with controls. The main limitations with the study were the lack of information on BMI and history of smoking in the control group and the nonrandomised study design. CONCLUSION: Metabolic surgery on patients with morbid obesity and pharmacologically treated hypertension was associated with lower risk for MACEs and all-cause mortality compared with age- and sex-matched controls with hypertension from the general population.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Hipertensão/metabolismo , Obesidade Mórbida/cirurgia , Adulto , Cirurgia Bariátrica/tendências , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Hipertensão/cirurgia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/mortalidade , Modelos de Riscos Proporcionais , Fatores de Risco , Suécia/epidemiologia
4.
PLoS Biol ; 18(9): e3000870, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32986697

RESUMO

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.


Assuntos
Envelhecimento/sangue , Lipidômica , Lipídeos/sangue , Obesidade/metabolismo , Caracteres Sexuais , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Metabolismo dos Lipídeos , Masculino , Menopausa/sangue , Pessoa de Meia-Idade , Circunferência da Cintura
5.
Hautarzt ; 71(10): 762-771, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32886132

RESUMO

Hidradenitis suppurativa (HS) is a chronic, recurrent cutaneous disease of the terminal hair follicle which manifests with deep-seated, painful nodules, abscesses, and sinus tract formation. The pathophysiology of the disease includes among various factors also dermatoendocrinologic variables: Correlations with metabolic syndrome, obesity, sex steroid hormones, and the improvement after antiandrogen therapy are some of the key points presented in this review. Hormonal treatment of HS can be an effective and inexpensive alternative or add-on therapy to classic HS treatments, especially in cases where antibiotics and/or biologics are ineffective or contraindicated.


Assuntos
Abscesso/etiologia , Doenças do Sistema Endócrino/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Hidradenite Supurativa/fisiopatologia , Síndrome Metabólica/metabolismo , Antagonistas de Androgênios/uso terapêutico , Diabetes Mellitus/metabolismo , Dislipidemias/metabolismo , Folículo Piloso , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/metabolismo , Hormônios/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Obesidade/metabolismo
6.
Ecotoxicol Environ Saf ; 203: 111041, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888612

RESUMO

Although the production and use of PCB153 have been banned globally, PCB153 pollution remains because of its persistence and long half-life in the environment. There is ongoing evidence that exposure to PCB153 may influence gut microbiota health and increase the risk of host health. It is needed to illuminate whether there are associations between gut microbiota dysregulation and PCB153-induced host diseases. Importantly, it is urgently needed to find specific strains as biomarkers to monitor PCB153 pollution and associated disorders. The work aims to investigate the change of gut microbiota composition, structure and diversity and various host physiological indexes, to ravel the chain causality of PCB153, gut microbiota health and host health, and to find potential gut microbiota markers for PCB153 pollution. Here, adult female mice were administrated with PCB153. Obtained results indicated that PCB153 led to gut microbiota health deterioration. PCB153 exposure also induced obesity, hepatic lipid accumulation, abdominal adipose tissue depots and dyslipidemia in mice. Furthermore, specific gut microbiota significantly correlated with the host health indexes. This work provides support for the relationship between gut microbiota aberrance derived from PCB153 and risk of host health, and offers some indications of possible indicative functions of gut microbiota on PCB153 pollution.


Assuntos
Dislipidemias/induzido quimicamente , Monitoramento Ambiental/métodos , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Bifenilos Policlorados/toxicidade , Animais , Biomarcadores/análise , Colo/microbiologia , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Feminino , Conteúdo Gastrointestinal/microbiologia , Microbioma Gastrointestinal/genética , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia , RNA Ribossômico 16S
7.
Front Immunol ; 11: 1997, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983141

RESUMO

Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). Therefore, there is a critical need to identify underlying metabolic factors associated with obesity that could be contributing toward increased susceptibility to SARS-CoV-2 in this vulnerable population. Here, we focus on the critical role of potent endogenous lipid metabolites known as specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. SPMs are generated during the transition of inflammation to resolution and have a vital role in directing damaged tissues to homeostasis; furthermore, SPMs display anti-viral activity in the context of influenza infection without being immunosuppressive. We cover evidence from rodent and human studies to show that obesity, and its co-morbidities, induce a signature of SPM deficiency across immunometabolic tissues. We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Finally, we highlight potential approaches to overcome the loss of SPMs using dietary and pharmacological interventions. Collectively, this mini-review underscores the need for mechanistic studies on how SPM deficiencies driven by obesity and environmental exposures may exacerbate the response to SARS-CoV-2.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Ácidos Docosa-Hexaenoicos/deficiência , Ácido Eicosapentaenoico/metabolismo , Ácido Linoleico/deficiência , Lipoxinas/deficiência , Obesidade/epidemiologia , Obesidade/imunologia , Pneumonia Viral/epidemiologia , Comorbidade , Infecções por Coronavirus/dietoterapia , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Inflamação/metabolismo , Ácido Linoleico/uso terapêutico , Lipoxinas/uso terapêutico , Morbidade , Obesidade/metabolismo , Pandemias , Pneumonia Viral/dietoterapia , Pneumonia Viral/virologia , Fatores de Risco
8.
Elife ; 92020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32930095

RESUMO

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.


Assuntos
Infecções por Coronavirus/microbiologia , Diabetes Mellitus/microbiologia , Obesidade/microbiologia , Pneumonia Viral/microbiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/virologia , Animais , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/microbiologia , Complicações do Diabetes/virologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/virologia , Regulação para Baixo , Interações entre Hospedeiro e Microrganismos , Humanos , Interações Microbianas , Obesidade/metabolismo , Obesidade/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Carga Viral
9.
Life Sci ; 259: 118191, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777302

RESUMO

Numerous population studies conducted worldwide indicate that the prevalence of asthma is higher in obese versus lean individuals. It has been reported that sensitized lean mice has a better recovery of lung inflammation in asthma. Extracellular matrix (ECM) plays an essential role in the structural support of the lungs regulating the airways diameter, thus preventing its collapse during expiration. ECM renewal by metalloproteinase (MMPs) enzymes is critical for pulmonary biology. There seems to be an imbalance of MMPs activity in asthma and obesity, which can impair the lung remodeling process. In this study, we characterized the pulmonary ECM of obese and lean mice, non-sensitized and sensitized with ovalbumin (OVA). Pharmacological intervention was performed by using anti-TNF-α, and MMP-8 and MMP-9 inhibitors in obese and lean sensitized mice. Activity of MMPs was assessed by gelatinase electrophorese, western blotting and zymogram in situ. Unbalance of MMP-2, MMP-8, MMP-9 and MMP-12 was detected in lung tissue of OVA-sensitized obese mice, which was accompanied by high degradation, corroborating an excessive deposition of types I and III collagen in pulmonary matrix of obese animals. Inhibitions of TNF-α and MMP-9 reduced this MMP imbalance, clearly suggesting a positive effect on pulmonary ECM. Obese and lean mice presented diverse phenotype of asthma regarding the ECM compounds and the inhibition of MMPs pathway could be a good alternative to regulate the activity in ECM lungs of asthmatic obese individuals.


Assuntos
Asma/etiologia , Asma/metabolismo , Metaloproteases/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Matriz Extracelular/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Inibidores de Proteases/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
11.
Nat Commun ; 11(1): 4018, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782301

RESUMO

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Consórcios Microbianos , Obesidade/microbiologia , Adulto , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bactérias/metabolismo , Estudos de Coortes , Disbiose/metabolismo , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Especificidade de Hospedeiro , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Obesidade/metabolismo
12.
Life Sci ; 258: 118153, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738361

RESUMO

AIMS: Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly with or without focal and segmental glomerulosclerosis lesions. Isothiocyanate sulforaphane (SFN) can protect kidneys from ORG-related damages. In this study, we investigated the effects of SFN as a preventive therapy or intervention for ORG to reveal its mechanism of action. MAIN METHODS: We established a mouse obesity model with preventive SFN or N-acetylcysteine treatment for 2 months. Thereafter, we used nuclear factor erythroid 2-related factor 2-deficient (Nrf2-/-) and wild type mice in our ORG model with SFN treatment. Finally, we generated a corresponding mouse podocyte model in vitro. The body weight, wet weight of perirenal-and peritesticular fat, and urinary albumin/creatinine ratio were assessed. We used periodic acid-Schiff staining and electron microscopy to assess the function of the kidneys and podocytes. In addition, we evaluated the expression of Nrf2 and podocyte-specific proteins by western blotting. KEY FINDINGS: Treatment with SFN reduced body weight, organ-associated fat weight, and urinary albumin/creatinine ratio in both the preventive treatment and disease intervention regimens. SFN treated mice exhibited higher expression levels of podocyte-specific proteins and better podocyte function. However, treatment with SFN did not affect these parameters in obese Nrf2-/- mice. Light chain 3 of microtubule-associated protein 1-II and metallothionein had higher expression in the wild type than in the Nrf2-/- mice. SIGNIFICANCE: Treatment with SFN limited ORG-induced damage by enhancing podocyte autophagy via Nrf2.


Assuntos
Isotiocianatos/uso terapêutico , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/complicações , Substâncias Protetoras/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Nefropatias/metabolismo , Glomérulos Renais/citologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Podócitos/citologia , Podócitos/efeitos dos fármacos , Podócitos/metabolismo
13.
Food Chem Toxicol ; 145: 111701, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32858131

RESUMO

Obesity and its related metabolic disorders, as well as infectious diseases like covid-19, are important health risks nowadays. It was recently documented that long-term fasting improves metabolic health and enhanced the total antioxidant capacity. The present study investigated the influence of a 10-day fasting on markers of the redox status in 109 subjects. Reducing power, 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical cation(ABTS) radical scavenging capacity, and hydroxyl radical scavenging capacity increased significantly, and indicated an increase of circulating antioxidant levels. No differences were detected in superoxide scavenging capacity, protein carbonyls, and superoxide dismutase when measured at baseline and after 10 days of fasting. These findings were concomitant to a decrease in blood glucose, insulin, glycated hemoglobin (HbA1c), total cholesterol, low-density lipoprotein (LDL) and triglycerides as well as an increase in total cholesterol/high-density lipoprotein (HDL) ratio. In addition, the well-being index as well as the subjective energy levels increased, documenting a good tolerability. There was an interplay between redox and metabolic parameters since lipid peroxidation baseline levels (thiobarbituric acid reactive substances [TBARS]) affected the ability of long-term fasting to normalize lipid levels. A machine learning model showed that a combination of antioxidant parameters measured at baseline predicted the efficiency of the fasting regimen to decrease LDL levels. In conclusion, it was demonstrated that long-term fasting enhanced the endogenous production of antioxidant molecules, that act protectively against free radicals, and in parallel improved the metabolic health status. Our results suggest that the outcome of long-term fasting strategies could be depending on the baseline values of the antioxidative and metabolic status of subjects.


Assuntos
Jejum/metabolismo , Depuradores de Radicais Livres/metabolismo , Obesidade/dietoterapia , Estresse Oxidativo/fisiologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Metabolismo dos Lipídeos/fisiologia , Peroxidação de Lipídeos/fisiologia , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Adulto Jovem
14.
Ugeskr Laeger ; 182(29)2020 07 13.
Artigo em Dinamarquês | MEDLINE | ID: mdl-32734864

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome corona virus 2. High age, hypertension, diabetes, and obesity are risk factors for severe COVID-19 with increased mortality. In this review, we discuss potential mechanisms by which diabetes and obesity modulate the host viral interactions and host-immune response. Glucose levels should be monitored rigorously, and patient-tailored aggressive treatment of hyperglycaemia is recommended, often with the use of insulin. Persons with diabetes and obesity are susceptible to severe outcomes from COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Diabetes Mellitus/virologia , Interações entre Hospedeiro e Microrganismos , Obesidade/complicações , Pneumonia Viral/complicações , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Sistema Endócrino , Humanos , Hiperglicemia/tratamento farmacológico , Insulina/uso terapêutico , Obesidade/metabolismo , Obesidade/virologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Fatores de Risco
15.
PLoS One ; 15(8): e0237974, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841271

RESUMO

BACKGROUND: Cardiometabolic disorders are frequently observed among those who have obesity as measured by body mass index (BMI). However, there is limited data available on the cardiometabolic profile of those who are non-obese by BMI but with a high body fat percentage (BFP), a phenotype frequently observed in the Indian population. We examined the prevalence of individuals with normal weight obesity (NWO) and the cardiometabolic profile of NWO individuals at high risk for type 2 diabetes(T2D) in a south Asian population. MATERIAL AND METHODS: In the Kerala Diabetes Prevention Program, individuals aged between 30 to 60 years were screened using the Indian Diabetes Risk Score(IDRS) in 60 rural communities in the Indian state of Kerala. We used data from the baseline survey of this trial for this analysis which included 1147 eligible high diabetes risk individuals(IDRS >60). NWO was defined as BMI within the normal range and a high BFP (as per Asia-pacific ethnicity based cut-off); Non-obese (NO) as normal BMI and BFP and overtly obese (OB) as BMI ≥25 kg/m2 irrespective of the BFP. Data on demographic, clinical and biochemical characteristics were collected using standardized questionnaires and protocols. Body fat percentage was assessed using TANITA body composition analyser (model SC330), based on bioelectrical impedance. RESULTS: The mean age of participants was 47.3 ± 7.5 years and 46% were women. The proportion with NWO was 32% (n = 364; 95% CI: 29.1 to 34.5%), NO was 17% (n = 200) and OB was 51% (n = 583). Among those with NWO, 19.7% had T2D, compared to 18.7% of those who were OB (p value = 0.45) and 8% with NO (p value = 0.003). Among those with NWO, mean systolic and diastolic blood pressure were 129 ± 20; 78 ± 12 mmHg, compared to 127 ± 17; 78±11 mmHg among those with OB (p value = 0.12;0.94) and 120 ± 16; 71±10 mmHg among with NO (p value<0.001; 0.001), respectively. A similar pattern of association was observed for LDL cholesterol and triglycerides. After adjusting for other risk factors, the odds of having diabetes (OR:2.72[95% CI:1.46-5.08]) and dyslipidemia (2.37[1.55-3.64]) was significantly more in individuals with NWO as compared to non-obese individuals. CONCLUSIONS: Almost one-third of this South Asian population, at high risk for T2D, had normal weight obesity. The significantly higher cardiometabolic risk associated with increased adiposity even in lower BMI individuals has important implications for recognition in clinical practice.


Assuntos
Tecido Adiposo/patologia , Peso Corporal , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/prevenção & controle , Miocárdio/metabolismo , Obesidade/epidemiologia , Obesidade/metabolismo , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fenótipo , Prevalência , Fatores de Risco
16.
Nat Commun ; 11(1): 4313, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855402

RESUMO

It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.


Assuntos
Adipócitos Bege/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Obesidade/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Termogênese/genética , Animais , Calorimetria Indireta , Linhagem Celular , Temperatura Baixa/efeitos adversos , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético/genética , Regulação da Expressão Gênica/fisiologia , Células HEK293 , Humanos , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Knockout , Obesidade/etiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas/genética , RNA-Seq , Gordura Subcutânea/citologia , Gordura Subcutânea/metabolismo , Proteína Desacopladora 1/metabolismo
17.
PLoS Negl Trop Dis ; 14(7): e0008464, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614822

RESUMO

Infection with parasitic helminths has been reported to improve insulin sensitivity and glucose homeostasis, lowering the risk for type 2 diabetes. However, little is known about its impact on whole-body lipid homeostasis, especially in obese individuals. For this purpose, a cross-sectional study was carried out in lean and overweight/obese adults residing in the Lambaréné region of Gabon, an area endemic for Schistosoma haematobium. Helminth infection status, peripheral blood immune cell counts, and serum metabolic and lipid/lipoprotein levels were analyzed. We found that urine S. haematobium egg-positive individuals exhibited lower serum total cholesterol (TC; 4.42 vs 4.01 mmol/L, adjusted mean difference [95%CI] -0.30 [-0.68,-0.06]; P = 0.109), high-density lipoprotein (HDL)-C (1.44 vs 1.12 mmol/L, -0.24 [-0.43,-0.06]; P = 0.009) and triglyceride (TG; 0.93 vs 0.72 mmol/L, -0.20 [-0.39,-0.03]; P = 0.022) levels than egg-negative individuals. However, when stratified according to body mass index, these effects were only observed in overweight/obese infected individuals. Similarly, significant negative correlations between the intensity of infection, assessed by serum circulating anodic antigen (CAA) concentrations, and TC (r = -0.555; P<0.001), HDL-C (r = -0.327; P = 0.068), LDL-C (r = -0.396; P = 0.025) and TG (r = -0.381; P = 0.032) levels were found in overweight/obese individuals but not in lean subjects. Quantitative lipidomic analysis showed that circulating levels of some lipid species associated with cholesterol-rich lipoprotein particles were also significantly reduced in overweight/obese infected individuals in an intensity-dependent manner. In conclusion, we reported that infection with S. haematobium is associated with improved lipid profile in overweight/obese individuals, a feature that might contribute reducing the risk of cardiometabolic diseases in such population.


Assuntos
Colesterol/sangue , Lipídeos/sangue , Obesidade/metabolismo , Sobrepeso/metabolismo , Esquistossomose Urinária/metabolismo , Adolescente , Adulto , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R211-R222, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609532

RESUMO

Although severe intermittent hypoxia (IH) is well known to induce deleterious cardiometabolic consequences, moderate IH may induce positive effects in obese individuals. The present study aimed to evaluate the effect of two hypoxic conditioning programs on cardiovascular and metabolic health status of overweight or obese individuals. In this randomized single-blind controlled study, 35 subjects (54 ± 9.3 yr, 31.7 ± 3.5 kg/m2) were randomized into three 8-wk interventions (three 1-h sessions per week): sustained hypoxia (SH), arterial oxygen saturation ([Formula: see text]) = 75%; IH, 5 min [Formula: see text] = 75% - 3 min normoxia; normoxia. Ventilation, heart rate, blood pressure, and tissue oxygenation were measured during the first and last hypoxic conditioning sessions. Vascular function, blood glucose and insulin, lipid profile, nitric oxide metabolites, and oxidative stress were evaluated before and after the interventions. Both SH and IH increased ventilation in hypoxia (+1.8 ± 2.1 and +2.3 ± 3.6 L/min, respectively; P < 0.05) and reduced normoxic diastolic blood pressure (-12 ± 15 and -13 ± 10 mmHg, respectively; P < 0.05), whereas changes in normoxic systolic blood pressure were not significant (+3 ± 9 and -6 ± 13 mmHg, respectively; P > 0.05). IH only reduced heart rate variability (e.g., root-mean-square difference of successive normal R-R intervals in normoxia -21 ± 35%; P < 0.05). Both SH and IH induced no significant change in body mass index, vascular function, blood glucose, insulin and lipid profile, nitric oxide metabolites, or oxidative stress, except for an increase in superoxide dismutase activity following SH. This study indicates that passive hypoxic conditioning in obese individuals induces some positive cardiovascular and respiratory improvements despite no change in anthropometric data and even a reduction in heart rate variability during IH exposure.


Assuntos
Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Sistema Cardiovascular/fisiopatologia , Frequência Cardíaca/fisiologia , Hipóxia/fisiopatologia , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Adulto , Sistema Cardiovascular/metabolismo , Colesterol/sangue , Feminino , Humanos , Hipóxia/metabolismo , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Sobrepeso/metabolismo , Método Simples-Cego , Triglicerídeos/sangue
19.
Arterioscler Thromb Vasc Biol ; 40(9): 2227-2243, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640901

RESUMO

OBJECTIVE: Perivascular adipose tissue (PVAT) surrounding arteries supports healthy vascular function. During obesity, PVAT loses its vasoprotective effect. We study pathological conversion of PVAT, which involves molecular changes in protein profiles and functional changes in adipocytes. Approach and Results: C57BL6/J mice were fed a 60% high-fat diet for 12 weeks or a cardioprotective 30% calorie-restricted diet for 5 weeks. Proteomic analysis identified PVAT as a molecularly distinct adipose depot, and novel markers for thermogenic adipocytes, such as GRP75 (stress-70 protein, mitochondrial), were identified. High-fat diet increased the similarity of protein signatures in PVAT and brown adipose, suggesting activation of a conserved whitening pathway. The whitening phenotype was characterized by suppression of UCP1 (uncoupling protein 1) and increased lipid deposition, leptin, and inflammation, and specifically in PVAT, elevated Notch signaling. Conversely, PVAT from calorie-restricted mice had decreased Notch signaling and less lipid. Using the Adipoq-Cre strain, we constitutively activated Notch1 signaling in adipocytes, which phenocopied the changes in PVAT caused by a high-fat diet, even on a standard diet. Preadipocytes from mouse PVAT expressed Sca1, CD140a, Notch1, and Notch2, but not CD105, showing differences compared with preadipocytes from other depots. Inhibition of Notch signaling during differentiation of PVAT-derived preadipocytes reduced lipid deposition and adipocyte marker expression. CONCLUSIONS: PVAT shares features with other adipose depots, but has a unique protein signature that is regulated by dietary stress. Increased Notch signaling in PVAT is sufficient to initiate the pathological conversion of PVAT by promoting adipogenesis and lipid accumulation and may thus prime the microenvironment for vascular disease.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Lipogênese , Obesidade/metabolismo , Receptores Notch/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Ataxina-1/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Restrição Calórica , Dieta Hiperlipídica , Modelos Animais de Doenças , Endoglina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/patologia , Fenótipo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Proteômica , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Notch/genética , Transdução de Sinais
20.
Arterioscler Thromb Vasc Biol ; 40(9): e240-e255, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698687

RESUMO

OBJECTIVE: To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K+) channels. Approach and Results: Endothelial dysfunction, observed as reduced dilations to flow, occurred after feeding mice a high-fat, Western diet for 8 weeks. The functional downregulation of endothelial Kir2.1 using dominant-negative Kir2.1 construct resulted in substantial reductions in the response to flow in mesenteric arteries of lean mice, whereas no effect was observed in arteries of obese mice. Overexpressing wild-type-Kir2.1 in endothelium of arteries from obese mice resulted in full recovery of the flow response. Exposing freshly isolated endothelial cells to fluid shear during patch-clamp electrophysiology revealed that the flow-sensitivity of Kir was virtually abolished in cells from obese mice. Atomic force microscopy revealed that the endothelial glycocalyx was stiffer and the thickness of the glycocalyx layer reduced in arteries from obese mice. We also identified that the length of the glycocalyx is critical to the flow-activation of Kir. Overexpressing Kir2.1 in endothelium of arteries from obese mice restored flow- and heparanase-sensitivity, indicating an important role for heparan sulfates in the flow-activation of Kir. Furthermore, the Kir2.1-dependent component of flow-induced vasodilation was lost in the endothelium of resistance arteries of obese humans obtained from biopsies collected during bariatric surgery. CONCLUSIONS: We conclude that obesity-induced impairment of flow-induced vasodilation is attributed to the loss of flow-sensitivity of endothelial Kir channels and propose that the latter is mediated by the biophysical alterations of the glycocalyx.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Glicocálix/metabolismo , Artérias Mesentéricas/metabolismo , Obesidade/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Vasodilatação , Adulto , Animais , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Feminino , Heparitina Sulfato/metabolismo , Humanos , Masculino , Mecanotransdução Celular , Potenciais da Membrana , Artérias Mesentéricas/fisiopatologia , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Fluxo Sanguíneo Regional
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