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1.
Gene ; 807: 145950, 2022 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-34481003

RESUMEN

This population-based longitudinal study is the first investigation that assesses the association of common MC4R SNPs with the obesity-related parameters over time and determines the effect of risk alleles during the three adulthood life periods (early, middle, and late) in a large Iranian cohort, a population with a unique genetic make-up that has been understudied and relatively unexplored. We obtained the genotype of 5370 unrelated adults who participated in the ongoing Tehran Cardiometabolic Genetic Study (TCGS) cohort project for the common MC4R SNPs. Linear regression and linear mixed model analyses were performed to examine the effect of MC4R polymorphisms on maximum BMI and other obesity-related factors over time. We recognized that several SNPs associated with the maximum BMI and the increased BMI, waist circumference, and waist-hip ratio across Iranian adults over a lifetime. Interestingly, we found that rs9954571-A has a yet unreported protective role against obesity-related factors, including BMI, waist circumference, waist-hip ratio, and triglyceride level. Additionally, a survey of the impact of the MC4R risk score throughout the adulthood life periods indicated that the MC4R risk score is influenced both the elevated BMI and waist circumference only during the early adulthood period. Our findings can expand our knowledge about the MC4R genetic variant's contributions to adulthood obesity and highlight the importance of evaluating the genetic components affecting obesity over a lifetime, which could be considered for obesity clinical screening and treatment.


Asunto(s)
Obesidad/genética , Receptor de Melanocortina Tipo 4/genética , Adulto , Alelos , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Irán/epidemiología , Estudios Longitudinales , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Obesidad/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Receptor de Melanocortina Tipo 4/metabolismo , Factores de Riesgo , Circunferencia de la Cintura/genética , Relación Cintura-Cadera/métodos
2.
Front Immunol ; 12: 732913, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34737743

RESUMEN

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.


Asunto(s)
COVID-19/inmunología , COVID-19/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , COVID-19/complicaciones , Progresión de la Enfermedad , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/metabolismo , Obesidad/complicaciones , Pronóstico , SARS-CoV-2/patogenicidad , Índice de Severidad de la Enfermedad
3.
J Med Food ; 24(11): 1153-1160, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34792395

RESUMEN

Obesity is associated with metabolic diseases, including insulin resistance, type 2 diabetes and dyslipidemia. Antiobesity drugs are available but have side effects. Hydroxy citric acid (HCA) with ATP-citrate lyase enzyme-inhibiting activity has been identified as a safe potential supplement for weight management and as an antiobesity agent. In the present study, we aim to test the antiobesity potential of the fruit rind powder of G. indica (a plant rich in HCA) in genetically obese rats. Forty-five-day-old Male WNIN/GR-Ob rats were divided equally into four groups with each group having six rats. Group 1 was fed with a standard powder diet (SPD), whereas Groups 2, 3, and 4 were fed with SPD containing 1%, 3%, and 5%, respectively, of G. indica powder for 12 weeks. Food intake, body composition, oral glucose tolerance test, plasma insulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipid profile, hepatic glycogen, ATP-citrate lyase, and Glucose-6-Phosphate dehydrogenase (G6PDH) were measured. Histological analysis of vital organs and Immunohistochemistry (IHC) analysis was carried out in liver sections for citrate lyase score. G. indica significantly decreased food intake, body weight, body fat %, hepatic and circulating triglycerides, cholesterol, and liver steatosis. In addition, G6PDH and ATP-citrate lyase enzyme activities were decreased along with an increase in liver glycogen. The IHC scores of citrate lyase were lower in treated groups. The results indicate that G. indica exerts favorable effects on obesity with a possible mechanism of anorectic effects, suppressed citrate lyase enzyme activity, and improved insulin sensitivity due to the modulation of carbohydrate metabolism by the phytochemicals and secondary metabolites.


Asunto(s)
Diabetes Mellitus Tipo 2 , Garcinia , Animales , Composición Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/metabolismo , Hígado/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/genética , Obesidad/metabolismo , Polvos/metabolismo , Ratas
4.
Nurs Clin North Am ; 56(4): 449-464, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34749887

RESUMEN

Obesity is a disease with several potential causes and contributors. This article provides a focused overview of key known causes of obesity and factors that contribute to obesity. Obesity ultimately results from impaired energy storage mechanisms, such as dysregulation of hunger, satiety, digestion, fat storage, and metabolic rate. In addition, myriad contributors promote its expression, including dietary factors, sleep quality and duration, psychological health and well-being, and tobacco cessation, among others. This article concludes with a discussion of the clinical relevance of causes and contributors in obesity prevention and treatment, which is paramount to providing effective, individualized clinical management.


Asunto(s)
Ingestión de Energía , Conducta Alimentaria , Obesidad , Conducta Sedentaria , Índice de Masa Corporal , Humanos , Hambre , Obesidad/etiología , Obesidad/metabolismo , Saciedad
5.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-34638731

RESUMEN

In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation.


Asunto(s)
Adipocitos Marrones/metabolismo , Adipoquinas/biosíntesis , Tejido Adiposo Pardo/metabolismo , Galectina 3/biosíntesis , Regulación de la Expresión Génica , Obesidad/metabolismo , Condicionamiento Físico Animal , Animales , Diferenciación Celular , Ratones
6.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-34638751

RESUMEN

Obesity is a risk factor for metabolic diseases including type 2 diabetes, nonalcoholic steatohepatitis (NASH), heart diseases, and cancer. This study aimed to investigate the anti-obesity effect of Polygalin C (PC) isolated from Polygala japonica Houtt. in 3T3-L1 adipocytes. Based on Oil Red O assay results, PC significantly decreased lipid accumulation compared to the control. We found that PC suppressed adipogenesis transcription factors including peroxisome proliferator-activated receptor γ (PPAR γ) and CCAAT/enhancer-binding protein (C/EBP) α, and lipogenic factors such as sterol regulatory element-binding protein 1c (SREBP 1c) and fatty acid synthase (FAS), in 3T3-L1 adipocytes using Western blotting and real-time polymerase chain reaction (PCR). Moreover, PC inhibited the differentiation of 3T3-L1 cells by regulating the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinase/protein kinase B (MAPK/Akt) signaling pathways. Additionally, we confirmed that PC inhibited early adipogenesis factors C/EBP ß and C/EBP δ. Therefore, PC inhibited adipogenesis and lipogenesis in vitro. Thus, PC appears to exert potential therapeutic effects on obesity by suppressing lipid metabolism.


Asunto(s)
Adipogénesis/efectos de los fármacos , Flavonoles/farmacología , Lipogénesis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Obesidad , Polygala/química , Células 3T3-L1 , Animales , Acido Graso Sintasa Tipo I/biosíntesis , Flavonoles/química , Flavonoles/aislamiento & purificación , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , PPAR gamma/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo
7.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-34638758

RESUMEN

BACKGROUND: Identifying those parameters that could potentially predict the deterioration of metabolically healthy phenotype is a matter of debate. In this field, epigenetics, in particular DNA methylation deserves special attention. RESULTS: The aim of the present study was to analyze the long-term evolution of methylation patterns in a subset of metabolically healthy subjects in order to search for epigenetic markers that could predict the progression to an unhealthy state. Twenty-six CpG sites were significantly differentially methylated, both at baseline and 11-year follow-up. These sites were related to 19 genes or pseudogenes; a more in-depth analysis of the methylation sites of these genes showed that CYP2E1 had 50% of the collected CpG sites differently methylated between stable metabolically healthy obesity (MHO) and unstable MHO, followed by HLA-DRB1 (33%), ZBTB45 (16%), HOOK3 (14%), PLCZ1 (14%), SLC1A1 (12%), MUC2 (12%), ZFPM2 (12.5%) and HLA-DQB2 (8%). Pathway analysis of the selected 26 CpG sites showed enrichment in pathways linked to th1 and th2 activation, antigen presentation, allograft rejection signals and metabolic processes. Higher methylation levels in the cg20707527 (ZFPM2) could have a protective effect against the progression to unstable MHO (OR: 0.21, 95%CI (0.067-0.667), p < 0.0001), whilst higher methylation levels in cg11445109 (CYP2E1) would increase the progression to MUO; OR: 2.72, 95%CI (1.094-6.796), p < 0.0014; respectively). CONCLUSIONS: DNA methylation status is associated with the stability/worsening of MHO phenotype. Two potential biomarkers of the transition to an unhealthy state were identified and deserve further investigation (cg20707527 and cg11445109). Moreover, the described differences in methylation could alter immune system-related pathways, highlighting these pathways as therapeutic targets to prevent metabolic deterioration in MHO patients.


Asunto(s)
Islas de CpG , Metilación de ADN , Epigénesis Genética , Obesidad/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Obesidad/genética , Fenotipo , Estudios Prospectivos
8.
J Med Microbiol ; 70(10)2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34623232

RESUMEN

Alteration in the composition of the gut microbiota can lead to a number of chronic clinical diseases. Akkermansia muciniphila is an anaerobic bacteria constituting 3-5% of the gut microbial community in healthy adults. This bacterium is responsible for degenerating mucin in the gut; its scarcity leads to diverse clinical disorders. In this review, we focus on the role of A. muciniphila in diabetes, obesity and atherosclerosis, as well as the use of this bacterium as a next-generation probiotic. In regard to obesity and diabetes, human and animal trials have shown that A. muciniphila controls the essential regulatory system of glucose and energy metabolism. However, the underlying mechanisms by which A. muciniphila alleviates the complications of obesity, diabetes and atherosclerosis are unclear. At the same time, its abundance suggests improved metabolic disorders, such as metabolic endotoxemia, adiposity insulin resistance and glucose tolerance. The role of A. muciniphila is implicated in declining aortic lesions and atherosclerosis. Well-characterized virulence factors, antigens and cell wall extracts of A. muciniphila may act as effector molecules in these diseases. These molecules may provide novel mechanisms and strategies by which this bacterium could be used as a probiotic for the treatment of obesity, diabetes and atherosclerosis.


Asunto(s)
Aterosclerosis/microbiología , Diabetes Mellitus/microbiología , Obesidad/microbiología , Probióticos , Akkermansia/fisiología , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Metabolismo Energético , Microbioma Gastrointestinal , Humanos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Probióticos/uso terapéutico
9.
J Clin Invest ; 131(17)2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34623331

RESUMEN

Pancreatic ß cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the ß cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in ß cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM ß cells contributes to ß cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in ß cells of patients with T2DM and demonstrated that its expression was associated with loss of ß cell transcriptional identity, intracellular alkalinization, and ß cell dysfunction. In addition, we generated a ß cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and ß cell dysfunction. Importantly, improved glucose tolerance and enhanced ß cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating ß cell identity and function. These results suggest that increased ß cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of ß cell failure and should be considered as a potential therapeutic target.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Simportadores de Sodio-Bicarbonato/metabolismo , Animales , Diabetes Mellitus Tipo 2/genética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Expresión Génica , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/prevención & control , Humanos , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Obesidad/genética , Obesidad/metabolismo , Simportadores de Sodio-Bicarbonato/deficiencia , Simportadores de Sodio-Bicarbonato/genética , Estrés Fisiológico
10.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-34638553

RESUMEN

Low-grade chronic inflammation plays a pivotal role in the pathogenesis of insulin resistance (IR), and skeletal muscle has a central role in this condition. NLRP3 inflammasome activation pathways promote low-grade chronic inflammation in several tissues. However, a direct link between IR and NLRP3 inflammasome activation in skeletal muscle has not been reported. Here, we evaluated the NLRP3 inflammasome components and their role in GLUT4 translocation impairment in skeletal muscle during IR. Male C57BL/6J mice were fed with a normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. The protein levels of NLRP3, ASC, caspase-1, gasdermin-D (GSDMD), and interleukin (IL)-1ß were measured in both homogenized and isolated fibers from the flexor digitorum brevis (FDB) or soleus muscle. GLUT4 translocation was determined through GLUT4myc-eGFP electroporation of the FBD muscle. Our results, obtained using immunofluorescence, showed that adult skeletal muscle expresses the inflammasome components. In the FDB and soleus muscles, homogenates from HFD-fed mice, we found increased protein levels of NLRP3 and ASC, higher activation of caspase-1, and elevated IL-1ß in its mature form, compared to NCD-fed mice. Moreover, GSDMD, a protein that mediates IL-1ß secretion, was found to be increased in HFD-fed-mice muscles. Interestingly, MCC950, a specific pharmacological NLRP3 inflammasome inhibitor, promoted GLUT4 translocation in fibers isolated from the FDB muscle of NCD- and HFD-fed mice. In conclusion, we found increased NLRP3 inflammasome components in adult skeletal muscle of obese insulin-resistant animals, which might contribute to the low-grade chronic metabolic inflammation of skeletal muscle and IR development.


Asunto(s)
Transportador de Glucosa de Tipo 4/metabolismo , Inflamasomas/metabolismo , Resistencia a la Insulina/fisiología , Interleucina-1beta/metabolismo , Músculo Esquelético/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Caspasa 1/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Furanos/farmacología , Indenos/farmacología , Inflamasomas/química , Interleucina-1beta/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Obesidad/inducido químicamente , Obesidad/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Sulfonamidas/farmacología
11.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-34638803

RESUMEN

Adipose tissue releases a large range of bioactive factors called adipokines, many of which are involved in inflammation, glucose homeostasis and lipid metabolism. Under pathological conditions such as obesity, most of the adipokines are upregulated and considered as deleterious, due to their pro-inflammatory, pro-atherosclerotic or pro-diabetic properties, while only a few are downregulated and would be designated as beneficial adipokines, thanks to their counteracting properties against the onset of comorbidities. This review focuses on six adipose-derived lipid-binding proteins that have emerged as key factors in the development of obesity and diabetes: Retinol binding protein 4 (RBP4), Fatty acid binding protein 4 (FABP4), Apolipoprotein D (APOD), Lipocalin-2 (LCN2), Lipocalin-14 (LCN14) and Apolipoprotein M (APOM). These proteins share structural homology and capacity to bind small hydrophobic molecules but display opposite effects on glucose and lipid metabolism. RBP4 and FABP4 are positively associated with metabolic syndrome, while APOD and LCN2 are ubiquitously expressed proteins with deleterious or beneficial effects, depending on their anatomical site of expression. LCN14 and APOM have been recently identified as adipokines associated with healthy metabolism. Recent findings on these lipid-binding proteins exhibiting detrimental or protective roles in human and murine metabolism and their involvement in metabolic diseases are also discussed.


Asunto(s)
Adipoquinas/metabolismo , Tejido Adiposo/metabolismo , Síndrome Metabólico/metabolismo , Animales , Apolipoproteínas D/metabolismo , Apolipoproteínas M/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Humanos , Lipocalina 2/metabolismo , Síndrome Metabólico/etiología , Obesidad/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo
12.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-34638990

RESUMEN

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 Diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin ß receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Péptidos/administración & dosificación , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/administración & dosificación , Animales , Sitios de Unión , Glucemia/metabolismo , Simulación por Computador , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Hiperinsulinismo/tratamiento farmacológico , Hiperinsulinismo/metabolismo , Hipoglucemiantes/síntesis química , Resistencia a la Insulina , Receptor beta de Linfotoxina/química , Receptor beta de Linfotoxina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismo , Péptidos/síntesis química , Miembro 14 de Receptores del Factor de Necrosis Tumoral/química , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/química , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo
13.
Nutrients ; 13(10)2021 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-34684358

RESUMEN

BACKGROUND: Obesity increases the severity of SARS-CoV-2 outcomes. Thus, this study tested whether obesogenic and ketogenic diets distinctly affect SARS-CoV-2 entry proteins and the renin-angiotensin system (RAS) in rat pulmonary and cardiac tissues. METHODS: Male Sprague-Dawley rats were fed either standard chow (SC), a high-fat sucrose-enriched diet (HFS), or a ketogenic diet (KD) for 16 weeks. Afterwards, levels of angiotensin converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), RAS components, and inflammatory genes were measured in the lungs and hearts of these animals. RESULTS: In the lungs, HFS elevated ACE2 and TMPRSS2 levels relative to SC diet, whereas the KD lowered the levels of these proteins and the gene expressions of toll-like receptor 4 and interleukin-6 receptor relative to HFS. The diets did not alter ACE2 and TMPRSS2 in the heart, although ACE2 was more abundant in heart than lung tissues. CONCLUSION: Diet-induced obesity increased the levels of viral entry proteins in the lungs, providing a mechanism whereby SARS-CoV-2 infectivity can be enhanced in obese individuals. Conversely, by maintaining low levels of ACE2 and TMPRSS2 and by exerting an anti-inflammatory effect, the KD can potentially attenuate the severity of infection and migration of SARS-CoV-2 to other ACE2-expressing tissues.


Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Dieta Alta en Grasa/efectos adversos , Dieta Cetogénica/métodos , Pulmón/metabolismo , Miocardio/metabolismo , Serina Endopeptidasas/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Biomarcadores/metabolismo , COVID-19/complicaciones , COVID-19/metabolismo , Modelos Animales de Enfermedad , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Ratas , Ratas Sprague-Dawley , Sistema Renina-Angiotensina , SARS-CoV-2 , Serina Endopeptidasas/genética , Internalización del Virus
14.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34638898

RESUMEN

The preference for high-calorie foods depends on sex and contributes to obesity development. Fibroblast growth factor 21 (FGF21) beneficially affects taste preferences and obesity, but its action has mainly been studied in males. The aim of this study was to compare the effects of FGF21 on food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with diet-induced obesity. Mice were injected with FGF21 or vehicle for 7 days. Body weight, choice between standard (SD) and high-fat (HFD) diets, blood parameters, and gene expression in white (WAT) and brown (BAT) adipose tissues, liver, muscles, and the hypothalamus were assessed. Compared to males, females had a greater preference for HFD; less WAT; lower levels of cholesterol, glucose, and insulin; and higher expression of Fgf21, Insr, Ppara, Pgc1, Acca and Accb in the liver and Dio2 in BAT. FGF21 administration decreased adiposity; blood levels of cholesterol, glucose, and insulin; hypothalamic Agrp expression, increased SD intake, decreased HFD intake independently of sex, and increased WAT expression of Pparg, Lpl and Lipe only in females. Thus, FGF21 administration beneficially affected mice of both sexes despite obesity-associated sex differences in metabolic characteristics, and it induced female-specific activation of gene expression in WAT.


Asunto(s)
Tejido Adiposo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/administración & dosificación , Expresión Génica/efectos de los fármacos , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/genética , Acido Graso Sintasa Tipo I/genética , Femenino , Factores de Crecimiento de Fibroblastos/genética , Insulina/sangre , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/etiología , Obesidad/genética , PPAR alfa/genética , Piruvato Quinasa/genética , Factores Sexuales
15.
Nutrients ; 13(10)2021 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-34684414

RESUMEN

Obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism, and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity-related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks. Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot. Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3ß (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.


Asunto(s)
Antioxidantes/farmacología , Ceramidas/biosíntesis , Suplementos Dietéticos , Insulina/metabolismo , Miocardio/metabolismo , Obesidad/metabolismo , Transducción de Señal/efectos de los fármacos , Alimentación Animal , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Peso Corporal , Dieta Alta en Grasa , Glucosa/metabolismo , Resistencia a la Insulina , Masculino , Redes y Vías Metabólicas , Modelos Animales , Obesidad/etiología , Fosforilación , Ratas , Roedores , Esfingolípidos/metabolismo
16.
Nutrients ; 13(10)2021 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-34684438

RESUMEN

Little is known about the difference in effectiveness of lifestyle intervention between women with PCOS and non-PCOS women. In a post hoc longitudinal analysis of a randomized, controlled trial, we aimed to investigate whether infertile women with PCOS and obesity (N = 87) responded differently to a 6-month lifestyle intervention program than infertile non-PCOS obese controls (N = 172). We evaluated several aspects of the intervention such as changes in diet, physical activity, and dropout rate, as well as the effect on weight, quality of life (QoL), and cardiometabolic outcomes. Multilevel analyses were used, and analyses were adjusted for baseline characteristics such as age, education, and smoking. Although BMI in both groups significantly decreased at 3 months and 6 months, there were no significant differences between the groups at 3 months (adjusted B: -0.3, 95% CI: -0.9 to 0.3, p = 0.35) and 6 months (adjusted B: 0.5, 95% CI: -0.4 to 1.4, p = 0.29). Women with PCOS and non-PCOS women had similar compliance with the lifestyle intervention in terms of actual change in diet and physical activity. Mental QoL scores were not different at either 3 or 6 months. Physical QoL scores were lower in women with PCOS compared with non-PCOS women at 3 months (adjusted B: -2.4, 95% CI: -4.8 to -0.06, p = 0.045) but not at 6 months. Cardiometabolic parameters did not differ between the groups. Our results showed that infertile women with PCOS and obesity and non-PCOS obese controls responded largely similarly to our lifestyle intervention and achieved the same level of improvement in markers of cardiometabolic health.


Asunto(s)
Biomarcadores , Dieta , Ejercicio Físico , Estilo de Vida , Obesidad/epidemiología , Síndrome del Ovario Poliquístico/epidemiología , Calidad de Vida , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Susceptibilidad a Enfermedades , Femenino , Evaluación del Impacto en la Salud , Humanos , Países Bajos/epidemiología , Obesidad/etiología , Obesidad/metabolismo , Síndrome del Ovario Poliquístico/etiología , Síndrome del Ovario Poliquístico/metabolismo , Vigilancia en Salud Pública , Sistema de Registros
17.
Nutrients ; 13(10)2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34684461

RESUMEN

(1) Background: Obesity and type 2 diabetes have been suspected to impact both intrinsic metabolism and function of circulating immune cells. (2) Methods: To further investigate this immunometabolic modulation, we profiled the phospholipidome of the peripheral blood mononuclear cells (PBMCs) in lean, normoglycemic obese (OBNG) and obese with dysglycemia (OBDysG) individuals. (3) Results: The global PBMCs phospholipidome is significantly downmodulated in OBDysG unlike OBNG patients when compared to lean ones. Multiple linear regression analyses show a strong negative relationship between the global PBMCs phospholipidome and parameters assessing insulin resistance. Even though all classes of phospholipid are affected, the relative abundance of each class is maintained with the exception of Lyso-PC/PC and Lyso-PE/PE ratios that are downmodulated in PBMCs of OBDysG compared to OBNG individuals. Interestingly, the percentage of saturated PC is positively associated with glycated hemoglobin (HbA1c). Moreover, a few lipid species are significantly downmodulated in PBMCs of OBDysG compared to OBNG individuals, making possible to distinguish the two phenotypes. (4) Conclusions: This lipidomic study highlights for the first-time modulations of the PBMCs phospholipidome in obese patients with prediabetes and type 2 diabetes. Such phospholipidome remodeling could disrupt the cell membranes and the lipid mediator's levels, driving an immune cell dysfunction.


Asunto(s)
Glucemia , Resistencia a la Insulina , Leucocitos Mononucleares/metabolismo , Lipidómica , Obesidad/metabolismo , Fosfolípidos/metabolismo , Adulto , Biomarcadores , Pesos y Medidas Corporales , Biología Computacional , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Hemoglobina A Glucada/metabolismo , Humanos , Lipidómica/métodos , Masculino , Espectrometría de Masas , Lípidos de la Membrana , Persona de Mediana Edad , Obesidad/sangre , Obesidad/etiología , Adulto Joven
18.
Nutrients ; 13(10)2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34684468

RESUMEN

The increased incidence of obesity, diabetes mellitus, aging, and associated comorbidities indicates the interplay between genetic and environmental influences. Several dietary components have been identified to play a role in the pathogenesis of the so-called "modern diseases", and their complications including advanced glycation end products (AGEs), which are generated during the food preparation and processing. Diet-derived advanced glycation end products (dAGEs) can be absorbed in the gastrointestinal system and contribute to the total body AGEs' homeostasis, partially excreted in the urine, while a significant amount accumulates to various tissues. Various in vitro, in vivo, and clinical studies support that dAGEs play an important role in health and disease, in a similar way to those endogenously formed. Animal studies using wild type, as well as experimental, animal models have shown that dAGEs contribute significantly to the pathogenesis of various diseases and their complications, and are involved in the changes related to the aging process. In addition, they support that dAGEs' restriction reduces insulin resistance, oxidative stress, and inflammation; restores immune alterations; and prevents or delays the progression of aging, obesity, diabetes mellitus, and their complications. These data can be extrapolated in humans and strongly support that dAGEs' restriction should be considered as an alternative therapeutic intervention.


Asunto(s)
Suplementos Dietéticos , Susceptibilidad a Enfermedades , Productos Finales de Glicación Avanzada/administración & dosificación , Productos Finales de Glicación Avanzada/metabolismo , Evaluación del Impacto en la Salud , Animales , Huesos/metabolismo , Diabetes Mellitus/etiología , Diabetes Mellitus/metabolismo , Homeostasis , Humanos , Modelos Animales , Músculos/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Especificidad de Órganos , Estrés Oxidativo
19.
Nutrients ; 13(10)2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34684470

RESUMEN

l-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.


Asunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Dieta con Restricción de Proteínas , Hepatocitos/metabolismo , Resistencia a la Insulina , Microcefalia/metabolismo , Obesidad/metabolismo , Fosfoglicerato-Deshidrogenasa/deficiencia , Trastornos Psicomotores/metabolismo , Convulsiones/metabolismo , Animales , Biología Computacional/métodos , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Glucosa/metabolismo , Insulina/metabolismo , Ratones , Obesidad/etiología , Especificidad de Órganos , Fosfoglicerato-Deshidrogenasa/metabolismo , Transducción de Señal
20.
Nutrients ; 13(10)2021 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-34684365

RESUMEN

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state. Participants were recruited as lean (n = 55, aged 8-17 years, BMI percentile 5-85%) and overweight and obese (OVOB, n = 228, aged 8-17 years, BMI percentile ≥ 85%). Untargeted metabolomics profiled 246 annotated metabolites in plasma at t0 and t60 min during the OGTT. Our results suggest that obesity and IR influence the switch from fatty acid (FA) to glucose oxidation in response to the OGTT. Obesity was associated with a blunted decline of acylcarnitines and fatty acid oxidation intermediates. In females, metabolites from the Fasted and Random-Fed OGTT were associated with HOMA-IR, including diacylglycerols, leucine/isoleucine, acylcarnitines, and phosphocholines. Our results indicate that at an early age, obesity and IR may influence the metabolome dynamics in response to a glucose challenge.


Asunto(s)
Ayuno/metabolismo , Conducta Alimentaria , Resistencia a la Insulina , Metaboloma , Obesidad/metabolismo , Caracteres Sexuales , Adolescente , Glucemia/metabolismo , Niño , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Cinética , Masculino , Obesidad/sangre
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