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BACKGROUND AND AIMS: Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host's innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction-associated steatotic liver disease (MASLD) have been little studied. APPROACH AND RESULTS: Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid-induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκß. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O -GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes. CONCLUSIONS: MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD.
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BACKGROUND: Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic inflammation leading to the development of metabolic diseases. The inflammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the inflammasomes in the regulation of gut barrier dysfunction and metabolic inflammation in the context of obesity and type 2 diabetes (T2D). METHODS: Blood samples obtained from 80 volunteers (n = 20 normal weight, n = 21 OB without T2D, n = 39 OB with T2D) and a subgroup of jejunum samples were used in a case-control study. Circulating levels of intestinal damage markers and expression levels of inflammasomes as well as their main effectors (IL-1ß and IL-18) and key inflammation-related genes were analyzed. The impact of inflammation-related factors, different metabolites and Akkermansia muciniphila in the regulation of inflammasomes and intestinal integrity genes was evaluated. The effect of blocking NLRP6 by using siRNA in inflammation was also studied. RESULTS: Increased circulating levels (P < 0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (P < 0.05) after weight loss. Patients with obesity and T2D exhibited decreased (P < 0.05) jejunum gene expression levels of NLRP6 and its main effector IL18 together with increased (P < 0.05) mRNA levels of inflammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (P < 0.05) mRNA levels of Nlrp1, Nlrp3 and Nlrp6 in the small intestinal tract obtained from rats with diet-induced obesity were found. NLRP6 expression was regulated by taurine, parthenolide and A. muciniphila in the human enterocyte cell line CCL-241. Finally, a significant decrease (P < 0.01) in the expression and release of MUC2 after the knockdown of NLRP6 was observed. CONCLUSIONS: The increased levels of intestinal damage markers together with the downregulation of NLRP6 and IL18 in the jejunum in obesity-associated T2D suggest a defective inflammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities.
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Diabetes Mellitus Tipo 2 , Inflamasomas , Humanos , Ratas , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Funcion de la Barrera Intestinal , Estudios de Casos y Controles , Inflamación , Obesidad/complicaciones , ARN Mensajero/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Receptores de Angiotensina/metabolismo , Receptores de Vasopresinas/metabolismoRESUMEN
The goal of obesity management is to improve health. Sustained weight loss of more than 10% overall bodyweight improves many of the complications associated with obesity (eg, prevention and control of type 2 diabetes, hypertension, fatty liver disease, and obstructive sleep apnoea), as well as quality of life. Maintenance of weight loss is the major challenge of obesity management. Like all chronic diseases, managing obesity requires a long-term, multimodal approach, taking into account each individual's treatment goals, and the benefit and risk of different therapies. In conjunction with lifestyle interventions, anti-obesity medications and bariatric surgery improve the maintenance of weight loss and associated health gains. Most available anti-obesity medications act on central appetite pathways to reduce hunger and food reward. In the past 5 years, therapeutic advances have seen the development of targeted treatments for monogenic obesities and a new generation of anti-obesity medications. These highly effective anti-obesity medications are associated with weight losses of more than 10% of overall bodyweight in more than two-thirds of clinical trial participants. Long-term data on safety, efficacy, and cardiovascular outcomes are awaited. Long-term studies have shown that bariatric surgical procedures typically lead to a durable weight loss of 25% and rapid, sustained improvements in complications of obesity, although they have not yet been compared with new-generation highly effective anti-obesity medications. Further work is required to determine optimal patient-specific treatment strategies, including combinations of lifestyle interventions, anti-obesity medications, endoscopic and bariatric surgical procedures, and to ensure equitable access to effective treatments.
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Fármacos Antiobesidad , Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Calidad de Vida , Obesidad/complicaciones , Obesidad/cirugía , Obesidad/tratamiento farmacológico , Cirugía Bariátrica/métodos , Fármacos Antiobesidad/uso terapéutico , Peso Corporal , Pérdida de PesoRESUMEN
BACKGROUND: Albuminuria is considered an early and sensitive marker of kidney dysfunction, but also an independent cardiovascular risk factor. Considering the possible relationship among metabolic liver disease, cardiovascular disease and chronic kidney disease, we aimed to evaluate the risk of developing albuminuria regarding the presence of epicardial adipose tissue and the steatotic liver disease status. METHODS: A retrospective long-term longitudinal study including 181 patients was carried out. Epicardial adipose tissue and steatotic liver disease were assessed by computed tomography. The presence of albuminuria at follow-up was defined as the outcome. RESULTS: After a median follow up of 11.2 years, steatotic liver disease (HR 3.15; 95% CI, 1.20-8.26; p = 0.02) and excess amount of epicardial adipose tissue (HR 6.12; 95% CI, 1.69-22.19; p = 0.006) were associated with an increased risk of albuminuria after adjustment for visceral adipose tissue, sex, age, weight status, type 2 diabetes, prediabetes, hypertriglyceridemia, hypercholesterolemia, arterial hypertension, and cardiovascular prevention treatment at baseline. The presence of both conditions was associated with a higher risk of developing albuminuria compared to having steatotic liver disease alone (HR 5.91; 95% CI 1.15-30.41, p = 0.033). Compared with the first tertile of visceral adipose tissue, the proportion of subjects with liver steatosis and abnormal epicardial adipose tissue was significantly higher in the second and third tertile. We found a significant correlation between epicardial fat and steatotic liver disease (rho = 0.43 [p < 0.001]). CONCLUSIONS: Identification and management/decrease of excess adiposity must be a target in the primary and secondary prevention of chronic kidney disease development and progression. Visceral adiposity assessment may be an adequate target in the daily clinical setting. Moreover, epicardial adipose tissue and steatotic liver disease assessment may aid in the primary prevention of renal dysfunction.
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Adiposidad , Albuminuria , Hígado Graso , Pericardio , Humanos , Estudios Retrospectivos , Masculino , Femenino , Pericardio/diagnóstico por imagen , Albuminuria/epidemiología , Albuminuria/diagnóstico , Albuminuria/fisiopatología , Persona de Mediana Edad , Factores de Riesgo , Anciano , Hígado Graso/epidemiología , Hígado Graso/diagnóstico , Hígado Graso/fisiopatología , Estudios Longitudinales , Factores de Tiempo , Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/fisiopatología , Tejido Adiposo/metabolismo , Medición de Riesgo , Hígado/diagnóstico por imagen , Hígado/patología , Grasa Intraabdominal/fisiopatología , Grasa Intraabdominal/diagnóstico por imagen , AdultoRESUMEN
Adolphe Quételet, a 19th-century Belgian sociologist and statistician, pioneered the incorporation of statistics into social sciences. He initiated the development of anthropometry since he was interested in identifying the proportions of the 'ideal man'. He devised a ratio between weight and height, originally termed the Quételet Index, and today widely known and used as the body mass index or BMI. In 1835, he demonstrated that a normal curve accommodates the distribution of human traits articulating his reasoning on human variance around the average. Quételet's long-lasting legacy of the establishment of a simple measure to classify people's weight relative to an ideal for their height endures today with minor variations having dramatically influenced public health agendas. While being very useful, the limitations of the BMI are well known. Thus, revisiting the beyond BMI paradigm is a necessity in the era of precision medicine with morphofunctional assessment representing the way forward via incorporation of body composition and functionality appraisal. While healthcare systems were originally designed to address acute illnesses, today's demands require a radical rethinking together with an original reappraisal of our diagnosis and treatment approaches from a multidimensional perspective. Embracing new methodologies is the way forward to advance the field, gain a closer look at the underlying pathophysiology of excess weight, keep the spotlight on improving diagnostic performance and demonstrate its clinical validity. In order to provide every patient with the most accurate diagnosis together with the most appropriate management, a high degree of standardization and personalization is needed.
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Índice de Masa Corporal , Obesidad , Humanos , Obesidad/diagnóstico , Obesidad/terapia , Sobrepeso/terapia , Sobrepeso/diagnósticoRESUMEN
BACKGROUND: Excessive lipid accumulation in the adipose tissue in obesity alters the endocrine and energy storage functions of adipocytes. Adipocyte lipid droplets represent key organelles coordinating lipid storage and mobilization in these cells. Recently, we identified the small GTPase, Rab34, in the lipid droplet proteome of adipocytes. Herein, we have characterized the distribution, intracellular transport, and potential contribution of this GTPase to adipocyte physiology and its regulation in obesity. METHODS: 3T3-L1 and human primary preadipocytes were differentiated in vitro and Rab34 distribution and trafficking were analyzed using markers of cellular compartments. 3T3-L1 adipocytes were transfected with expression vectors and/or Rab34 siRNA and assessed for secretory activity, lipid accumulation and expression of proteins regulating lipid metabolism. Proteomic and protein interaction analyses were employed for the identification of the Rab34 interactome. These studies were combined with functional analysis to unveil the role played by the GTPase in adipocytes, with a focus on the actions conveyed by Rab34 interacting proteins. Finally, Rab34 regulation in response to obesity was also evaluated. RESULTS: Our results show that Rab34 localizes at the Golgi apparatus in preadipocytes. During lipid droplet biogenesis, Rab34 translocates from the Golgi to endoplasmic reticulum-related compartments and then reaches the surface of adipocyte lipid droplets. Rab34 exerts distinct functions related to its intracellular location. Thus, at the Golgi, Rab34 regulates cisternae integrity as well as adiponectin trafficking and oligomerization. At the lipid droplets, this GTPase controls lipid accumulation and lipolysis through its interaction with the E1-ubiquitin ligase, UBA1, which induces the ubiquitination and proteasomal degradation of the fatty acid transporter and member of Rab34 interactome, FABP5. Finally, Rab34 levels in the adipose tissue and adipocytes are regulated in response to obesity and related pathogenic insults (i.e., fibrosis). CONCLUSIONS: Rab34 plays relevant roles during adipocyte differentiation, including from the regulation of the oligomerization (i.e., biological activity) and secretion of a major adipokine with insulin-sensitizing actions, adiponectin, to lipid storage and mobilization from lipid droplets. Rab34 dysregulation in obesity may contribute to the altered adipokine secretion and lipid metabolism that characterize adipocyte dysfunction in conditions of excess adiposity.
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Adiponectina , Proteómica , Humanos , Adipocitos , Adipoquinas , GTP Fosfohidrolasas , Obesidad , Lípidos , Proteínas de Unión a Ácidos GrasosRESUMEN
OBJECTIVE: p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. DESIGN: We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D). RESULTS: We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index. CONCLUSIONS: These results demonstrate that p63 physiologically regulates glucose homeostasis.
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Diabetes Mellitus Tipo 2 , Sirtuina 1 , Transactivadores , Animales , Ratones , Glucosa/metabolismo , Hígado/metabolismo , Piruvatos/metabolismo , Sirtuina 1/metabolismo , Transactivadores/metabolismoRESUMEN
Eating behavior and food-related decision making are among the most complex of the motivated behaviors, and understanding the neurobiology of eating behavior, and its developmental dynamics, is critical to advancing the nutritional sciences and public health. Recent advances from both human and animal studies are revealing that individual capacity to make health-promoting food decisions varies based on biological and physiological variation in the signaling pathways that regulate the homeostatic, hedonic, and executive functions; past developmental exposures and current life-stage; the food environment; and complications of chronic disease that reinforce the obese state. Eating rate drives increased calorie intake and represents an important opportunity to lower rates of food consumption and energy intake through product reformulation. Understanding human eating behaviors and nutrition in the context of neuroscience can strengthen the evidence base from which dietary guidelines are derived and can inform policies, practices, and educational programs in a way that increases the likelihood they are adopted and effective for reducing rates of obesity and other diet-related chronic disease.
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OBJECTIVE: To assess how inaccurately the body mass index (BMI) is used to diagnose obesity compared to body fat percentage (BF%) measurement and to compare the cardiometabolic risk in children and adolescents with or without obesity according to BMI but with a similar BF%. METHODS: A retrospective cross-sectional investigation was conducted including 553 (378 females/175 males) white children and adolescents aged 6-17 years, 197 with normal weight (NW), 144 with overweight (OW) and 212 with obesity (OB) according to BMI. In addition to BMI, BF% measured by air displacement plethysmography, as well as markers of cardiometabolic risk had been determined in the existing cohort. RESULTS: We found that 7% of subjects considered as NW and 62% of children and adolescents classified as OW according to BMI presented a BF% within the obesity range. Children and adolescents without obesity by the BMI criterion but with obesity by BF% exhibited higher blood pressure and C-reactive protein (CRP) in boys, and higher blood pressure, glucose, uric acid, CRP and white blood cells count, as well as reduced HDL-cholesterol, in girls, similar to those with obesity by BMI and BF%. Importantly, both groups of subjects with obesity by BF% showed a similarly altered glucose homeostasis after an OGTT as compared to their NW counterparts. CONCLUSIONS: Results from the present study suggest increased cardiometabolic risk factors in children and adolescents without obesity according to BMI but with obesity based on BF%. Being aware of the difficulty in determining body composition in everyday clinical practice, our data show that its inclusion could yield clinically useful information both for the diagnosis and treatment of overweight and obesity.
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Adiposidad , Hipertensión , Masculino , Femenino , Humanos , Adolescente , Niño , Índice de Masa Corporal , Sobrepeso , Estudios Transversales , Estudios Retrospectivos , Obesidad/diagnóstico , Obesidad/epidemiología , Proteína C-Reactiva , GlucosaRESUMEN
In this thematic issue on phenotyping the obesities, prominent international experts offer an insightful and comprehensive collection of articles covering the current knowledge in the field. In order to actually capture all the polyhedral determinants of the diverse types of obesity, the granularity of the phenotypic information acquired must be expanded in the context of a personalized approach. Whilst the use of precision medicine has been successfully implemented in areas like cancer and other diseases, health care providers are more reluctant to embrace detailed phenotyping to guide diagnosis, treatment and prevention in obesity. Given its multiple complex layers, phenotyping necessarily needs to go beyond the multi-omics approach and incorporate all the diverse spheres that conform the reality of people living with obesity. Potential barriers, difficulties, roadblocks and opportunities together with their interaction in a syndemic context are analyzed. Plausible lacunae are also highlighted in addition to pointing to the need of redefining new conceptual frameworks. Therefore, this extraordinary collection of state-ofthe-art reviews provides useful information to both experienced clinicians and trainees as well as academics to steer clinical practice and research in the management of people living with obesity irrespective of practice setting or career stage.
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Obesidad , Utopias , Humanos , Obesidad/diagnósticoRESUMEN
Bariatric surgery (BS) is the most effective long-term treatment for severe obesity. This review summarizes the main nutritional deficiencies before and after BS, as well as current dietary and supplementation recommendations to avoid them. Likewise, we have reviewed all those aspects that in recent years have been shown to be related to postoperative weight loss (WL) and its subsequent maintenance, such as hormonal changes, dietary patterns, changes in food preference, adherence to recommendations and follow-up, genetic factors and microbiota, among others. Despite all the knowledge, nutritional deficiencies and weight regain after BS are frequent. It is essential to continue studying in this field in order to establish more precise recommendations according to the individual characteristics of patients. It is also a major objective to understand more deeply the role of the factors involved in WL and its maintenance. This will allow the development of precision treatments and nutrition for patients with obesity, optimizing their benefit after BS.
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Cirugía Bariátrica , Desnutrición , Obesidad Mórbida , Humanos , Obesidad/cirugía , Estado Nutricional , Obesidad Mórbida/cirugíaRESUMEN
Obesity is the most extended metabolic alteration worldwide increasing the risk for the development of cardiometabolic alterations such as type 2 diabetes, hypertension, and dyslipidemia. Body mass index (BMI) remains the most frequently used tool for classifying patients with obesity, but it does not accurately reflect body adiposity. In this document we review classical and new classification systems for phenotyping the obesities. Greater accuracy of and accessibility to body composition techniques at the same time as increased knowledge and use of cardiometabolic risk factors is leading to a more refined phenotyping of patients with obesity. It is time to incorporate these advances into routine clinical practice to better diagnose overweight and obesity, and to optimize the treatment of patients living with obesity.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Circunferencia de la Cintura , Obesidad , Índice de Masa Corporal , Adiposidad , Composición Corporal , Factores de RiesgoRESUMEN
Obesity is a complex disease that relapses frequently and associates with multiple complications that comprise a worldwide health priority because of its rising prevalence and association with numerous complications, including metabolic disorders, mechanic pathologies, and cancer, among others. Noteworthy, excess adiposity is accompanied by chronic inflammation, oxidative stress, insulin resistance, and subsequent organ dysfunction. This dysfunctional adipose tissue is initially stored in the visceral depot, overflowing subsequently to produce lipotoxicity in ectopic depots like liver, heart, muscle, and pancreas, among others. People living with obesity need a diagnostic approach that considers an exhaustive pathophysiology and complications assessment. Thus, it is essential to warrant a holistic diagnosis and management that guarantees an adequate health status, and quality of life. The present review summarizes the different complications associated with obesity, at the same time, we aim to fostering a novel framework that enhances a patient-centered approach to obesity management in the precision medicine era.
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Adiposidad , Resistencia a la Insulina , Humanos , Calidad de Vida , Obesidad/diagnóstico , Obesidad/terapia , Obesidad/complicaciones , Tejido Adiposo/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina/fisiologíaRESUMEN
BACKGROUND: It has become increasingly important to identify molecular markers for accurately diagnosing prostate cancer (PCa) stages between localized PCa (LPC) and locally advanced PCa (LAPC). However, there is a lack of profiling both epigenome-wide DNA methylation and transcriptome for the same patients with PCa at different stages. This study aims to identify epitranscriptomic biomarkers screened in the peri-prostatic (PP) adipose tissue for predicting LPC and LAPC. METHODS: We profiled gene expression and DNA methylation of 10 PCa patients' PP adipose tissue (4 LPC and 6 LAPC). Differential analysis was used to identify differentially methylated CpG sites and expressed genes. An integrative analysis of the microarray gene expression profiles and DNA methylation profiles was conducted using LASSO (least absolute shrinkage and selection operator) between each studied gene and the CpG sites in their promoter region. This epitranscriptomic signature was constructed by combining the association and differential analyses. The signature was then refined using the genetic mutation data of >1500 primary PCa and metastasis PCa samples from 4 different studies. We determined genes that were the most significantly affected by mutations. Machine learning models were built to evaluate the classification ability of the identified signature using the gene expression profiles from three external cohorts. RESULTS: From the LASSO-based association analysis, we identified 56 genes presenting significant anti-correlation between the expression level and the methylation level of at least one CpG site in the promoter region (p-value<5 × 10-8). From the differential analysis, we detected 16,405 downregulated genes and 9485 genes containing at least one hypermethylated CpG site. We identified 30 genes that showed anti-correlation, down-regulation and hyper-methylation simultaneously. Using genetic mutation data, we determined that 6 of the 30 genes showed significant differences (adjusted p-value<0.05) in mutation frequencies between the primary PCa and metastasis PCa samples. The identified 30 genes performed well in distinguishing PCa patients with metastasis from PCa patient without metastasis (area under the receiver operating characteristic curve (AUC) = 0.81). The gene signature also performed well in distinguishing PCa patients with high risk of progression from PCa patients with low risk of progression (AUC = 0.88). CONCLUSIONS: We established an integrative framework to identify differentially expressed genes with an aberrant methylation pattern on PP adipose tissue that may represent novel candidate molecular markers for distinguishing between LPC and LAPC.
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Metilación de ADN , Neoplasias de la Próstata , Biomarcadores/metabolismo , Islas de CpG , Epigenoma , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Regiones Promotoras Genéticas , Neoplasias de la Próstata/metabolismo , TranscriptomaRESUMEN
Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white-like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2, Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4 °C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2, Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.
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Acuaporinas , Cirugía Bariátrica , Animales , Masculino , Ratas , Tejido Adiposo Pardo/metabolismo , Acuaporinas/metabolismo , Células Endoteliales/metabolismo , Glicerol/metabolismo , Obesidad/metabolismo , Ratas WistarRESUMEN
Type 2 and type 1 diabetes are common endocrine disorders with a progressively increasing incidence worldwide. These chronic, systemic diseases have multiorgan implications, and the whole gastrointestinal (GI) tract represents a frequent target in terms of symptom appearance and interdependent pathophysiological mechanisms. Metabolic alterations linked with diabetic complications, neuropathy and disrupted hormone homeostasis can lead to upper and/or lower GI symptoms in up to 75% of diabetic patients, with multifactorial involvement of the oesophagus, stomach, upper and lower intestine, and of the gallbladder. On the other hand, altered gastrointestinal motility and/or secretions are able to affect glucose and lipid homeostasis in the short and long term. Finally, diabetes has been linked with increased cancer risk at different levels of the GI tract. The presence of GI symptoms and a comprehensive assessment of GI function should be carefully considered in the management of diabetic patients to avoid further complications and to ameliorate the quality of life. Additionally, the presence of gastrointestinal dysfunction should be adequately managed to improve metabolic homeostasis, the efficacy of antidiabetic treatments and secondary prevention strategies.
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Diabetes Mellitus , Enfermedades Gastrointestinales , Diabetes Mellitus/epidemiología , Enfermedades Gastrointestinales/etiología , Tracto Gastrointestinal , Glucosa , Hormonas , Humanos , Hipoglucemiantes , Lípidos , Calidad de VidaRESUMEN
Academic medicine fosters research that moves from discovery to translation, at the same time as promoting education of the next generation of professionals. In the field of obesity, the supposed integration of knowledge, discovery and translation research to clinical care is being particularly hampered. The classification of obesity based on the body mass index does not account for several subtypes of obesity. The lack of a universally shared definition of "obesities" makes it impossible to establish the real burden of the different obesity phenotypes. The individual's genotype, adipotype, enterotype and microbiota interplays with macronutrient intake, appetite, metabolism and thermogenesis. Further investigations based on the concept of differently diagnosed "obesities" are required.
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Obesidad , Índice de Masa Corporal , Humanos , Obesidad/metabolismoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.
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Hepatopatías Alcohólicas , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Fibrosis , Humanos , Hígado/patología , Cirrosis Hepática/complicaciones , Hepatopatías Alcohólicas/patología , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Factores de RiesgoRESUMEN
Dysfunctional adipose tissue (AT) in the context of obesity leads to chronic inflammation together with an altered extracellular matrix (ECM) remodelling, favouring cancer development and progression. Recently, the influence of dermatopontin (DPT) in AT remodelling and inflammation has been proposed. We aimed to evaluate the role of DPT in the development of obesity-associated colon cancer (CC). Samples obtained from 73 subjects [26 lean (LN) and 47 with obesity (OB)] were used in a case-control study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (42 without CC and 31 with CC). In vitro studies in the adenocarcinoma HT-29 cell line were performed to analyse the impact of pro- and anti-inflammatory mediators on the transcript levels of DPT as well as the effect of DPT on ECM remodelling and inflammation. Although obesity increased (p < 0.05) the circulating levels of DPT, its concentrations were significantly decreased (p < 0.05) in patients with CC. Gene expression levels of DPT in the colon from patients with CC were downregulated and, oppositely, a tendency towards increased mRNA levels in visceral AT was found. We further showed that DPT expression levels in HT-29 cells were enhanced (p < 0.05) by inflammatory factors (LPS, TNF-α and TGF-ß), whereas the anti-inflammatory IL-4 decreased (p < 0.05) its expression levels. We also demonstrated that DPT upregulated (p < 0.05) the mRNA of key molecules involved in ECM remodelling (COL1A1, COL5A3, TNC and VEGFA) whereas decorin (DCN) expression was downregulated (p < 0.05) in HT-29 cells. Finally, we revealed that the adipocyte-conditioned medium obtained from volunteers with OB enhanced (p < 0.01) the expression of DPT in HT-29 and Caco-2 cells. The decreased circulating and expression levels of DPT in the colon together with the tendency towards increased levels in visceral AT in patients with CC and its influence on the expression of ECM proteins suggest a possible role of DPT in the OB-associated CC.
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Neoplasias del Colon , Proteínas de la Matriz Extracelular , Células CACO-2 , Estudios de Casos y Controles , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Inflamación/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , ARN Mensajero/metabolismoRESUMEN
Bariatric surgery has been recognized as the safest and most effective procedure for controlling type 2 diabetes (T2D) and obesity in carefully selected patients. The aim of the present study was to compare the effects of Sleeve Gastrectomy (SG) and Single Anastomosis Duodenoileal Bypass with SG (SADI-S) on the metabolic profile of diet-induced obese rats. A total of 35 four-week-old male Wistar rats were submitted to surgical interventions (sham operation, SG and SADI-S) after 4 months of being fed a high-fat diet. Body weight, metabolic profile and the expression of molecules involved in the control of subcutaneous white (SCWAT), brown (BAT) and beige (BeAT) adipose tissue function were analyzed. SADI-S surgery was associated with significantly decreased amounts of total fat pads (p < 0.001) as well as better control of lipid and glucose metabolism compared to the SG counterparts. An improved expression of molecules involved in fat browning in SCWAT and in the control of BAT and BeAT differentiation and function was observed following SADI-S. Together, our findings provide evidence that the enhanced metabolic improvement and their continued durability after SADI-S compared to SG rely, at least in part, on the improvement of the BeAT phenotype and function.