RESUMEN
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
BACKGROUND: Satellitosis or in-transit metastasis (S-ITM) has clinical outcomes comparable to node-positivity in cutaneous squamous cell carcinoma (cSCC). There is a need to stratify the risk groups. OBJECTIVE: To determine which prognostic factors of S-ITM confer an increased risk of relapse and cSCC-specific-death. METHODS: A retrospective, multicenter cohort study. Patients with cSCC developing S-ITM were included. Multivariate competing risk analysis evaluated which factors were associated with relapse and specific death. RESULTS: Of a total of 111 patients with cSCC and S-ITM, 86 patients were included for analysis. An S-ITM size of ≥20 mm, >5 S-ITM lesions, and a primary tumor deep invasion was associated with an increased cumulative incidence of relapse (subhazard ratio [SHR]: 2.89 [95% CI, 1.44-5.83; P = .003], 2.32 [95% CI, 1.13-4.77; P = .021], and 2.863 [95% CI, 1.25-6.55; P = .013]), respectively. Several >5 S-ITM lesions were also associated with an increased probability of specific death (SHR: 3.48 [95% CI, 1.18-10.2; P = .023]). LIMITATIONS: Retrospective study and heterogeneity of treatments. CONCLUSION: The size and the number of S-ITM lesions confer an increased risk of relapse and the number of S-ITM an increased risk of specific-death in patients with cSCC presenting with S-ITM. These results provide new prognostic information and can be considered in the staging guidelines.
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Carcinoma de Células Escamosas , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Estudios Retrospectivos , Pronóstico , Neoplasias Cutáneas/patología , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Factores de Riesgo , Recurrencia , Estadificación de NeoplasiasRESUMEN
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
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.
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Diabetes Mellitus Tipo 2 , Obesidad Mórbida , Tejido Adiposo/cirugía , Anastomosis Quirúrgica/efectos adversos , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/cirugía , Dieta , Gastrectomía/métodos , Glucosa , Íleon , Lípidos , Masculino , Obesidad/complicaciones , Obesidad/cirugía , Obesidad Mórbida/cirugía , Ratas , Ratas Wistar , Estudios RetrospectivosRESUMEN
Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.
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Adipogénesis , Dieta Alta en Grasa/efectos adversos , Inflamación/genética , Muramidasa/genética , Tejido Adiposo/metabolismo , Animales , Técnicas de Silenciamiento del Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/genética , Ratas WistarRESUMEN
Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the biology of skin cancer. In this paper, we review the viral agents responsible for different types of skin cancer, especially for solid skin tumors. We focus on human papillomavirus and squamous cell cancers, Merkel cell polyomavirus and Merkel cell carcinoma, and human herpesvirus 8 and Kaposi's sarcoma.
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Neoplasias Cutáneas/virología , Virus/patogenicidad , Animales , ADN Viral/genética , Humanos , Piel/virología , Virus/genéticaRESUMEN
OBJECTIVE: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). METHODS: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. RESULTS: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.
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Neoplasias del Colon/sangre , Obesidad/sangre , Factores de Empalme de ARN/sangre , Anciano , Carcinogénesis/genética , Neoplasias del Colon/genética , Matriz Extracelular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Masculino , Persona de Mediana Edad , Obesidad/genética , Factores de Empalme de ARN/genéticaRESUMEN
Angiopoietin-like protein 8 (ANGPTL8) is an hepatokine altered in several metabolic conditions, such as obesity, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease (NAFLD). We sought to explore whether ANGPTL8 is involved in NAFLD amelioration after bariatric surgery in experimental models and patients with severe obesity. Plasma ANGPTL8 was measured in 170 individuals before and 6 months after bariatric surgery. Hepatic ANGPTL8 expression was evaluated in liver biopsies of patients with severe obesity undergoing bariatric surgery with available liver pathology analysis (n = 75), as well as in male Wistar rats with diet-induced obesity subjected to sham operation, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) (n = 65). The effect of ANGPTL8 on lipogenesis was assessed in human HepG2 hepatocytes under palmitate-induced lipotoxic conditions. Plasma concentrations and hepatic expression of ANGPTL8 were increased in patients with obesity-associated NAFLD in relation to the degree of hepatic steatosis. Sleeve gastrectomy and RYGB improved hepatosteatosis and reduced the hepatic ANGPTL8 expression in the preclinical model of NAFLD. Interestingly, ANGPTL8 inhibited steatosis and expression of lipogenic factors (PPARG2, SREBF1, MOGAT2 and DGAT1) in palmitate-treated human hepatocytes. Together, ANGPTL8 is involved in the resolution of NAFLD after bariatric surgery partially by the inhibition of lipogenesis in steatotic hepatocytes.
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Proteína 8 Similar a la Angiopoyetina/metabolismo , Cirugía Bariátrica , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/cirugía , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Hormonas Peptídicas/metabolismo , Adulto , Proteína 8 Similar a la Angiopoyetina/sangre , Proteína 8 Similar a la Angiopoyetina/genética , Animales , Modelos Animales de Enfermedad , Femenino , Gastrectomía , Derivación Gástrica , Hepatocitos/metabolismo , Humanos , Lipogénesis , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad Mórbida/complicaciones , Hormonas Peptídicas/sangre , Hormonas Peptídicas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation.
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Adipoquinas/inmunología , Inflamación/inmunología , Grasa Intraabdominal/inmunología , Obesidad/inmunología , Adipoquinas/metabolismo , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Humanos , Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Obesidad/metabolismoRESUMEN
AIMS/HYPOTHESIS: Iron excess in adipose tissue is known to promote adipose tissue dysfunction. Here, we aimed to investigate the possible role of haem oxygenase 1 (HMOX1) in iron excess-induced adipose tissue dysfunction. METHODS: Cross-sectionally, HMOX1 gene expression in subcutaneous and visceral adipose tissue was analysed in two independent cohorts (n = 234 and 40) in relation to obesity. We also evaluated the impact of weight loss (n = 21), weight gain (in rats, n = 20) on HMOX1 mRNA; HMOX1 mRNA levels during human adipocyte differentiation; the effects of inflammation and iron on adipocyte HMOX1; and the effects of HMOX1-induced activity on adipocyte mitochondrial respiratory function, glucose uptake and adipogenesis. RESULTS: Adipose tissue HMOX1 was increased in obese participants (p = 0.01) and positively associated with obesity-related metabolic disturbances, and markers of iron accumulation, inflammation and oxidative stress (p < 0.01). HMOX1 was negatively correlated with mRNAs related to mitochondrial biogenesis, the insulin signalling pathway and adipogenesis (p < 0.01). These associations were replicated in an independent cohort. Bariatric surgery-induced weight loss led to reduced HMOX1 (0.024 ± 0.010 vs 0.010 ± 0.004 RU, p < 0.0001), whereas in rats, high-fat diet-induced weight gain resulted in increased Hmox1 mRNA levels (0.22 ± 0.15 vs 0.54 ± 0.22 RU, p = 0.005). These changes were in parallel with changes in BMI and adipose tissue markers of iron excess, adipogenesis and inflammation. In human adipocytes, iron excess and inflammation led to increased HMOX1 mRNA levels. HMOX1 induction (by haem arginate [hemin] administration), resulted in a significant reduction of mitochondrial respiratory capacity (including basal respiration and spare respiratory capacity), glucose uptake and adipogenesis in parallel with increased expression of inflammatory- and iron excess-related genes. CONCLUSIONS/INTERPRETATION: HMOX1 is an important marker of iron excess-induced adipose tissue dysfunction and metabolic disturbances in human obesity.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Glucosa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hierro/metabolismo , Adulto , Animales , Cirugía Bariátrica , Hemo-Oxigenasa 1/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Aumento de Peso/fisiología , Pérdida de Peso/fisiologíaRESUMEN
We aimed to investigate the effects of two physical exercise models, voluntary physical activity (VPA) and endurance training (ET) as preventive and therapeutic strategies, respectively, on lipid accumulation regulators and mitochondrial content in VAT of rats fed a high-fat diet (HFD). Sprague-Dawley rats (6 weeks old, n=60) were assigned into sedentary and VPA groups fed isoenergetic diets: standard (S, 35 kcal% fat) or HFD (71 kcal% fat). The VPA groups had free access to wheel running during the entire protocol. After 9 weeks, half of the sedentary animals were exercised on a treadmill while maintaining the dietary treatments. The HFD induced no changes in plasma non-esterified fatty acids (NEFA) and glycerol levels and decreased oxidative phosphorylation (OXPHOS) subunit IV and increased truncated/full-length sterol regulatory element-binding transcription factor 1c (SREBP1c) ratio in epididymal white adipose tissue (eWAT). VPA decreased plasma glycerol levels, aquaglyceroporin 7 (AQP7) and increased subunit I of cytochrome c oxidase (COX) protein, in standard diet fed animals. Eight weeks of ET decreased body weight, visceral adiposity and adipocyte size and plasma NEFA and glycerol levels, as well as AQP7 protein expression in eWAT. ET increased fatty acid translocase (FAT/CD36), mitochondrial content of complexes IV and V subunits, mitochondrial biogenesis and dynamic (mitofusins and optic atrophy 1)-related proteins. Moreover, lipogenesis-related markers (SREBP1c and acetyl CoA carboxylase) were reduced after 8 weeks of ET. In conclusion, ET-induced alterations reflect a positive effect on mitochondrial function and the overall VAT metabolism of HFD-induced obese rats.
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Dieta Alta en Grasa , Grasa Intraabdominal/metabolismo , Metabolismo de los Lípidos , Mitocondrias/metabolismo , Actividad Motora/fisiología , Obesidad/metabolismo , Resistencia Física/fisiología , Tejido Adiposo Blanco/metabolismo , Adiposidad , Animales , Acuaporinas/metabolismo , Biomarcadores/metabolismo , Ácidos Grasos no Esterificados/sangre , Glicerol/sangre , Lipogénesis/fisiología , Masculino , Obesidad/sangre , Obesidad/prevención & control , Fosforilación Oxidativa , Ratas Sprague-Dawley , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoAsunto(s)
Investigación Biomédica/normas , COVID-19/prevención & control , Gobierno , Investigadores , Comunicación Académica/normas , Vacunas contra la COVID-19/uso terapéutico , Educación de Pregrado en Medicina , Humanos , Retractación de Publicación como Asunto , SARS-CoV-2 , Estudiantes de Medicina , Tratamiento Farmacológico de COVID-19RESUMEN
Adipose tissue constitutes an extremely active endocrine organ with a network of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a huge variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins, and vasoactive factors, collectively termed adipokines. Obesity is associated with adipose tissue dysfunction leading to the onset of several pathologies including type 2 diabetes, dyslipidemia, nonalcoholic fatty liver, or hypertension, among others. The mechanisms underlying the development of obesity and its associated comorbidities include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. Recently, the potential role of brown and beige adipose tissue in the protection against obesity has been also recognized. In contrast to white adipocytes, which store energy in the form of fat, brown and beige fat cells display energy-dissipating capacity through the promotion of triacylglycerol clearance, glucose disposal, and generation of heat for thermogenesis. Identification of the morphological and molecular changes in white, beige, and brown adipose tissue during weight gain is of utmost relevance for the identification of pharmacological targets for the treatment of obesity and its associated metabolic diseases.
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Adipocitos Marrones/metabolismo , Adipocitos Blancos/metabolismo , Adipoquinas/metabolismo , Citocinas/metabolismo , Metabolismo Energético , Obesidad/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Glucosa/metabolismo , Humanos , Hipertensión/metabolismo , Modelos Biológicos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Transducción de Señal , Termogénesis , Triglicéridos/metabolismo , Aumento de PesoRESUMEN
BACKGROUND: Bariatric surgery (BS) has proven to be an effective treatment for morbid obesity. Osteopontin (OPN) is a proinflammatory cytokine involved in the development of obesity. The aim of our study was to determine the effect of weight loss following BS on circulating levels of OPN in humans. METHODS: Body composition and circulating concentrations of OPN and markers of bone metabolism were determined in obese patients who underwent Roux-en-Y gastric bypass (RYGB; n = 40) or sleeve gastrectomy (SG; n = 11). RESULTS: Patients who underwent RYGB or SG showed decreased body weight (P < 0.001) and body fat percentage (P < 0.001) as well as lower insulin resistance. However, plasma OPN levels were significantly increased after RYGB (P < 0.001) but remained unchanged following SG (P = 0.152). Patients who underwent RYGB also showed significantly increased C-terminal telopeptide of type-I collagen (ICTP) (P < 0.01) and osteocalcin (P < 0.001) while bone mineral density tended to decrease (P = 0.086). Moreover, OPN concentrations were positively correlated with the bone resorption marker ICTP after surgery. On the other hand, patients who underwent SG showed significantly increased ICTP levels (P < 0.05), and the change in OPN was positively correlated with the change in ICTP and negatively with the change in vitamin D after surgery (P < 0.05). CONCLUSIONS: RYGB increased circulating OPN levels, while they remained unaltered after SG. The increase in OPN levels after RYGB could be related to the increased bone resorption in relation to its well-known effects on bone of this malabsorptive procedure in comparison to the merely restrictive SG.
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Gastrectomía/métodos , Derivación Gástrica , Osteopontina/sangre , Adulto , Fosfatasa Alcalina/sangre , Densidad Ósea , Proteína C-Reactiva/análisis , Colágeno Tipo I/sangre , Femenino , Fibrinógeno/análisis , Humanos , Insulina/sangre , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Osteocalcina/sangre , Péptidos/sangre , Vitamina D/sangre , Pérdida de PesoRESUMEN
Bariatric surgery has become a recognized and effective procedure for treating obesity and type 2 diabetes (T2D). Our objective was to directly compare the caloric intake-independent effects of sleeve gastrectomy (SG) and single anastomosis duodenoileal bypass with SG (SADI-S) on glucose tolerance in rats with diet-induced obesity (DIO) and to elucidate the differences between bariatric surgery and caloric restriction.A total of 120 adult male Wistar rats with DIO and insulin resistance were randomly assigned to surgical (sham operation, SG, and SADI-S) and dietary (pair-feeding the amount of food eaten by animals undergoing the SG or SADI-S surgeries) interventions. Body weight and food intake were weekly monitored, and 6 weeks after interventions, fasting plasma glucose, oral glucose and insulin tolerance tests, plasma insulin, adiponectin, GIP, GLP-1, and ghrelin levels were determined.The body weight of SADI-S rats was significantly (p < 0.001) lower as compared to the sham-operated, SG, and pair-fed groups. Furthermore, SADI-S rats exhibited decreased whole body fat mass (p < 0.001), lower food efficiency rates (p < 0.001), and increased insulin sensitivity, as well as improved glucose and lipid metabolism compared to that of the SG and pair-fed rats.SADI-S was more effective than SG, or caloric restriction, in improving glycemic control and metabolic profile, with a higher remission of insulin resistance as well as long-term weight loss.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Obesidad Mórbida , Ratas , Masculino , Animales , Ratas Wistar , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/cirugía , Control Glucémico , Obesidad/etiología , Obesidad/cirugía , Obesidad/metabolismo , Anastomosis Quirúrgica/métodos , Gastrectomía/métodos , Insulina , Dieta , GlucosaRESUMEN
BACKGROUND: The estimation of obesity-associated cardiometabolic risk does not usually take into account body composition or the distribution of adiposity. The aim of the present study was to assess the clinical usefulness of a novel obesity phenotyping system based on the combination of actual body fat percentage (BF%) and waist circumference (WC) according to the cardiometabolic risk estimation. METHODS: A classification matrix combining BF% and WC as measures of both amount and distribution of adiposity establishing nine body phenotypes (3 BF% x 3 WC) was developed. Individuals were grouped in five different cardiometabolic risk phenotypes. We conducted a validation study in a large cohort of White subjects from both genders representing a wide range of ages and adiposity (n = 12,754; 65 % females, aged 18-88 years). RESULTS: The five risk groups using the matrix combination of BF% and WC exhibited a robust linear distribution regarding cardiometabolic risk, estimated by the Metabolic Syndrome Severity Score, showing a continuous increase between groups with significant differences (P < 0.001) among them, as well as in other cardiometabolic risk factors. An additional 24 % of patients at very high risk was detected with the new classification system proposed (P < 0.001) as compared to an equivalent matrix using BMI and WC instead of BF% and WC. CONCLUSIONS: A more detailed phenotyping should be a priority in the diagnosis and management of patients with obesity. Our classification system allows to gradually estimate the cardiometabolic risk according to BF% and WC, thus representing a novel and useful tool for both research and clinical practice.
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Adiposidad , Factores de Riesgo Cardiometabólico , Síndrome Metabólico , Obesidad , Fenotipo , Circunferencia de la Cintura , Humanos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Adulto , Anciano de 80 o más Años , Adolescente , Adulto Joven , Síndrome Metabólico/diagnóstico , Medición de Riesgo/métodos , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiologíaRESUMEN
The underlying mechanisms for the development and progression of nonalcoholic fatty liver disease (NAFLD) are complex and multifactorial. Within the last years, experimental and clinical evidences support the role of ghrelin in the development of NAFLD. Ghrelin is a gut hormone that plays a major role in the short-term regulation of appetite and long-term regulation of adiposity. The liver constitutes a target for ghrelin, where this gut-derived peptide triggers intracellular pathways regulating lipid metabolism, inflammation, and fibrosis. Interestingly, circulating ghrelin levels are altered in patients with metabolic diseases, such as obesity, type 2 diabetes, and metabolic syndrome, which, in turn, are well-known risk factors for the pathogenesis of NAFLD. This review summarizes the molecular and cellular mechanisms involved in the hepatoprotective action of ghrelin, including the reduction of hepatocyte lipotoxicity via autophagy and fatty acid ß-oxidation, mitochondrial dysfunction, endoplasmic reticulum stress and programmed cell death, the reversibility of the proinflammatory phenotype in Kupffer cells, and the inactivation of hepatic stellate cells. Together, the metabolic and inflammatory pathways regulated by ghrelin in the liver support its potential as a therapeutic target to prevent NAFLD in patients with metabolic disorders.
Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ghrelina , Diabetes Mellitus Tipo 2/metabolismo , Hígado/metabolismo , Hepatocitos/metabolismo , Obesidad/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2022.832185.].