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1.
Trends Endocrinol Metab ; 33(8): 587-599, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35697585

RESUMEN

Owing to its unique capacity to clear macronutrients from circulation and use them to produce heat, thermogenic fat is capable of regulating glucose, lipids, and branched-chain amino acids (BCAA) circulatory levels. At the same time, its activity yields a higher energy expenditure, thereby conferring protection against cardiometabolic diseases. Our knowledge on the mechanisms of uptake and intracellular metabolism of such energy substrates into thermogenic fat has meaningfully evolved in recent years. This has allowed us to better understand how the thermogenic machinery processes those molecules to utilize them as substrates for heating up the body. Here, we discuss recent advances in the molecular and cellular regulatory process that governs the uptake and metabolism of such substrates within thermogenic fat.


Asunto(s)
Tejido Adiposo Pardo , Calor , Tejido Adiposo Pardo/metabolismo , Metabolismo Energético/fisiología , Humanos , Termogénesis/genética , Proteína Desacopladora 1/metabolismo
2.
Int J Obes (Lond) ; 46(6): 1145-1154, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35173278

RESUMEN

BACKGROUND: Exercise is an important strategy in the management of diabetes. Experimental studies have shown that exercise acts, at least in part, by inducing the production of myokines that improve metabolic control and activate brown/beige adipose tissue depots. Combined training (CT) is recommended by the major diabetes guidelines due to its metabolic and cardiovascular benefits, however, its impact on brown/beige adipose tissue activities has never been tested in humans with overweight and type 2 diabetes (T2D). Here, we evaluated the effects of 16-week combined training (CT) program on brown adipose tissue activity; browning and autophagy markers, and serum pro-thermogenic/inflammatory inducers in patients with overweight and T2D. METHODS: Thirty-four patients with overweight and T2D were assigned to either a control group (CG) or a combined training group (CTG) in a randomized and controlled study. Functional/fitness parameters, anthropometry/body composition parameters, blood hormone/biochemical parameters, thermogenic/autophagic gene expression in subcutaneous adipose tissue were evaluated before and at the end of the intervention. In addition, cold-induced 18-Fluoroxyglucose Positron Emission Computed Tomography (18F-FDG PET/CT) was performed in the training group before and after the end of the intervention. RESULTS: CT increased cervical/supraclavicular brown adipose tissue (BAT) thermogenic activity (p = 0.03) as well as in perirenal adipose tissue (p = 0.02). In addition, CT increased the expression of genes related to thermogenic profile (TMEM26: + 95%, p = 0.04; and EPSTI1: + 26%, p = 0.03) and decreased autophagic genes (ULK1: -15%, p = 0.04; LC3: -5%, p = 0.02; and ATG4: -22%, p < 0.001) in subcutaneous adipose tissue. There were positive correlations between Δ% BAT activity with Δ% of post training energy expenditure cold exposure, HDL-c, IL4, adiponectin, irisin, meteorin-like, and TMEM26 and ZIC1 genes, besides negative correlations with LDL-c, total cholesterol and C-reactive protein. CONCLUSION: This is the first evidence of the beneficial actions of CT on adipose tissue thermogenic activity in humans, and it adds important support for the recommendation of CT as a strategy in the management of diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2 , Sobrepeso , Tejido Adiposo Pardo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Fluorodesoxiglucosa F18/metabolismo , Humanos , Sobrepeso/metabolismo , Sobrepeso/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Termogénesis/genética
3.
Cardiovasc Diabetol ; 20(1): 74, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771149

RESUMEN

BACKGROUND: The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. METHODS: In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). RESULTS: Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by - 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and - 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. CONCLUSIONS: Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.


Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucemia/efectos de los fármacos , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Glucósidos/uso terapéutico , Gliburida/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Vasodilatación/efectos de los fármacos , Adulto , Anciano , Compuestos de Bencidrilo/efectos adversos , Biomarcadores/sangre , Glucemia/metabolismo , Brasil , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Quimioterapia Combinada , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Glucósidos/efectos adversos , Gliburida/efectos adversos , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Factores de Tiempo , Resultado del Tratamiento
4.
Nutr Metab Cardiovasc Dis ; 30(2): 254-264, 2020 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-31753789

RESUMEN

BACKGROUND AND AIM: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. We investigated if potentially other HDL protective actions may be affected with weight gain and these changes may occur even before the obesity range in a cross-sectional analysis. METHODS AND RESULTS: Lipid profile, body mass index (BMI), biochemical measurements, and carotid intima-media thickness (cIMT) were obtained in this cross-sectional study with 899 asymptomatic individuals. Lipoproteins were separated by ultracentrifugation and HDL physical-chemical characterization, CEC, antioxidant activity, anti-inflammatory activity, HDL-mediated platelet aggregation inhibition were measured in a randomly-selected subgroup (n = 101). Individuals with increased HDL-C had an attenuated increase in cIMT with elevation of BMI (interaction effect ß = -0.054; CI 95% -0.0815, -0.0301). CEC, HDL-C, HDL size and HDL-antioxidant activity were negatively associated with cIMT. BMI was inversely correlated with HDL-mediated inhibition of platelet aggregation (Spearman's rho -0.157, p < 0.03) and CEC (Spearman's rho -0.32, p < 0.001), but surprisingly it was directly correlated with the antioxidant activity (Spearman's rho 0.194, p = 0.052). Thus, even in non-obese, non-diabetic individuals, increased BMI is associated with a wide change in protective functions of HDL, reducing CEC and increasing antioxidant activity. In these subjects, decreased HDL concentration, size or function are related to increased atherosclerotic burden. CONCLUSION: Our findings demonstrate that in non-obese, non-diabetic individuals, the increasing values of BMI are associated with impaired protective functions of HDL and concomitant increase in atherosclerotic burden.


Asunto(s)
HDL-Colesterol/sangre , Dislipidemias/sangre , Sobrepeso/sangre , Aumento de Peso , Adulto , Anciano , Antioxidantes/análisis , Biomarcadores/sangre , Índice de Masa Corporal , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Grosor Intima-Media Carotídeo , Estudios Transversales , Dislipidemias/diagnóstico , Dislipidemias/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sobrepeso/diagnóstico , Sobrepeso/fisiopatología , Agregación Plaquetaria , Medición de Riesgo , Factores de Riesgo , Adulto Joven
5.
Arterioscler Thromb Vasc Biol ; 39(8): 1550-1564, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31189429

RESUMEN

Despite decades of therapeutic advances, myocardial infarction remains a leading cause of death worldwide. Recent studies have identified HDLs (high-density lipoproteins) as a potential candidate for mitigating coronary ischemia/reperfusion injury via a broad spectrum of signaling pathways. HDL ligands, such as S1P (sphingosine-1-phosphate), Apo (apolipoprotein) A-I, clusterin, and miRNA, may influence the opening of the mitochondrial channel, insulin sensitivity, and production of vascular autacoids, such as NO, prostacyclin, and endothelin-1. In parallel, antioxidant activity and sequestration of oxidized molecules provided by HDL can attenuate the oxidative stress that triggers ischemia/reperfusion. Nevertheless, during myocardial infarction, oxidation and the capture of oxidized and proinflammatory molecules generate large phenotypic and functional changes in HDL, potentially limiting its beneficial properties. In this review, new findings from cellular and animal models, as well as from clinical studies, will be discussed to describe the cardioprotective benefits of HDL on myocardial infarction. Furthermore, mechanisms by which HDL modulates cardiac function and potential strategies to mitigate postmyocardial infarction risk damage by HDL will be detailed throughout the review.


Asunto(s)
Lipoproteínas HDL/fisiología , Infarto del Miocardio/prevención & control , Animales , Colesterol/metabolismo , Células Endoteliales/fisiología , Glucosa/metabolismo , Homeostasis , Humanos , Lipoproteínas HDL/sangre , Lisofosfolípidos/fisiología , Estrés Oxidativo , Transducción de Señal/fisiología , Esfingosina/análogos & derivados , Esfingosina/fisiología
7.
Drugs ; 77(5): 493-503, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28233273

RESUMEN

The complexity of neural circuits that control food intake and energy balance in the hypothalamic nuclei explains some of the constraints involved in the prevention and treatment of obesity. Two major neuronal populations present in the arcuate nucleus control caloric intake and energy expenditure: one population co-expresses orexigenic agouti-related peptide (AgRP) and neuropeptide Y and the other expresses the anorexigenic anorectic neuropeptides proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART). In addition to integrating signals from neurotransmitters and hormones, the hypothalamic systems that regulate energy homeostasis are affected by nutrients. Fat-rich diets, for instance, elicit hypothalamic inflammation (reactive activation and proliferation of microglia, a condition named gliosis). This process generates resistance to the anorexigenic hormones leptin and insulin, contributing to the genesis of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have increasingly been used to treat type 2 diabetes mellitus. One compound (liraglutide) was recently approved for the treatment of obesity. Although most studies suggest that GLP-1RAs promote weight loss mainly due to their inhibitory effect on food intake, other central effects that have been described for native GLP-1 and some GLP-1RAs in rodents and humans encourage future clinical trials to explore additional mechanisms that potentially underlie the beneficial effects observed with this drug class. In this article we review the most relevant data exploring the mechanisms involved in the effects of GLP-1RAs in the brain-adipocyte axis.


Asunto(s)
Adipocitos/efectos de los fármacos , Encéfalo/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Adipocitos/metabolismo , Animales , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación
8.
Neuroradiology ; 58(11): 1103-1108, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27561739

RESUMEN

INTRODUCTION: We investigated whether MR diffusion tensor imaging (DTI) analysis of the cervical spinal cord could aid the (differential) diagnosis of sensory neuronopathies, an underdiagnosed group of diseases of the peripheral nervous system. METHODS: We obtained spinal cord DTI and T2WI at 3 T from 28 patients, 14 diabetic subjects with sensory-motor distal polyneuropathy, and 20 healthy controls. We quantified DTI-based parameters and looked at the hyperintense T2W signal at the spinal cord posterior columns. Fractional anisotropy and mean diffusivity values at C2-C3 and C3-C4 levels were compared between groups. We also compared average fractional anisotropy (mean of values at C2-C3 and C3-C4 levels). A receiver operating characteristic (ROC) curve was used to determine diagnostic accuracy of average fractional anisotropy, and we compared its sensitivity against the hyperintense signal in segregating patients from the other subjects. RESULTS: Mean age and disease duration were 52 ± 10 and 11.4 ± 9.3 years in the patient group. Eighteen subjects had idiopathic disease and 6 dysimmune etiology. Fractional anisotropy at C3-C4 level and average fractional anisotropy were significantly different between patients and healthy controls (p < 0.001 and <0.001) and between patients and diabetic subjects (p = 0.019 and 0.027). Average fractional anisotropy presented an area under the curve of 0.838. Moreover, it had higher sensitivity than visual detection of the hyperintense signal (0.86 vs. 0.54), particularly for patients with short disease duration. CONCLUSION: DTI-based analysis enables in vivo detection of posterior column damage in sensory neuronopathy patients and is a useful diagnostic test for this condition. It also helps the differential diagnosis between sensory neuronopathy and distal polyneuropathies.


Asunto(s)
Imagen de Difusión Tensora/métodos , Polineuropatías/diagnóstico , Polineuropatías/patología , Radiculopatía/diagnóstico por imagen , Radiculopatía/patología , Médula Espinal/diagnóstico por imagen , Médula Espinal/patología , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuritis , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
9.
Curr Atheroscler Rep ; 17(10): 57, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26300554

RESUMEN

Obesity is a highly prevalent disease in the world and with a major impact on global health. While genetic components are also involved in its pathogenesis, in recent years, it has shown a critical role of the innate and adaptive immune cell response in many tissues triggered by excess of nutrients such as lipids and glucose. Free fatty acids and other nutrient-related signals induce damage such as insulin resistance in the peripheral tissues but also in the brain. Specifically in the hypothalamus, these metabolic signals can trigger significant changes in the control of energy balance. Recent studies have shown that saturated fat disrupts melanocortin signaling of hypothalamic neuronal subgroups pivotal to energy control. Bariatric surgery is a treatment option for obesity when other tools have failed, because it is more effective than pharmacotherapy concerning of weight loss itself and in improvement of obesity-related comorbidities. Here, we review the mechanisms by which Roux-en Y gastric bypass (RYGB) can change peripheral signals that modulate melanocortin circuits involved in the regulation of energy balance.


Asunto(s)
Encéfalo/metabolismo , Obesidad/cirugía , Animales , Cirugía Bariátrica , Metabolismo Energético , Humanos , Resistencia a la Insulina , Obesidad/metabolismo , Estudios Observacionales como Asunto
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