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1.
Front Physiol ; 12: 713118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539438

RESUMO

The combination of machine learning methods together with computational modeling and simulation of the cardiovascular system brings the possibility of obtaining very valuable information about new therapies or clinical devices through in-silico experiments. However, the application of machine learning methods demands access to large cohorts of patients. As an alternative to medical data acquisition and processing, which often requires some degree of manual intervention, the generation of virtual cohorts made of synthetic patients can be automated. However, the generation of a synthetic sample can still be computationally demanding to guarantee that it is clinically meaningful and that it reflects enough inter-patient variability. This paper addresses the problem of generating virtual patient cohorts of thoracic aorta geometries that can be used for in-silico trials. In particular, we focus on the problem of generating a cohort of patients that meet a particular clinical criterion, regardless the access to a reference sample of that phenotype. We formalize the problem of clinically-driven sampling and assess several sampling strategies with two goals, sampling efficiency, i.e., that the generated individuals actually belong to the target population, and that the statistical properties of the cohort can be controlled. Our results show that generative adversarial networks can produce reliable, clinically-driven cohorts of thoracic aortas with good efficiency. Moreover, non-linear predictors can serve as an efficient alternative to the sometimes expensive evaluation of anatomical or functional parameters of the organ of interest.

2.
J Hepatol ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34555423

RESUMO

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. LAY SUMMARY: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis.

3.
Biomater Sci ; 9(21): 7076-7091, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34397074

RESUMO

Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism, catalyzing the first step to fatty acid oxidation (FAO). Inhibiting CPT1A, especially in the brain, can have several pharmacological benefits, such as in treating obesity and brain cancer. C75-CoA is a strong competitive inhibitor of CPT1A. However, due to its negatively charged nature, it has low cellular permeability. Herein, we report the use of poly-ion complex (PIC) micelles to deliver the specific CPT1A inhibitors (±)-, (+)-, and (-)-C75-CoA into U87MG glioma cells and GT1-7 neurons. PIC micelles were formed through charge-neutralization of the cargo with the cationic side chain of PEG-poly{N-[N'-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-PAsp(DET)), forming particles with 55 to 65 nm diameter. Upon short-term incubation with cells, the micelle-encapsulated CPT1A inhibitors resulted in up to 5-fold reduction of ATP synthesis compared to the free drug, without an apparent decline in cell viability. Micelle treatment showed a discernible decrease in 14C-palmitate oxidation into CO2 and acid-soluble metabolites, confirming that the substantial lowering of ATP production has resulted from FAO inhibition. Micelle treatment also diminished IC50 by 2 to 4-fold over the free drug-treated U87MG after long-term incubation. To measure the cellular uptake of these CoA-adduct loaded PIC micelles, we synthesized a fluorescent CoA derivative and prepared Fluor-CoA micelles which showed efficient internalization in the cell lines, both in 2D and 3D culture models, especially in neurons where uptake reached up to 3-fold over the free dye. Our results starkly demonstrate that the PIC micelles are a promising delivery platform for anionic inhibitors of CPT1A in glioma cells and neurons, laying the groundwork for future research or clinical applications.


Assuntos
Metabolismo dos Lipídeos , Micelas , Encéfalo , Coenzima A , Oxirredução , Polietilenoglicóis
4.
Biochem Pharmacol ; 192: 114723, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364887

RESUMO

Both obesity and aging are associated with the development of metabolic diseases such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation of adipose tissue is one of the mechanisms implicated in the progression of these diseases. Obesity and aging trigger adipose tissue alterations that ultimately lead to a pro-inflammatory phenotype of the adipose tissue-resident immune cells. Obesity and aging also share other features such as a higher visceral vs. subcutaneous adipose tissue ratio and a decreased lifespan. Here, we review the common characteristics of obesity and aging and the alterations in white adipose tissue and resident immune cells. We focus on the adipose tissue metabolic derangements in obesity and aging such as inflammation and adipose tissue remodeling.


Assuntos
Adipócitos Brancos/imunologia , Tecido Adiposo Branco/imunologia , Envelhecimento/imunologia , Distribuição da Gordura Corporal/métodos , Obesidade/imunologia , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Humanos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Obesidade/metabolismo , Obesidade/patologia
5.
Insects ; 12(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34357272

RESUMO

Grapholita molesta is an important pest of stone and pome fruits. In commercial orchards, integrated pest management programs use pheromone traps to monitor the population dynamics of G. molesta and adjust treatments. Phenology models can be used to forecast the population phenology of pests and to help optimise the time point at which to spray the orchards with insecticides. In the present study, the adult population phenologies of G. molesta in two provinces of north-east Spain were studied, as well as their fit to the phenology model most used in both provinces. Weekly captures of adults in pheromone traps through the season were recorded over 5 y in a large number of commercial orchards, and these data were used to determine the number of generations of G. molesta in each province. The results show significant differences between provinces in the generation time, being 97 degree days (DD) shorter in the Lleida province than in the Girona province. In Girona province, four generations were registered, while five were detected in Lleida. As a result of the differences found, the phenology model was not able to predict precisely the population dynamics in the Girona province.

6.
Cells ; 10(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209378

RESUMO

Phagocytosis is an inherent function of tissue macrophages for the removal of apoptotic cells and cellular debris during acute and chronic injury; however, the dynamics of this event during fibrosis development is unknown. We aim to prove that during the development of kidney fibrosis in the unilateral ureteral obstruction (UUO) model, there are some populations of macrophage with a reduced ability to phagocytose, and whether the infusion of a population of phagocytic macrophages could reduce fibrosis in the murine model UUO. For this purpose, we have identified the macrophage populations during the development of fibrosis and have characterized their phagocytic ability and their expression of CPT1a. Furthermore, we have evaluated the therapeutic effect of macrophages overexpressing CPT1a with high phagocytic skills. We evidenced that the macrophage population which exhibits high phagocytic ability (F4/80low-CD11b) in fibrotic animals decreases during the progression of fibrosis while the macrophage population with lower phagocytic ability (F4/80high-CD11b) in fibrotic conditions, conversely, increases and CPT1a macrophage cell therapy with a strengthening phagocytic ability is associated with a therapeutic effect on kidney fibrosis. We have developed a therapeutic approach to reduce fibrosis in the UUO model by enrichment of the kidney resident macrophage population with a higher proportion of exogenous phagocytic macrophages overexpressing CPT1a.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Rim/patologia , Macrófagos/transplante , Fagocitose , Obstrução Ureteral/complicações , Animais , Antígeno CD11b/metabolismo , Carnitina O-Palmitoiltransferase/genética , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Perfilação da Expressão Gênica , Masculino , Camundongos , Células RAW 264.7
7.
Biochem Pharmacol ; 190: 114640, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34087244

RESUMO

Physical inactivity is a major public health problem that contributes to the development of several pathologies such as obesity, type 2 diabetes and cardiovascular diseases. Regular exercise mitigates the progression of these metabolic problems and contributes positively to memory and behavior. Therefore, public health agencies have incorporated exercise in the treatment of widespread disorders. The hypothalamus, specifically the ventromedial and the arcuate nuclei, responds to exercise activity and modulates energy metabolism through stimulation of the sympathetic nervous system and catecholamine secretion into the circulation. In addition, physical performance enhances cognitive functions and memory, mediated mostly by an increase in brain-derived neurotrophic factor levels in brain. During exercise training, skeletal muscle myofibers remodel their biochemical, morphological and physiological state. Moreover, skeletal muscle interacts with other organs by the release into the circulation of myokines, molecules that exhibit autocrine, paracrine and endocrine functions. Several studies have focused on the role of skeletal muscle and tissues in response to physical activity. However, how the hypothalamus could influence the skeletal muscle task in the context of exercise is less studied. Here, we review recent data about hypothalamus-skeletal muscle crosstalk in response to physical activity and focus on specific aspects such as the neuroendocrinological effects of exercise and the endocrine functions of skeletal muscle, to provide a perspective for future study directions.


Assuntos
Metabolismo Energético/fisiologia , Exercício Físico/fisiologia , Hipotálamo/fisiologia , Músculo Esquelético/fisiologia , Humanos , Transdução de Sinais
8.
Insects ; 12(4)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917008

RESUMO

Cacopsylla pyri (L.) (Hemiptera: Psyllidae) is a key pest of pear orchards in Spain. The large number of insecticide treatments necessary for control may be an important contributor to the emergence of resistance. Laboratory toxicity and biochemical assays are necessary to validate the existence of insecticide resistance and establish the underlying mechanisms. All the methodologies developed to evaluate enzyme activity in C. pyri to date have incorporated "pools" of adults to detect minimum activity ranges. In this study, we determined the optimal working conditions for evaluation of the activities of esterase, glutathione S-transferase and NADPH-cytochrome P450 reductase in individual insects via colorimetric methods using a microplate reader. The main factors affecting enzymatic analysis activity, such as enzyme source and substrate concentration, filter wavelength, buffer pH, reaction time and additives, were evaluated for optimization. Determining the frequency of resistant individuals within a population could be used as an indicator for the evolution of insecticide resistance over time. Two laboratory strains, one of them selected with cypermethrin, and two field populations were analyzed for this purpose. The data obtained revealed high values and great variation in the activity ranges of esterase (EST) in the insecticide-selected population as well as in the field populations validating the applied methodology.

9.
iScience ; 24(2): 102128, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33659885

RESUMO

Many metabolic pathways, including lipid metabolism, are rewired in tumors to support energy and biomass production and to allow adaptation to stressful environments. Neuroblastoma is the second deadliest solid tumor in children. Genetic aberrations, as the amplification of the MYCN-oncogene, correlate strongly with disease progression. Yet, there are only a few molecular targets successfully exploited in the clinic. Here we show that inhibition of fatty acid synthesis led to increased neural differentiation and reduced tumor burden in neuroblastoma xenograft experiments independently of MYCN-status. This was accompanied by reduced levels of the MYCN or c-MYC oncoproteins and activation of ERK signaling. Importantly, the expression levels of genes involved in de novo fatty acid synthesis showed prognostic value for neuroblastoma patients. Our findings demonstrate that inhibition of de novo fatty acid synthesis is a promising pharmacological intervention strategy for the treatment of neuroblastoma independently of MYCN-status.

10.
Gut ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526437

RESUMO

OBJECTIVES: Coeliac disease (CD) is a complex autoimmune disorder that develops in genetically susceptible individuals. Dietary gluten triggers an immune response for which the only available treatment so far is a strict, lifelong gluten free diet. Human leucocyte antigen (HLA) genes and several non-HLA regions have been associated with the genetic susceptibility to CD, but their role in the pathogenesis of the disease is still essentially unknown, making it complicated to develop much needed non-dietary treatments. Here, we describe the functional involvement of a CD-associated single-nucleotide polymorphism (SNP) located in the 5'UTR of XPO1 in the inflammatory environment characteristic of the coeliac intestinal epithelium. DESIGN: The function of the CD-associated SNP was investigated using an intestinal cell line heterozygous for the SNP, N6-methyladenosine (m6A)-related knock-out and HLA-DQ2 mice, and human samples from patients with CD. RESULTS: Individuals harbouring the risk allele had higher m6A methylation in the 5'UTR of XPO1 RNA, rendering greater XPO1 protein amounts that led to downstream nuclear factor kappa B (NFkB) activity and subsequent inflammation. Furthermore, gluten exposure increased overall m6A methylation in humans as well as in in vitro and in vivo models. CONCLUSION: We identify a novel m6A-XPO1-NFkB pathway that is activated in CD patients. The findings will prompt the development of new therapeutic approaches directed at m6A proteins and XPO1, a target under evaluation for the treatment of intestinal disorders.

11.
Eur J Endocrinol ; 184(4): 533-541, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33524007

RESUMO

Context: The endocrine and immunological properties of subcutaneous vs visceral adipose tissue (sWAT and vWAT, respectively) have turned a milestone in the study of metabolic diseases. The cytokine S100A4 is increased in obesity and has a role in adipose tissue dysfunction. However, the cellular source and its potential role in hepatic damage in obesity has not been elucidated. Objective: We aim to study the regulation of S100A4 in immune cells present in sWAT and vWAT, as well as its potential role as a circulating marker of hepatic inflammation and steatosis. Design: A cohort of 60 patients with obesity and distinct metabolic status was analyzed. CD11b+ myeloid cells and T cells were isolated from sWAT and vWAT by magnetic-activating cell sorting, and RNA was obtained. S100A4 gene expression was measured, and correlation analysis with clinical data was performed. Liver biopsies were obtained from 20 patients, and S100A4 circulating levels were measured to check the link with hepatic inflammation and steatosis. Results: S100A4 gene expression was strongly upregulated in sWAT- vs vWAT-infiltrated CD11b+ cells, but this modulation was not observed in T cells. S100A4 mRNA levels from sWAT (and not from vWAT) CD11b+ cells positively correlated with glycemia, triglycerides, TNF-α gene expression and proliferation markers. Finally, circulating S100A4 directly correlated with liver steatosis and hepatic inflammatory markers. Conclusion: Our data suggest that sWAT-infiltrated CD11b+ cells could be a major source of S100A4 in obesity. Moreover, our correlations identify circulating S100A4 as a potential novel biomarker of hepatic damage and steatosis.


Assuntos
Tecido Adiposo Branco/patologia , Antígeno CD11b/análise , Fígado Gorduroso/sangue , Células Mieloides/química , Obesidade/complicações , Proteína A4 de Ligação a Cálcio da Família S100/análise , Tecido Adiposo Branco/química , Tecido Adiposo Branco/metabolismo , Adulto , Idoso , Animais , Biomarcadores/análise , Biomarcadores/sangue , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Expressão Gênica , Humanos , Gordura Intra-Abdominal/química , Gordura Intra-Abdominal/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Células RAW 264.7 , Proteína A4 de Ligação a Cálcio da Família S100/sangue , Proteína A4 de Ligação a Cálcio da Família S100/genética , Gordura Subcutânea/química , Gordura Subcutânea/patologia
12.
J Clin Invest ; 131(5)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33465052

RESUMO

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.


Assuntos
Carnitina O-Palmitoiltransferase/biossíntese , Regulação Enzimológica da Expressão Gênica , Túbulos Renais/enzimologia , Insuficiência Renal Crônica/prevenção & controle , Animais , Carnitina O-Palmitoiltransferase/genética , Modelos Animais de Doenças , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Fibrose , Túbulos Renais/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética
13.
Int J Neuropsychopharmacol ; 24(1): 77-88, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-32951039

RESUMO

BACKGROUND: Prenatal alcohol exposure is a leading cause of neurobehavioral and neurocognitive deficits collectively known as fetal alcohol spectrum disorders, including eating disorders and increased risk for substance abuse as very common issues. In this context, the present study aimed to assess the interaction between prenatal and lactation alcohol exposure (PLAE) and a high-fat diet (HFD) during childhood and adolescence. METHODS: Pregnant C57BL/6 mice underwent a procedure for alcohol binge drinking during gestation and lactation periods. Subsequently, PLAE female offspring were fed with an HFD for 8 weeks, and thereafter, nutrition-related parameters as well as their response to cocaine were assessed. RESULTS: In our model, feeding young females with an HFD increased their triglyceride blood levels but did not induce overweight compared with those fed with a standard diet. Moreover, PLAE affected how females responded to the fatty diet as they consumed less food than water-exposed offspring, consistent with a lower gain of body weight. HFD increased the psychostimulant effects of cocaine. Surprisingly, PLAE reduced the locomotor responses to cocaine without modifying cocaine-induced reward. Moreover, PLAE prevented the striatal overexpression of cannabinoid 1 receptors induced by an HFD and induced an alteration of myelin damage biomarker in the prefrontal cortex, an effect that was mitigated by an HFD-based feeding. CONCLUSION: Therefore, in female offspring, some effects triggered by one of these factors, PLAE or an HFD, were blunted by the other, suggesting a close interaction between the involved mechanisms.

14.
Nutrients ; 12(11)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105762

RESUMO

Obesity and its associated metabolic diseases are currently a priority research area. The increase in global prevalence at different ages is having an enormous economic and health impact. Genetic and environmental factors play a crucial role in the development of obesity, and diet is one of the main factors that contributes directly to the obesogenic phenotype. Scientific evidence has shown that increased fat intake is associated with the increase in body weight that triggers obesity. Rodent animal models have been extremely useful in the study of obesity since weight gain can easily be induced with a high-fat diet. Here, we review the dietary patterns and physiological mechanisms involved in the dynamics of energy balance. We report the main dietary options for the study of obesity and the variables to consider in the use of a high-fat diet, and assess the progression of obesity and diet-induced thermogenesis.


Assuntos
Dieta Hiperlipídica , Modelos Animais , Obesidade , Animais , Peso Corporal , Gorduras na Dieta/administração & dosagem , Ingestão de Energia , Metabolismo Energético , Feminino , Masculino , Camundongos , Obesidade/etiologia , Obesidade/fisiopatologia , Ratos , Termogênese , Ganho de Peso
15.
Mol Metab ; 42: 101097, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33049408

RESUMO

OBJECTIVE: Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and ß-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. METHODS: The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. RESULTS: BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. CONCLUSIONS: This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and ß-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.


Assuntos
Tecido Adiposo Marrom/metabolismo , Sirtuína 1/metabolismo , Adipócitos/metabolismo , Adipócitos/fisiologia , Adipócitos Marrons/metabolismo , Adipócitos Marrons/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/fisiologia , Animais , Metabolismo Energético , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Inflamação/prevenção & controle , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Obesidade/metabolismo , Receptores Adrenérgicos beta/metabolismo , Sirtuína 1/genética , Sirtuína 1/fisiologia , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo
16.
FASEB J ; 34(9): 11816-11837, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32666604

RESUMO

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.


Assuntos
Biomarcadores/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos/metabolismo , Terapia Genética/métodos , Metabolismo dos Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Animais , Carnitina O-Palmitoiltransferase/genética , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/etiologia , Obesidade/metabolismo , Oxirredução , Triglicerídeos/metabolismo
17.
Nanomedicine (Lond) ; 15(16): 1617-1636, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32618490

RESUMO

Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood-brain barrier and the lack of specificity of the drugs for the diseased cells. Nanomedicine-based approaches provide promising opportunities for overcoming these limitations. Although many previous reviews are focused on brain targeting with nanomedicines in general, none of those are concerned explicitly on the neurons, while targeting neuronal cells in central nervous diseases is now one of the biggest challenges in nanomedicine and neuroscience. We review the most relevant advances in nanomedicine design and strategies for neuronal drug delivery that might successfully bridge the gap between laboratory and bedside treatment in neurology.


Assuntos
Nanopartículas , Preparações Farmacêuticas , Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Nanomedicina , Neurônios
18.
Biochem Pharmacol ; 177: 113973, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283053

RESUMO

The epidemic of obesity has become pandemic, putting a significant burden on the world's healthcare system. While the heritability of the disease is high, all the identified genetic variants associated to obesity account for a very small percentage of phenotypic variation. The origins of the obesity pandemic cannot be explained exclusively due to genetic factors. In recent years, epigenetic studies have offered valuable information for a deeper understanding of the steep increase in global obesity rates. Existing evidence indicate that environmental exposures induce alterations to the epigenome, leading to the transmission of obesity risk across generations. In this review, we provide insight into the epigenetic disturbances associated with obesity and discuss the impact of harmful diets, particularly calorie-dense foods, in the epigenetic regulation of obesity. The epigenetics of obesity is an expanding area of research, and current reports suggest potential in the use of epigenetic mechanisms as clinical biomarkers and therapeutic candidates.


Assuntos
Metilação de DNA , Epigênese Genética , Predisposição Genética para Doença/genética , Obesidade/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Dieta , Humanos , Leptina/genética , Obesidade/complicações , Pró-Opiomelanocortina/genética , Receptor Tipo 4 de Melanocortina/genética
19.
Metabolism ; 106: 154191, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32112822

RESUMO

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) plays a key role in fatty acid metabolism and glucose homeostasis. In the context of dyslipemia, LRP1 is upregulated in the heart. Our aim was to evaluate the impact of cardiomyocyte LRP1 deficiency on high fat diet (HFD)-induced cardiac and metabolic alterations, and to explore the potential mechanisms involved. METHODS: We used TnT-iCre transgenic mice with thoroughly tested suitability to delete genes exclusively in cardiomyocytes to generate an experimental mouse model with conditional Lrp1 deficiency in cardiomyocytes (TNT-iCre+-LRP1flox/flox). FINDINGS: Mice with Lrp1-deficient cardiomyocytes (cm-Lrp1-/-) have a normal cardiac function combined with a favorable metabolic phenotype against HFD-induced glucose intolerance and obesity. Glucose intolerance protection was linked to higher hepatic fatty acid oxidation (FAO), lower liver steatosis and increased whole-body energy expenditure. Proteomic studies of the heart revealed decreased levels of cardiac pro-atrial natriuretic peptide (pro-ANP), which was parallel to higher ANP circulating levels. cm-Lrp1-/- mice showed ANP signaling activation that was linked to increased fatty acid (FA) uptake and increased AMPK/ ACC phosphorylation in the liver. Natriuretic peptide receptor A (NPR-A) antagonist completely abolished ANP signaling and metabolic protection in cm-Lrp1-/- mice. CONCLUSIONS: These results indicate that an ANP-dependent axis controlled by cardiac LRP1 levels modulates AMPK activity in the liver, energy homeostasis and whole-body metabolism.


Assuntos
Resistência à Insulina/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Miócitos Cardíacos/metabolismo , Obesidade/genética , Adenilato Quinase/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Metabolismo dos Lipídeos/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Obesidade/metabolismo , Obesidade/patologia
20.
Obes Surg ; 30(6): 2375-2381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32133589

RESUMO

BACKGROUND: In contrast to the energy-storing role of white adipose tissue (WAT), brown adipose tissue (BAT) acts as the main site of non-shivering thermogenesis in mammals and has been reported to play a role in protection against obesity and associated metabolic alterations in rodents. Infrared thermography (IRT) has been proposed as a novel non-invasive, safe, and quick method to estimate BAT thermogenic activation in humans. The aim of this study is to determine whether the IRT could be a potential new tool to estimate BAT thermogenic activation in patients with severe obesity in response to bariatric surgery. METHODS: Supraclavicular BAT thermogenic activation was evaluated using IRT in a cohort of 31 patients (50 ± 10 years old, BMI = 44.5 ± 7.8; 15 undergoing laparoscopy sleeve gastrectomy and 16 Roux-en-Y gastric bypass) at baseline and 6 months after a bariatric surgery. Clinical parameters were determined at these same time points. RESULTS: Supraclavicular BAT-related activity was detected in our patients by IRT after a cooling stimulus. The BAT thermogenic activation was higher at 6 months after laparoscopy sleeve gastrectomy (0.06 ± 0.1 vs 0.32 ± 0.1), while patients undergoing to a roux-en-Y gastric bypass did not change their thermogenic response using the same cooling stimulus (0.09 ± 0.1 vs 0.08 ± 0.1). CONCLUSIONS: Our study postulates the IRT as a potential tool to evaluate BAT thermogenic activation in patients with obesity before and after a bariatric surgery. Further studies are needed to evaluate differences between LSG technique and RYGB on BAT activation.


Assuntos
Cirurgia Bariátrica , Derivação Gástrica , Obesidade Mórbida , Tecido Adiposo Marrom , Gastrectomia , Humanos , Obesidade Mórbida/cirurgia , Termogênese , Termografia
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