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1.
Toxicol Lett ; 339: 78-87, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33387635

RESUMO

Obesity is a complex disease with many causes, including a possible role for environmental chemicals. Perfluorohexane sulfonate (PFHxS) is one of many per- and polyfluoroalkyl substances (PFASs) frequently detected in humans and it is suspected to be an obesogenic compound. We examined the potential long-term effects of PFHxS on metabolic parameters in rats after developmental exposure to 0.05, 5 or 25 mg/kg bw/day, with or without co-exposure to a background mixture of twelve endocrine disrupting chemicals (EDmix). Both male and female offspring showed signs of lower birth weight following intrauterine exposure. Female offspring exposed to both PFHxS and EDmix had increased body weight in adulthood. The retroperitoneal fat pad was larger in the PFHxS-exposed female offspring when compared to those exposed to EDmix alone. An attempt to detect putative molecular markers in the fat tissue by performing whole transcriptome profiling revealed no significant changes between groups and there were no significant effects on plasma leptin levels in exposed females. Our results show that early life exposure to endocrine disrupting chemicals can influence body weight later in life, but the effect is not necessarily reflected in changed gene expression in the fat tissue.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Disruptores Endócrinos/metabolismo , Disruptores Endócrinos/toxicidade , Obesidade/induzido quimicamente , Ácidos Sulfônicos/metabolismo , Ácidos Sulfônicos/toxicidade , Ganho de Peso/efeitos dos fármacos , Adipócitos/metabolismo , Adulto , Animais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos
2.
Chem Biol Interact ; 336: 109369, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33422521

RESUMO

Consumption of foods rich in phenolic compounds can be beneficial for health. This study aimed to examine whether the consumption of a phenolic-rich smoothie, based on juçara, strawberry and banana, ameliorates metabolic status and liver damage of diet-induced obese mice. Forty male C57BL/6J mice were assigned into four groups (n = 10) and fed control diet with free access to water (C) or phenolic-rich smoothie (C-S), or fed high-fat diet with free access to water (HF) or phenolic-rich smoothie (HF-S) for five weeks. HF and HF-S groups had higher body weight gains than the C group, however the HF had a greater adipose index, higher plasma levels of glucose, insulin and leptin, as well as higher plasma and hepatic steatosis than C, C-S and HF-S groups. The liver oxidative stress markers were reduced in C-S and HF-S groups and the activity of catalase and glutathione peroxidase were higher compared with their counterparts. The present study suggests that regular consumption of a phenolic-rich smoothie improves the liver antioxidant status, prevents metabolic disorders and ameliorates non-alcoholic fatty liver disease caused by high-fat diet consumption.


Assuntos
Antioxidantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Fenóis/uso terapêutico , Animais , Antioxidantes/química , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/induzido quimicamente , Fenóis/química
3.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430045

RESUMO

Plant-based nutritional supplementation has been shown to attenuate and reduce mortality in the processes of both acute and chronic disorders, including diabetes, obesity, cardiovascular disease, cancer, inflammatory diseases, and neurological and neurodegenerative disorders. Low-level systemic inflammation is an important contributor to these afflictions and diets enriched in phytochemicals can slow the progression. The goal of this study was to determine the impact of lipopolysaccharide (LPS)-induced inflammation on changes in glucose and insulin tolerance, performance enhancement, levels of urinary neopterin and concentrations of neurotransmitters in the striatum in mouse models. Both acute and chronic injections of LPS (2 mg/kg or 0.33 mg/kg/day, respectively) reduced glucose and insulin tolerance and elevated neopterin levels, which are indicative of systemic inflammatory responses. In addition, there were significant decreases in striatal neurotransmitter levels (dopamine and DOPAC), while serotonin (5-HT) levels were essentially unchanged. LPS resulted in impaired execution in the incremental loading test, which was reversed in mice on a supplemental plant-based diet, improving their immune function and maintaining skeletal muscle mitochondrial activity. In conclusion, plant-based nutritional supplementation attenuated the metabolic changes elicited by LPS injections, causing systemic inflammatory activity that contributed to both systemic and neurological alterations.


Assuntos
Inflamação/dietoterapia , Músculo Esquelético/metabolismo , Obesidade/dietoterapia , Compostos Fitoquímicos/farmacologia , Animais , Dieta , Suplementos Nutricionais , Modelos Animais de Doenças , Dopamina/metabolismo , Glucose/metabolismo , Inflamação/induzido quimicamente , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Músculo Esquelético/efeitos dos fármacos , Neopterina/urina , Obesidade/induzido quimicamente , Obesidade/patologia , Serotonina/metabolismo
4.
Am J Physiol Gastrointest Liver Physiol ; 320(2): G166-G174, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33325808

RESUMO

Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were intravenously injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced nonalcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride (T) and free fatty acid (FFA) levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis, and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD.NEW & NOTEWORTHY Human CES2 attenuates high-fat/cholesterol/fructose diet-induced steatohepatitis and reverses steatohepatitis in db/db mice. Mechanistically, human CES2 induces lipolysis, fatty acid and glucose oxidation, and inhibits hepatic glucose production, inflammation, lipid oxidation, and apoptosis. Our data suggest that human CES2 may be targeted for treatment of non-alcoholic steatohepatitis (NASH).


Assuntos
Carboxilesterase/metabolismo , Hepatócitos/enzimologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/terapia , Ácido 3-Hidroxibutírico/sangue , Ácido 3-Hidroxibutírico/metabolismo , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Animais , Apoptose/fisiologia , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Glicemia , Carboxilesterase/genética , Dieta/efeitos adversos , Hidroxiprolina/sangue , Hidroxiprolina/metabolismo , Metabolismo dos Lipídeos , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Obesidade/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo
5.
Food Chem ; 340: 128169, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33007695

RESUMO

Polyphenols from cambuci (CBC) (Campomanesia phaea (O. Berg.)), a Brazilian native fruit, were investigated on therapeutic actions mitigating insulin resistance and hepatic steatosis in high-fat-sucrose diet (HFS) induced obese mice. For this, C57BL/6J mice fed with a obesogenic and diabetogenic HFS diet were administered with either water or two CBC doses (36 or 74 mg gallic acid equivalent (GAE)/kg body weight) by gavage from week 6 to week 14 (end-point) of HFS feeding. CBC reduced body weight gain, inflammation, hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance in liver and skeletal muscle of obese mice, and such effects were associated with activation of Akt and AMPK in these tissues. In conclusion, polyphenols from CBC show important therapeutic actions ameliorating obesity-associated complications.


Assuntos
Resistência à Insulina , Myrtaceae/química , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações , Polifenóis/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Frutas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Polifenóis/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-33333918

RESUMO

Obesity and metabolic-related diseases, among which diabetes, are prominent public health challenges of the 21st century. It is now well acknowledged that pollutants are a part of the equation, especially endocrine-disrupting chemicals (EDCs) that interfere with the hormonal aspect. The aim of the review is to focus on adipose tissue, a central regulator of energy balance and metabolic homeostasis, and to highlight the significant differences in the endocrine and metabolic aspects of adipose tissue between males and females which likely underlie the differences of the response to exposure to EDCs between the sexes. Moreover, the study also presents an overview of several mechanisms of action by which pollutants could cause adipose tissue dysfunction. Indeed, a better understanding of the mechanism by which environmental chemicals target adipose tissue and cause metabolic disturbances, and how these mechanisms interact and sex specificities are essential for developing mitigating and sex-specific strategies against metabolic diseases of chemical origin. In particular, considering that a scenario without pollutant exposure is not a realistic option in our current societies, attenuating the deleterious effects of exposure to pollutants by acting on the gut-adipose tissue axis may constitute a new direction of research.


Assuntos
Tecido Adiposo , Tecido Adiposo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Sistema Endócrino , Poluentes Ambientais/toxicidade , Feminino , Humanos , Masculino , Obesidade/induzido quimicamente , Caracteres Sexuais
7.
Ecotoxicol Environ Saf ; 203: 111041, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888612

RESUMO

Although the production and use of PCB153 have been banned globally, PCB153 pollution remains because of its persistence and long half-life in the environment. There is ongoing evidence that exposure to PCB153 may influence gut microbiota health and increase the risk of host health. It is needed to illuminate whether there are associations between gut microbiota dysregulation and PCB153-induced host diseases. Importantly, it is urgently needed to find specific strains as biomarkers to monitor PCB153 pollution and associated disorders. The work aims to investigate the change of gut microbiota composition, structure and diversity and various host physiological indexes, to ravel the chain causality of PCB153, gut microbiota health and host health, and to find potential gut microbiota markers for PCB153 pollution. Here, adult female mice were administrated with PCB153. Obtained results indicated that PCB153 led to gut microbiota health deterioration. PCB153 exposure also induced obesity, hepatic lipid accumulation, abdominal adipose tissue depots and dyslipidemia in mice. Furthermore, specific gut microbiota significantly correlated with the host health indexes. This work provides support for the relationship between gut microbiota aberrance derived from PCB153 and risk of host health, and offers some indications of possible indicative functions of gut microbiota on PCB153 pollution.


Assuntos
Dislipidemias/induzido quimicamente , Monitoramento Ambiental/métodos , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Bifenilos Policlorados/toxicidade , Animais , Biomarcadores/análise , Colo/microbiologia , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Feminino , Conteúdo Gastrointestinal/microbiologia , Microbioma Gastrointestinal/genética , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia , RNA Ribossômico 16S
8.
PLoS One ; 15(9): e0238750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886728

RESUMO

PURPOSE: The purpose of this study was to use a mouse model of diet-induced obesity to determine if corneal dysfunction begins prior to the onset of sustained hyperglycemia and if the dysfunction is ameliorated by diet reversal. METHODS: Six-week-old male C57BL/6 mice were fed a high fat diet (HFD) or a normal diet (ND) for 5-15 weeks. Diet reversal (DiR) mice were fed a HFD for 5 weeks, followed by a ND for 5 or 10 weeks. Corneal sensitivity was determined using aesthesiometry. Corneal cytokine expression was analyzed using a 32-plex Luminex assay. Excised corneas were prepared for immunofluorescence microscopy to evaluate diet-induced changes and wound healing. For wounding studies, mice were fed a HFD or a ND for 10 days prior to receiving a central 2mm corneal abrasion. RESULTS: After 10 days of HFD consumption, corneal sensitivity declined. By 10 weeks, expression of corneal inflammatory mediators increased and nerve density declined. While diet reversal restored nerve density and sensitivity, the corneas remained in a heightened inflammatory state. After 10 days on the HFD, corneal circadian rhythms (limbal neutrophil accumulation, epithelial cell division and Rev-erbα expression) were blunted. Similarly, leukocyte recruitment after wounding was dysregulated and accompanied by delays in wound closure and nerve recovery. CONCLUSION: In the mouse, obesogenic diet consumption results in corneal dysfunction that precedes the onset of sustained hyperglycemia. Diet reversal only partially ameliorated this dysfunction, suggesting a HFD diet may have a lasting negative impact on corneal health that is resistant to dietary therapeutic intervention.


Assuntos
Córnea/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Hiperglicemia/fisiopatologia , Obesidade/induzido quimicamente , Obesidade/complicações , Animais , Composição Corporal/efeitos dos fármacos , Córnea/efeitos dos fármacos , Modelos Animais de Doenças , Homeostase/efeitos dos fármacos , Hiperglicemia/complicações , Leucócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo , Cicatrização/efeitos dos fármacos
9.
Proc Natl Acad Sci U S A ; 117(33): 20149-20158, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747560

RESUMO

The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.


Assuntos
Regulação da Expressão Gênica/fisiologia , Obesidade/induzido quimicamente , Obesidade/genética , Sinaptotagminas/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Predisposição Genética para Doença , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo , Sinaptotagminas/genética
10.
Am J Physiol Renal Physiol ; 319(3): F476-F486, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32715758

RESUMO

miRNAs provide fine tuning of gene expression via inhibition of translation. miR-451 has a modulatory role in cell cycling via downregulation of mechanistic target of rapamycin. We aimed to test whether chronic systemic inhibition of miR-451 would enhance renal fibrosis (associated with deranged autophagy). Adult TallyHo/Jng mice (obese insulin resistant) were randomized to two treatment groups to receive either miR-451 inhibition [via a locked nucleic acid construct] or a similar scrambled locked nucleic acid control for 8 wk. All mice were fed a high-fat diet (60% kcal from fat) ad libitum and humanely euthanized after 12 wk. Kidneys and blood were collected for analysis. Renal expression of miR-451 was sixfold lower in inhibitor-treated mice compared with control mice. miR-451 inhibition increased kidney weight and collagen and glycogen deposition. Blood chemistry revealed significantly higher Na+ and anion gap (relative metabolic acidosis) in inhibitor-treated mice. Western blot analysis and immunohistochemistry of the kidney revealed that the inhibitor increased markers of renal injury and fibrosis, e.g., kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, transforming growth factor-ß, 14-3-3 protein-ζ, mechanistic target of rapamycin, AMP-activated protein kinase-α, calcium-binding protein 39, matrix metallopeptidase-9, and the autophagy receptor sequestosome 1. In contrast, the inhibitor reduced the epithelial cell integrity marker collagen type IV and the autophagy markers microtubule-associated protein 1A/1B light chain 3B and beclin-1. Taken together, these results support a protective role for miR-451 in reducing renal fibrosis by enhancing autophagy in obese mice.


Assuntos
Autofagia/fisiologia , Rim/patologia , MicroRNAs/antagonistas & inibidores , Animais , Autofagia/efeitos dos fármacos , Dieta Hiperlipídica , Fibrose , Regulação da Expressão Gênica , Resistência à Insulina , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/induzido quimicamente , Peptídeos , Distribuição Aleatória , Transdução de Sinais
11.
PLoS One ; 15(6): e0229806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555600

RESUMO

The A2 adenosine receptors play an important role, among others, in the regulation of inflammatory process and glucose homeostasis in diabetes and obesity. Thus, the presented project evaluated of influence of the selective antagonist of A2A adenosine receptor-KD-64 as compared to the known non-selective antagonist-caffeine on these two particular processes. Two different inflammation models were induced namely local and systemic inflammation. Obesity was induced in mice by high-fat diet and the tested compounds (KD-64 and caffeine) were administrated for 21 days. KD-64 showed anti-inflammatory effect in both tested inflammation models and administered at the same dose as ketoprofen exerted stronger effect than this reference compound. Elevated levels of IL-6 and TNF-α observed in obese control mice were significantly lowered by the administration of KD-64 and were similar to the values observed in control non-obese mice. Interestingly, caffeine increased the levels of these parameters. In contrast to caffeine which had no influence on AlaT activity, KD-64 administration significantly lowered AlaT activity in the obese mice. Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance. Thus, the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Dieta/efeitos adversos , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Cafeína/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Interleucina-6/sangue , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Peritônio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
12.
Ecotoxicol Environ Saf ; 201: 110785, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32505049

RESUMO

Environmental pollutants may play a role in the aetiology of obesity beyond conventional factors. The associations between environmental exposure to aldehydes and obesity remain unclear. The objective of this study is to determine whether aldehyde exposure is associated with obesity in adults. We analysed data from 1977 participants in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 aged ≥ 18 years. Obesity was assessed through body mass index (BMI) measurements. Generalized linear regression and restricted cubic spline models were analysed to assess the association between aldehydes and outcomes. After multivariable adjustment, isopentanaldehyde was inversely associated with obesity, while no significant association was observed between any other aldehydes and obesity. Compared with the lowest quartile, the adjusted odds ratio (OR) of obesity with a 95% confidence interval (CI) for the highest quartile was 0.50 (0.35, 0.70) for isopentanaldehyde. Analyses using a restricted cubic spline indicated that the association between isopentanaldehyde and obesity is nonlinear. Threshold effect analysis demonstrated that the inflection point of isopentanaldehyde was 1.26 ng/ml. Each 1-fold increase in isopentanaldehyde exhibited an 18% decrease in the odds of obesity (OR 0.82, 95% CI 0.79-1.09) on the left side of the inflection point and an 81% decrease (OR 0.19, 95% CI 0.08-0.45) on the right side of the inflection point. Similar associations were also observed among isopentanaldehyde and abdominal obesity, BMI, and waist circumference. These cross-sectional results show a nonlinear and inverse association between isopentanaldehyde and obesity.


Assuntos
Aldeídos/sangue , Exposição Ambiental/análise , Poluentes Ambientais/sangue , Obesidade/epidemiologia , Adulto , Idoso , Índice de Massa Corporal , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/sangue , Obesidade/induzido quimicamente , Razão de Chances , Estados Unidos/epidemiologia , Circunferência da Cintura
13.
J Nutr ; 150(8): 2131-2138, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32533770

RESUMO

BACKGROUND: Although polyphenol-rich cranberry extracts reportedly have an antiobesity effect, the exact reason for this remains unclear. OBJECTIVES: In light of the reported health benefits of the polyphenolic compounds in cranberry, we investigated the effects and mechanism of a cranberry polyphenolic extract (CPE) in high-fat diet (HFD)-fed obese mice. METHODS: The distributions of individual CPE compounds were characterized by HPLC fingerprinting. Male C57BL/6J mice (4 wk old) were fed for 16 wk normal diet (ND, 10% fat energy) or HFD (60% fat energy) with or without 0.75% CPE in drinking water (HFD + CPE). Body and adipose depot weights, indices of glucose metabolism, energy expenditure (EE), and expression of genes related to brown adipose tissue (BAT) thermogenesis, and inguinal/epididymal white adipose tissue (iWAT/eWAT) browning were measured. RESULTS: After 16 wk, the body weight was 22.5% lower in the CPE-treated mice than in the HFD group but remained 17.9% higher than in the ND group. CPE treatment significantly increased EE compared with that of the ND and HFD groups. The elevated EE was linked with BAT thermogenesis, and iWAT/eWAT browning, shown by the induction of thermogenic genes, especially uncoupling protein 1 (Ucp1), and browning-related genes, including Cd137, a member of the tumor necrosis factor receptor superfamily (Tnfrsf9). The mRNA expression and abundance of uncoupling protein 1 in BAT of CPE-fed mice were 5.78 and 1.47 times higher than in the HFD group, and 0.61 and 1.12 times higher than in the ND group, respectively. Cd137 gene expression in iWAT and eWAT of CPE-fed mice were 2.35 and 3.13 times higher than in the HFD group, and 0.84 and 1.39 times higher than in the ND group, respectively. CONCLUSIONS: Dietary CPE reduced but did not normalize HFD-induced body weight gain in male C57BL/6J mice, possibly by affecting energy metabolism.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Obesidade/induzido quimicamente , Obesidade/prevenção & controle , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Vaccinium macrocarpon/química , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Polifenóis/química , Termogênese/efeitos dos fármacos
14.
Int. j. morphol ; 38(3): 755-760, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098316

RESUMO

SUMMARY: The objective of this study was to describe the effects of monosodium glutamate on the collagen of the parotid gland in an obesity model. 18 newborn male Sprague Dawley rats were used (first control group; second group of MSG1: 4 mg/g of monosodium glutamate weight, 5 doses, and third group of MSG2: 4 mg/g of monosodium glutamate, 5 doses, maintained for 8 and 16 weeks respectively). The content and type of collagen were analyzed, in addition to the levels of cholesterol, glucose, triglycerides and uric acid. Monosodium glutamate produced an increase in the obesity rates of the MSG2 group, in addition to an increase in blood cholesterol, glucose and uric acid levels compared to the control group. Type III collagen in the MSG2 group showed a statistically significant increase. Monosodium glutamate induced obesity, in addition to an increase in type III collagen fibers.


RESUMEN: El objetivo de este estudio fue describir los efectos del glutamato monosódico sobre el colágeno de la glándula parótida en un modelo de obesidad. Se utilizaron 18 ratas Sprague Dawley machos recién nacidas (primer grupo control; segundo grupo MSG1: 4 mg/g de peso de glutamato monosódico, 5 dosis, y tercer grupo MSG2: 4 mg/g de glutamato monosódico, 5 dosis, mantenidas durante 8 y 16 semanas respectivamente). Se analizó el contenido y el tipo de colágeno, además de los niveles de colesterol, glucosa, triglicéridos y ácido úrico. El glutamato monosódico produjo un aumento en las tasas de obesidad del grupo MSG2, además de un aumento en los niveles de colesterol en sangre, glucosa y ácido úrico en comparación con el grupo control. El colágeno tipo III en el grupo MSG2 mostró un aumento estadísticamente significativo. La obesidad inducida por glutamato monosódico, además de un aumento en las fibras de colágeno tipo III.


Assuntos
Animais , Masculino , Ratos , Glândula Parótida , Glutamato de Sódio/toxicidade , Colágeno/efeitos dos fármacos , Obesidade/induzido quimicamente , Glândulas Salivares/efeitos dos fármacos , Triglicerídeos/sangue , Ácido Úrico/sangue , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Colágeno/análise , Ratos Sprague-Dawley , Modelos Animais de Doenças , Animais Recém-Nascidos
15.
J Med Chem ; 63(13): 6784-6801, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32433887

RESUMO

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.


Assuntos
Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Dieta/efeitos adversos , Descoberta de Drogas , Resistência à Insulina , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/química , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Obesidade/induzido quimicamente , Conformação Proteica , Inibidores de Proteínas Quinases/uso terapêutico
16.
Toxicol Appl Pharmacol ; 398: 115009, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32353385

RESUMO

Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation.


Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/metabolismo
17.
Toxicol Appl Pharmacol ; 399: 115068, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445754

RESUMO

Volatile organic compounds (VOCs), such as vinyl chloride (VC), can be directly toxic at high concentrations. However, we have shown that 'nontoxic' exposures to VC and its metabolite chloroethanol (CE) enhances experimental non-alcoholic fatty liver disease (NAFLD), suggesting an unpredicted interaction. Importantly, VOC exposure has been identified as a potential risk factor for the development of obesity and its sequelae in humans. As there is a known axis between adipose and hepatic tissue in NAFLD, the impact of CE on white adipose tissue (WAT) inflammation and lipolysis was investigated. Mice were administered CE (or vehicle) once, after 10 weeks of being fed high-fat or low-fat diet (LFD). CE significantly enhanced hepatic steatosis and inflammation caused by HFD. HFD significantly increased the size of epididymal fat pads, which was enhanced by CE. The relative size of adipocyte lipid droplets increased by HFD + CE, which was also correlated with increased expression of lipid-associated proteins (e.g., PLINs). CE also enhanced HFD-induced indices of WAT inflammation, and ER stress. Hepatic-derived circulating FGF21, a major modulator of WAT lipolysis, which is hypothesized to thereby regulate hepatic steatosis, was significantly increased by CE in animals fed HFD. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH, involving the liver-adipose axis in this process. Specifically, CE enhances local inflammation and alters lipid metabolism and WAT-mediated hepatic steatosis due to changes in WAT lipolysis.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cloreto de Vinil/toxicidade , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo
18.
Diabetes ; 69(6): 1292-1305, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32234722

RESUMO

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in patients with diabetes. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mammalian target of rapamycin (mTOR) and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight and whole-body fat and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function and reduced cardiac fat accumulation and mitochondrial injury. Additionally, EMPA significantly augmented Sestrin2 levels and increased AMPK and endothelial nitric oxide synthase phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.


Assuntos
Adenilato Quinase/metabolismo , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Cardiopatias/tratamento farmacológico , Obesidade/induzido quimicamente , Peroxidases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adenilato Quinase/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/etiologia , Homeostase , Camundongos , Oxirredução , Peroxidases/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
19.
Int J Mol Med ; 45(4): 1237-1249, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32124969

RESUMO

The present study aimed to investigate the relationship between the protective effects of exendin­4 (EX­4) on lipotoxicity­induced oxidative stress and meta­inflammation in ß­cells and the toll­like receptor 4 (TLR4)/NF­κB signaling pathway. Lipotoxicity, hydrogen peroxide (H2O2)­induced oxidative stress in ß cells, obese Sprague Dawley rats and TLR4 truncation rats were utilized in the present study. The expression levels were detected by western blotting; cell apoptosis was detected by TUNEL assay; and the intracellular reactive oxygen species (ROS) levels were analyzed using a ROS assay kit. The findings of the present study showed that EX­4 inhibited the expression of TLR4, NF­κB p65 subunit and p47phox in a concentration­dependent manner, and decreased the intracellular level of ROS. Additionally, silencing of TLR4 expression enhanced the protective effects of EX­4, while overexpression of TLR4 attenuated these protective influences. Simultaneously, it was demonstrated that TLR4 was involved in the process of EX­4 intervention to inhibit H2O2­induced oxidative stress in islet ß­cells. Moreover, it was found that EX­4 also inhibited TLR4­ or NF­κB agonist­induced oxidative stress. These results were also confirmed in an animal model of obese rats, in which EX­4 was able to improve the function of ß­cells, attenuate oxidative stress, and inhibit the expression levels of TLR4 and NF­κB p65 subunit in the pancreas of the diet­induced obese rats. Furthermore, truncation of the TLR4 gene in SD rats delayed the aforementioned damage. In summary, EX­4 may inhibit lipotoxicity­induced oxidative stress in ß­cells by inhibiting the activation of the TLR4/NF­κB signaling pathway.


Assuntos
Exenatida/farmacologia , Células Secretoras de Insulina/metabolismo , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Linhagem Celular , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
20.
Chemosphere ; 251: 126392, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32146191

RESUMO

Emerging evidence indicated that disruption of circadian rhythm (CR) induced metabolic disorders, including dysregulation of energy homeostasis and lipid dysfunction, which was associated with ambient fine particulate matter (PM2.5) as well. However, the role and mechanism of CR in PM2.5-mediated metabolic disorder remain unknown. In the present study, we investigated circadian rhythmic characteristics and explored the effect of PM2.5 on oscillating clock of lipid function and metabolism in white adipose tissue (WAT) and brown adipose tissue (BAT). C57BL/6 mice were exposed to PM2.5 in a whole-body inhalational exposure system. After 10 weeks, the expression of clock-related genes exhibits more robust CR in BAT than WAT, with the acrophase of PER2 in both types of adipose tissue being significantly decreased at ZT12 and Bmal1 increased at ZT0/24 in WAT in response to PM2.5 exposure. In addition, both CR pattern and expression levels of Sirt1 got significantly inhibited by PM2.5 exposure in WAT, accompanied with adipose dysfunction evidenced by inhibited pattern and expression levels of adipokines at the same ZT time points. Finally, a similar phase right shift from ZT4 to ZT12 in both Sirt3 and Ucp1 in BAT was induced by PM2.5 exposure. These findings indicate that disruption of the CR in adipose tissues could be an important way by which PM2.5 exposure induces metabolic disorder and provide potential targets for further investigation.


Assuntos
Tecido Adiposo/metabolismo , Ritmo Circadiano , Exposição por Inalação/efeitos adversos , Material Particulado/toxicidade , Tecido Adiposo Marrom , Tecido Adiposo Branco , Adiposidade , Animais , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Material Particulado/análise , Proteína Desacopladora 1
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