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1.
PLoS One ; 15(8): e0231234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804947

RESUMO

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19- to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.


Assuntos
Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/farmacologia , Síndrome Metabólica/metabolismo , Animais , Biomarcadores/metabolismo , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Rim/metabolismo , Masculino , Síndrome Metabólica/complicações , Miocárdio/metabolismo , Obesidade/complicações , Ratos , Ratos Endogâmicos , Ratos Zucker , Volume Sistólico/fisiologia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
2.
Life Sci ; 256: 117965, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32544463

RESUMO

BACKGROUND: Several studies have proved that physical activity (PA) regulates energetic metabolism associated with mitochondrial dynamics through AMPK activation in healthy subjects. Obesity, a condition that induces oxidative stress, mitochondrial dysfunction, and low AMPK activity leads to mitochondrial fragmentation. However, few studies describe the effect of PA on mitochondrial dynamics regulation in obesity. AIM: The present study aimed to evaluate the effect of a single session of PA on mitochondrial dynamics regulation as well as its effect on mitochondrial function and organization in skeletal muscles of obese rats (Zucker fa/fa). MAIN METHODS: Male Zucker lean and Zucker fa/fa rats aged 12 to 13 weeks were divided into sedentary and subjected-to-PA (single session swimming) groups. Gastrocnemius muscle was dissected into isolated fibers, mitochondria, mRNA, and total proteins for their evaluation. KEY FINDINGS: The results showed that PA increased the Mfn-2 protein level in the lean and obese groups, whereas Drp1 levels decreased in the obese group. OMA1 protease levels increased in the lean group and decreased in the obese group. Additionally, AMPK analysis parameters (expression, protein level, and activity) did not increase in the obese group. These findings correlated with the partial restoration of mitochondrial function in the obese group, increasing the capacity to maintain the membrane potential after adding calcium as a stressor, and increasing the transversal organization level of the mitochondria analyzed in isolated fibers. SIGNIFICANCE: These results support the notion that obese rats subjected to PA maintain mitochondrial function through mitochondrial fusion activation by an AMPK-independent mechanism.


Assuntos
Mitocôndrias/patologia , Fibras Musculares Esqueléticas/patologia , Obesidade/patologia , Condicionamento Físico Animal , Adenilato Quinase/metabolismo , Animais , Biomarcadores/metabolismo , Citrato (si)-Sintase/metabolismo , DNA Mitocondrial/metabolismo , Regulação da Expressão Gênica , Masculino , Potencial da Membrana Mitocondrial , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Tamanho do Órgão , Estresse Oxidativo , Fosforilação , Ratos Zucker
3.
PLoS One ; 15(5): e0232399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374790

RESUMO

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.


Assuntos
Insuficiência Cardíaca/etiologia , Obesidade/complicações , Animais , Pressão Sanguínea/fisiologia , Colágeno/metabolismo , Diástole/fisiologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Masculino , Síndrome Metabólica/complicações , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Zucker , Caracteres Sexuais , Volume Sistólico/fisiologia , Magreza/fisiopatologia , Remodelação Ventricular/fisiologia
4.
Clin Sci (Lond) ; 134(10): 1167-1180, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32458968

RESUMO

In the present study, we evaluated the metabolic effects of green tea polyphenols (GTPs) in high-fat diet (HFD) fed Zucker fatty (ZF) rats, in particular the effects of GTP on skeletal muscle insulin sensitivity. Body weight, visceral fat, glucose tolerance, lipid profiles and whole-body insulin sensitivity were measured in HFD-fed ZF rats after 8-week-treatment with GTP (200 mg/kg of body weight) or saline (5 ml/kg of body weight). Zucker lean rats were studied as controls. Ex vivo insulin-mediated muscle glucose uptake was assessed. Immunoblotting was used to evaluate the expression of key insulin signalling proteins in skeletal muscle. GTP treatment attenuated weight gain (P<0.05) and visceral fat accumulation (27.6%, P<0.05), and significantly reduced fasting serum glucose (P<0.05) and insulin (P<0.01) levels. Homoeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, was lower (P<0.01) in GTP-treated animals compared with ZF controls. Moreover, insulin-stimulated glucose uptake by isolated soleus muscle was increased (P<0.05) in GTP-ZF rats compared with ZF-controls. GTP treatment attenuated the accumulation of ectopic lipids (triacyl- and diacyl-glycerols), enhanced the expression and translocation of glucose transporter-4, and decreased pSer612IRS-1 and increased pSer473Akt2 expression in skeletal muscle. These molecular changes were also associated with significantly decreased activation of the inhibitory (muscle-specific) protein kinase (PKC) isoform, PKC-θ. Taken together, the present study has shown that regular ingestion of GTP exerts a number of favourable metabolic and molecular effects in an established animal model of obesity and insulin resistance. The benefits of GTP are mediated in part by inhibiting PKC-θ and improving muscle insulin sensitivity.


Assuntos
Resistência à Insulina , Insulina/metabolismo , Músculo Esquelético/metabolismo , Polifenóis/farmacologia , Transdução de Sinais , Chá/química , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Glucose/metabolismo , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 4/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Isoenzimas/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Transporte Proteico/efeitos dos fármacos , Ratos Zucker
5.
Nutrients ; 12(4)2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252339

RESUMO

The present study tested the hypothesis that the liver lipid-lowering effect of insect meal (IM) is caused by its low methionine concentration. A total of fifty, male obese Zucker rats were randomly assigned to five groups of 10 rats each (casein (C), IM, IM + Met, IM + Cys, and IM + EAA). While group C received a diet with casein, the IM-fed groups received a diet with IM as the protein source. In groups IM + Met, IM + Cys and IM + EAA, the diets were additionally supplemented with methionine, cysteine and essential amino acids (EAA), respectively. Hepatic concentrations of triacylglycerols and cholesterol, and hepatic mRNA levels and activities of lipogenic and cholesterogenic enzymes were markedly lower in the IM-fed groups than in group C (p < 0.05). All of these parameters either did not differ across the IM-fed groups or were only slightly higher in groups IM + Met, IM + Cys and IM+EAA than in the group IM. In conclusion, the results indicate that a difference in the amino acid composition between IM and casein, a low concentration of methionine in IM and a reduced cysteine synthesis secondary to a decreased methionine availability resulting from feeding IM are not causative for the lipid-lowering effect of IM.


Assuntos
Aminoácidos Essenciais/metabolismo , Aminoácidos Sulfúricos/metabolismo , Proteínas na Dieta/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Aminoácidos Essenciais/administração & dosagem , Aminoácidos Sulfúricos/administração & dosagem , Animais , Caseínas/metabolismo , Cisteína/metabolismo , Proteínas na Dieta/administração & dosagem , Insetos , Lipídeos/análise , Masculino , Ratos , Ratos Zucker
6.
Cardiovasc Diabetol ; 19(1): 19, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070346

RESUMO

BACKGROUND: Empagliflozin (empa), a selective sodium-glucose cotransporter (SGLT)2 inhibitor, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk independent of glycemic control. The cardiovascular protective effect of empa was evaluated in an experimental model of metabolic syndrome, the obese ZSF1 rat, and its' lean control. METHODS: Lean and obese ZSF1 rats were either non-treated or treated with empa (30 mg/kg/day) for 6 weeks. Vascular reactivity was assessed using mesenteric artery rings, systolic blood pressure by tail-cuff sphygmomanometry, heart function and structural changes by echocardiography, and protein expression levels by Western blot analysis. RESULTS: Empa treatment reduced blood glucose levels from 275 to 196 mg/dl in obese ZSF1 rats whereas normoglycemia (134 mg/dl) was present in control lean ZSF1 rats and was unaffected by empa. Obese ZSF1 rats showed increased systolic blood pressure, and blunted endothelium-dependent relaxations associated with the appearance of endothelium-dependent contractile responses (EDCFs) compared to control lean rats. These effects were prevented by the empa treatment. Obese ZSF1 rats showed increased weight of the heart and of the left ventricle volume without the presence of diastolic or systolic dysfunction, which were improved by the empa treatment. An increased expression level of senescence markers (p53, p21, p16), tissue factor, VCAM-1, SGLT1 and SGLT2 and a down-regulation of eNOS were observed in the aortic inner curvature compared to the outer one in the control lean rats, which were prevented by the empa treatment. In the obese ZSF1 rats, no such effects were observed. The empa treatment reduced the increased body weight and weight of lungs, spleen, liver and perirenal fat, hyperglycemia and the increased levels of total cholesterol and triglycerides in obese ZSF1 rats, and increased blood ketone levels and urinary glucose excretion in control lean and obese ZSF1 rats. CONCLUSION: Empa reduced glucose levels by 28% and improved both endothelial function and cardiac remodeling in the obese ZSF1 rat. Empa also reduced the increased expression level of senescence, and atherothrombotic markers at arterial sites at risk in the control lean, but not obese, ZSF1 rat.


Assuntos
Compostos Benzidrílicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Glucosídeos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Obesidade/complicações , Ratos Zucker , Sístole
7.
Cardiovasc Diabetol ; 19(1): 24, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093680

RESUMO

BACKGROUND: Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl). METHODS: Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting. RESULTS: We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1ß, TGF-ß1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably. CONCLUSIONS: In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.


Assuntos
Doença da Artéria Coronariana/prevenção & controle , Circulação Coronária/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Resistência à Insulina , Liraglutida/farmacologia , Microcirculação/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Zucker , Cloreto de Sódio na Dieta , Remodelação Ventricular/efeitos dos fármacos
8.
Oxid Med Cell Longev ; 2020: 6372935, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089774

RESUMO

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.


Assuntos
Angiotensina I/metabolismo , Antioxidantes/metabolismo , Glucose/metabolismo , Imidazóis/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Animais , Imidazóis/farmacologia , Masculino , Ratos , Ratos Zucker
9.
Toxicol Appl Pharmacol ; 390: 114899, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31981641

RESUMO

High-fat diet (HFD)-induced obesity is implicated in diabetic nephropathy (DN). EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, has multiple biological functions; however, its protective effect against DN is yet to be properly understood. This study was aimed to explore the protective effect of EX-527 against DN in HFD-induced diabetic Zucker (ZDF) rats. After 21 weeks of continually feeding HFD to the rats, the apparent characteristics of progressive DN were observed, which included an increase in kidney weight (~160%), hyperglycemia, oxidative stress, and inflammatory cytokines, and subsequent renal cell damage. However, the administration of EX-527 for 10 weeks significantly reduced the blood glucose concentration and kidney weight (~59%). Furthermore, EX-527 significantly reduced the serum concentration of transforming growth factor-ß1 (49%), interleukin (IL)-1ß (52%), and IL-6 in the HFD-fed rats. Overall, the antioxidant activities significantly increased, and oxidative damage to lipids or DNA was suppressed. Particularly, EX-527 significantly reduced blood urea nitrogen (81%), serum creatinine (71%), microalbumin (43%), and urinary excretion of protein-based biomarkers. Histopathological examination revealed expansion of the extracellular mesangial matrix and suppression of glomerulosclerosis following EX-527 administration. EX-527 downregulated the expression of α-SMA (~64%), TGF-ß (25%), vimentin, α-tubulin, fibronectin, and collagen-1 in the kidneys of the HFD-fed rats. Additionally, EX-527 substantially reduced claudin-1 and SIRT1 expression, but increased the expression of SIRT3 in the kidneys of the HFD-fed rats. EX-527 also inhibited the growth factor receptors, including EGFR, PDGFR-ß, and STAT3, which are responsible for the anti-fibrotic effect of SIRT-1. Therefore, the administration of EX-527 protects against HFD-induced DN.


Assuntos
Carbazóis/farmacologia , Nefropatias Diabéticas/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Animais , Biomarcadores/sangue , Glicemia , Citocinas/genética , Citocinas/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/etiologia , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos , Ratos Zucker
10.
Am J Physiol Endocrinol Metab ; 318(3): E343-E356, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891537

RESUMO

Diabetic nephropathy (DN) is one of the most important renal complications associated with diabetes, and the mechanisms are yet to be fully understood. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin-D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The aim of the present study was to explore the potential mechanism by which 1,25(OH)2D3 reduced oxidative stress in diabetic rat kidneys. In this study, we established a vitamin D-deficient spontaneous diabetes model: 5-6 wk of age Zucker diabetic fatty (ZDF) rats were treated with or without 1,25(OH)2D3 for 7 wk, age-matched Zucker lean rats served as control. Results showed that ZDF rats treated with 1,25(OH)2D3 had decreased body mass, food intake, water intake, and urine volume. 1,25(OH)2D3 ameliorated urine glucose, blood glucose and abnormal glucose tolerance. Additionally, 1,25(OH)2D3 significantly lowered microalbuminuria, decreased the glomerular basement membrane thickness, and in some degree inhibited glomerular hypertrophy, mesangial expansion, and tubular dilatation. Furthermore, 1,25(OH)2D3 attenuated renal oxidative damage, as reflected by the levels of malondialdehyde, reduced glutathione, 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and reactive oxygen species production, and notably inhibited poly(ADP-ribose) polymerase-1 (PARP1), activated sirtuin 1 (SIRT1), and decreased the expression of NADPH oxidase 4 (NOX4). Of interest, the abovementioned proteins could be involved in the antioxidant mechanism of 1,25(OH)2D3 in diabetic rat kidneys. Our study showed that oxidative stress might be a major contributor to DN pathogenesis and uncovered the antioxidant role of 1,25(OH)2D3 in diabetic nephropathy that was associated with the PARP1/SIRT1/ NOX4 pathway.


Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Teste de Tolerância a Glucose , Masculino , Ratos , Ratos Zucker , Urodinâmica/efeitos dos fármacos
11.
Org Biomol Chem ; 18(5): 931-940, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31922157

RESUMO

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Compostos de Espiro/farmacologia , Tiazóis/farmacologia , Animais , Glicemia/metabolismo , Ciclização , Teoria da Densidade Funcional , Glicogênio/metabolismo , Glicogênio Fosforilase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Concentração Inibidora 50 , Cinética , Lactonas/síntese química , Lactonas/química , Oxirredução , Ratos Zucker , Compostos de Espiro/síntese química , Compostos de Espiro/química , Estereoisomerismo , Temperatura , Tiazóis/síntese química , Tiazóis/química
12.
FASEB J ; 34(2): 2312-2325, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908001

RESUMO

The epidemiological evidence regarding the association of obesity with liver disease and possibly hepatocellular carcinoma highlights the need for investigations of whether obesity itself could induce the differential expression of genes commonly associated with the initial phase of liver tumorigenesis, and whether such phenomenon could be reversed after a weight loss intervention. In this study, obese Zucker rats were found to have dysregulated cell proliferation, antioxidative defenses, and tumor suppressor gene expression in association with liver dysfunction parameters, as well as oxidative stress and inflammation. Importantly, after a 4-week weight loss protocol of energy restriction and/or exercise, this effect on the liver carcinogenesis-related genes was reversed concomitantly with reductions in the fat mass, hepatic lipid content, oxidative stress, and inflammation. The findings indicate that the oxidative stress and inflammation associated with excess adiposity promote dysregulation of the genes involved in liver tumorigenesis. This is clinically relevant because these effects were detectable in the liver without evidence of a tumoral mass and were reversed after weight loss. Consequently, this study reveals the susceptibility of obese individuals to the initiation of a hepatocarcinogenic process, and how this can be prevented by achieving a healthy body weight.


Assuntos
Restrição Calórica , Regulação da Expressão Gênica , Inflamação/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Perda de Peso , Animais , Inflamação/patologia , Fígado/patologia , Masculino , Obesidade/patologia , Ratos , Ratos Zucker
13.
J Pharmacol Exp Ther ; 373(1): 92-102, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31992608

RESUMO

Pharmacological treatment with dual amylin and calcitonin receptor agonists (DACRAs) cause significant weight loss and improvement of glucose homeostasis. In this study, the maximally efficacious dose of the novel DACRA, KeyBiosciencePeptide (KBP)-066, was investigated. Two different rat models were used: high-fat diet (HFD)-fed male Sprague-Dawley rats and male Zucker diabetic fatty (ZDF, fa/fa) rats to determine the maximum weight loss and glucose homeostatic effect, respectively. One acute study and one chronic study was performed in HFD rats. Two chronic studies were performed in ZDF rats: a preventive and an interventive. All studies covered a dose range of 5, 50, and 500 µg/kg KBP-066 delivered by subcutaneous injection. Treatment with KBP-066 resulted in a significant weight reduction of 13%-16% and improved glucose tolerance in HFD rats, which was independent of dose concentration. Dosing with 50 and 500 µg/kg led to a transient but significant increase in blood glucose, both in the acute and the chronic study in HFD rats. All doses of KBP-066 significantly improved glucose homeostasis in ZDF rats, both in the preventive and interventive study. Moreover, dosing with 50 and 500 µg/kg preserved insulin secretion to a greater extent than 5 µg/kg when compared with ZDF vehicle rats. Taken together, these results show that maximum weight loss is achieved with 5 µg/kg, which is within the range of previously reported DACRA dosing, whereas increasing dosing concentration to 50 and 500 µg/kg may further improve preservation of insulin secretion compared with 5 µg/kg in diabetic ZDF rats. SIGNIFICANCE STATEMENT: Here we show that KeyBiosciencePeptide (KBP)-066 induces an equally potent body weight loss across a broad dose range in obese rats. However, higher dosing of KBP-066 may improve insulin action in diabetic rats both as preventive and interventive treatment.


Assuntos
Agonistas dos Receptores da Amilina/farmacologia , Resistência à Insulina/fisiologia , Receptores da Calcitonina/agonistas , Receptores da Calcitonina/fisiologia , Perda de Peso/efeitos dos fármacos , Perda de Peso/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Zucker
14.
Am J Physiol Endocrinol Metab ; 318(2): E216-E223, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794262

RESUMO

Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-13C]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-13C]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.


Assuntos
Aminoácidos de Cadeia Ramificada/deficiência , Dieta , Miocárdio/metabolismo , Obesidade/metabolismo , Triglicerídeos/metabolismo , Acetilcoenzima A/metabolismo , Aminoácidos de Cadeia Ramificada/sangue , Animais , Glucose/metabolismo , Masculino , Malonil Coenzima A/metabolismo , Metabolômica , Palmitatos/metabolismo , Proteínas Quinases/metabolismo , Ratos , Ratos Zucker
15.
Curr Med Chem ; 27(2): 240-257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31486745

RESUMO

BACKGROUND: Obesity is a major cardiovascular risk factor which dramatically impairs endothelium- dependent vasodilation and leads to hypertension and vascular damage. The impairment of the vasomotor response to extracellular autacoids, e.g., acetylcholine, mainly depends on the reduced Nitric Oxide (NO) bioavailability, which hampers vasorelaxation in large conduit arteries. In addition, obesity may affect Endothelium-Dependent Hyperpolarization (EDH), which drives vasorelaxation in small resistance arteries and arterioles. Of note, endothelial Ca2+ signals drive NO release and trigger EDH. METHODS: A structured search of bibliographic databases was carried out to retrieve the most influential, recent articles on the impairment of vasorelaxation in animal models of obesity, including obese Zucker rats, and on the remodeling of the endothelial Ca2+ toolkit under conditions that mimic obesity. Furthermore, we searched for articles discussing how dietary manipulation could be exploited to rescue Ca2+-dependent vasodilation. RESULTS: We found evidence that the endothelial Ca2+ could be severely affected by obese vessels. This rearrangement could contribute to endothelial damage and is likely to be involved in the disruption of vasorelaxant mechanisms. However, several Ca2+-permeable channels, including Vanilloid Transient Receptor Potential (TRPV) 1, 3 and 4 could be stimulated by several food components to stimulate vasorelaxation in obese individuals. CONCLUSION: The endothelial Ca2+ toolkit could be targeted to reduce vascular damage and rescue endothelium- dependent vasodilation in obese vessels. This hypothesis remains, however, to be probed on truly obese endothelial cells.


Assuntos
Hipertensão , Obesidade/complicações , Animais , Cálcio , Células Endoteliais , Endotélio Vascular , Hipertensão/etiologia , Ratos , Ratos Zucker , Vasodilatação
16.
Int J Vitam Nutr Res ; 90(1-2): 23-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30843770

RESUMO

Type 2 diabetes mellitus is characterized by the inability to regulate blood glucose levels due to insulin resistance, resulting in hyperglycemia and hyperinsulinemia. Research has shown that consuming soy and fiber may protect against type 2 diabetes mellitus. We performed a study to determine whether supplementing diet with soy extract (0.5% weight of diet) or fiber (as red wheat bran; 11.4% weight of diet) would decrease serum insulin and blood glucose levels in a pre-diabetic/metabolic syndrome animal model. In our study, female obese Zucker rats were fed either a control diet (n = 8) or control diet supplemented with either soy extract (n = 7) or red wheat bran (n = 8) for seven weeks. Compared to rats consuming control diet, rats fed treatment diets had significantly lower (p-value < 0.05) fasting serum insulin (control = 19.34±1.6; soy extract = 11.1±1.54; red wheat bran = 12.4±1.11) and homeostatic model assessment of insulin resistance values (control = 2.16±0.22; soy extract = 1.22±0.21; red wheat bran = 1.54±0.16). Non-fasted blood glucose was also significantly lower (p-value < 0.05) in rats fed treatment diets compared to rats consuming control diet at weeks four (control = 102.63±5.67; soy extract = 80.14±2.13; red wheat bran = 82.63±3.16), six (control = 129.5±10.83; soy extract = 89.14±2.48; red wheat bran = 98.13±3.54), and seven (control = 122.25±8.95; soy extract = 89.14±4.52; red wheat bran = 84.75±4.15). Daily intake of soy extract and red wheat bran may protect against type 2 diabetes mellitus by maintaining normal glucose homeostasis.


Assuntos
Diabetes Mellitus Tipo 2 , Glucose/metabolismo , Insulinas , Animais , Dieta , Fibras na Dieta/administração & dosagem , Feminino , Glucose/química , Obesidade/metabolismo , Extratos Vegetais/química , Ratos , Ratos Zucker
17.
J Cell Physiol ; 235(2): 1601-1614, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31304602

RESUMO

Obesity-associated conditions represent major global health and financial burdens and understanding processes regulating adipogenesis could lead to novel intervention strategies. This study shows that adhesion G-protein coupled receptor 56 (GPR56) gene transcripts are reduced in abdominal visceral white adipose tissue derived from obese Zucker rats versus lean controls. Immunostaining in 3T3-L1 preadipocytes reveals both mitotic cell restricted surface and low level general expression patterns of Gpr56. Gpr56 transcripts are differentially expressed in 3T3-L1 cells during adipogenesis. Transient knockdown (KD) of Gpr56 in 3T3-L1 cells dramatically inhibits differentiation through reducing the accumulation of both neutral cellular lipids (56%) and production of established adipogenesis Pparγ 2 (60-80%), C/ebpα (40-78%) mediator, and Ap2 (56-80%) marker proteins. Furthermore, genome editing of Gpr56 in 3T3-L1 cells created CW2.2.4 and RM4.2.5.5 clones (Gpr56 -/- cells) with compound heterozygous deletion frameshift mutations which abolish adipogenesis. Genome edited cells have sustained levels of the adipogenesis inhibitor ß-catenin, reduced proliferation, reduced adhesion, altered profiles, and or abundance of extracellular matrix component gene transcripts for fibronectin, types I, III, and IV collagens and loss of actin stress fibers. ß-catenin KD alone is insufficient to restore adipogenesis in Gpr56 -/- cells. Together these data show that Gpr56 is required for adipogenesis in 3T3-L1 cells. This report is the first demonstration that Gpr56 participates in regulation of the adipogenesis developmental program. Modulation of the levels of this protein and/or its biological activity may represent a novel target for development of therapeutic agents for the treatment of obesity.


Assuntos
Adipócitos/metabolismo , Adipogenia/fisiologia , Receptores Acoplados a Proteínas-G/metabolismo , Células 3T3-L1 , Animais , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Obesidade/metabolismo , Ratos , Ratos Zucker
18.
Cells ; 8(12)2019 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-31847428

RESUMO

We elucidate the relevance of fibroblast growth factor 15 (FGF15) in liver transplantation (LT) using rats with both steatotic and non-steatotic organs from donors after cardiocirculatory death (DCD). Compared to LT from non-DCDs, the induction of cardiocirculatory death (CD) increases hepatic damage, proliferation, and intestinal and circulatory FGF15. This is associated with high levels of FGF15, bilirubin and bile acids (BAs), and overexpression of the enzyme involved in the alternative BA synthesis pathway, CYP27A1, in non-steatotic livers. Furthermore, CD activates the proliferative pathway, Hippo/YAP, in these types of liver. Blocking FGF15 action in LT from DCDs does not affect CYP27A1 but causes an overexpression of CYP7A, an enzyme from the classic BA synthesis pathway, and this is related to further accumulation of BAs and exacerbated damage. FGF15 inhibition also impairs proliferation without changing Hippo/YAP. In spite of worse damage, steatosis prevents a proliferative response in livers from DCDs. In steatotic grafts, CD does not modify CYP7A1, CYP27A1, BA, or the Hippo/YAP pathway, and FGF15 is not involved in damage or proliferation. Thus, endogenous FGF15 protects against BA accumulation and damage and promotes regeneration independently of the Hippo/YAP pathway, in non-steatotic LT from DCDs. Herein we show a minor role of FGF15 in steatotic LT from DCDs.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Ácidos e Sais Biliares/metabolismo , Proliferação de Células/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/metabolismo , Fígado Gorduroso/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Insuficiência Cardíaca/metabolismo , Fígado/patologia , Transplante de Fígado/métodos , Masculino , Proteínas Serina-Treonina Quinases , Ratos , Ratos Zucker , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Food Funct ; 10(12): 7926-7939, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31773121

RESUMO

Redox balance, autophagy and apoptosis are main processes involved in the development of diabetic nephropathy. Epidemiological and animal studies suggest that cocoa might reduce the risk of diabetic complications. However, the molecular mechanisms responsible for these potential preventive activities and whether cocoa exerts beneficial effects on dysregulated signalling pathways involved in cellular antioxidant defence, autophagy and apoptosis in the diabetic kidney remain largely unknown. Therefore, this work investigated the effect of a cocoa-rich diet on the mentioned processes in the renal cortex of Zucker Diabetic Fatty (ZDF) rats. Male ZDF rats were fed either a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet (10-20 weeks-of-life). ZDF rats fed with cocoa decreased body weight and glucose and insulin levels, and improved renal function. Cocoa intake further prevented the enhanced renal cortical oxidative stress in diabetic rats by regulating the antioxidant defence system and close-related proteins to cytoprotection and cell response; thus, cocoa diminished oxidative markers (reactive oxygen species and carbonyl groups) and NADPH-oxidase-4 levels, and restored key enzymatic antioxidant activities (superoxide dismutase and catalase), nuclear-erythroid-2-related factor-2, and ERK-MAPK levels, as well as sirtuin-1/5'-AMP-activated-protein kinase signalling. Moreover, in ZDF rats cocoa-rich diet contributed to alleviation of the renal cortical injury through autophagy activation (p62 upregulation, and downregulation of beclin-1 and LC3), and inhibition of apoptosis (Bcl-xL stimulation and suppression of Bax and caspases-9 and -3). These findings provide the first in vivo evidence on the molecular mechanisms of cocoa to circumvent renal cortical damage that involve improvement of antioxidant competences, stimulation of autophagy and suppression of apoptosis in ZDF rats.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cacau/química , Diabetes Mellitus/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Glicemia/metabolismo , Catalase/genética , Catalase/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Humanos , Insulina/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Zucker , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
20.
Food Funct ; 10(12): 8218-8229, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31701992

RESUMO

Previously, we reported that feeding soy protein isolate (SPI) reduced liver steatosis in obese rats compared to those fed a casein (CAS)-based diet; however, the mechanism for this protection is unknown. To gain insight into the ability of SPI to ameliorate liver steatosis, we conducted transcriptomic (RNAseq) analysis on liver samples from obese rats fed either the SPI- or CAS-based diets (n = 8 per group) for 8 weeks using an Ilumina HiSeq with 100 base paired end reads for sequencing. Data were analyzed by Ingenuity Pathway Analysis (IPA) software using a P < 0.05 and 1.3-fold differential expression cutoff values between the SPI- and CAS-based groups. To independently validate the RNAseq data, we conducted targeted mRNA expression analysis using quantitative PCR (qPCR) on a subset of differently expressed genes. The results indicate that mRNA expression by qPCR concurred with RNAseq for NPTX2, GPT, INMT, and HAL that were up-regulated in SPI-fed rats (P < 0.05) and PRSS8, AJUBA, CSF2RB, and Cyp2c12 that were down-regulated (P < 0.05) in SPI-fed rats compared to CAS-fed rats. Our findings may shed light on understanding mechanisms enabling SPI diet to reduce liver steatosis in this obese Zucker rat model.


Assuntos
Caseínas/metabolismo , Fígado Gorduroso/dietoterapia , Fígado Gorduroso/genética , Fígado/metabolismo , Obesidade/dietoterapia , Obesidade/genética , Proteínas de Soja/metabolismo , Animais , Subunidade beta Comum dos Receptores de Citocinas/genética , Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Fígado Gorduroso/metabolismo , Expressão Gênica , Humanos , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Obesidade/metabolismo , Reação em Cadeia da Polimerase , Ratos , Ratos Zucker
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