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1.
J Hazard Mater ; 416: 126182, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492953

RESUMO

Exposure to ambient particulate matters (PMs) has been associated with a variety of lung diseases, and high-fat diet (HFD) was reported to exacerbate PM-induced lung dysfunction. However, the underlying mechanisms for the combined effects of HFD and PM on lung functions remain poorly unraveled. By performing a comparative proteomic analysis, the current study investigated the global changes of histone post-translational modifications (PTMs) in rat lung exposed to long-term, real-world PMs. In result, after PM exposure the abundance of four individual histone PTMs (1 down-regulated and 3 up-regulated) and six combinatorial PTMs (1 down-regulated and 5 up-regulated) were significantly altered in HFD-fed rats while only one individual PTM was changed in rats with normal diet (ND) feeding. Histones H3K18ac, H4K8ac and H4K12ac were reported to be associated with DNA damage response, and we found that these PTMs were enhanced by PM in HFD-fed rats. Together with the elevated DNA damage levels in rat lungs following PM and HFD co-exposure, we demonstrate that PM exposure combined with HFD could induce lung injury through altering more histone modifications accompanied by DNA damage. Overall, these findings will augment our knowledge of the epigenetic mechanisms for pulmonary toxicity caused by ambient PM and HFD exposure.


Assuntos
Dieta Hiperlipídica , Lesão Pulmonar , Animais , Dieta Hiperlipídica/efeitos adversos , Código das Histonas , Pulmão , Material Particulado/toxicidade , Processamento de Proteína Pós-Traducional , Proteômica , Ratos
2.
J Nutr Sci Vitaminol (Tokyo) ; 67(4): 217-224, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34470996

RESUMO

It is well known that dietary fiber stimulates the release of satiety hormones such as glucagon-like peptide-1 (GLP-1), which in turn suppresses appetite. In order to evaluate appetite regulating role of enzymatically synthesized glycogen (ESG, one of the resistant starch), we examined the effects of dietary supplementation of ESG on food intake and cecal proglucagon gene expression in normal and high fat diet-fed mice. Twenty four male ICR mice were weighed and assigned to four groups: normal diet group; normal diet containing 25% ESG group; high-fat diet (HFD) group; HFD containing 25% ESG group. Each group was fed the relevant diets for 3 wk. All data were analyzed by a two-way ANOVA with the main effects of HFD and ESG. ESG significantly decreased food intake and increased the weight of the cecum and cecal content. Plasma total short chain fatty acids concentration was significantly elevated by ESG. The mRNA levels of proglucagon in the cecum and plasma total GLP-1 concentration were significantly increased by ESG. The mRNA levels of appetite regulating neuropeptides such as neuropeptide Y, agouti-related protein, proopiomelanocortin, and cocain- and amphetamine-regulating transcript in the hypothalamus were not influenced by ESG. There is no significant interaction between diet and ESG in any parameters. These results suggest that ESG-induced upregulation of GLP-1 production in the cecum suppresses food intake in mice and that fecal fermentation may be involved in the anorexigenic effect.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Glicogênio , Animais , Ceco , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos , Masculino , Camundongos , Camundongos Endogâmicos ICR
3.
Nat Commun ; 12(1): 5249, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475397

RESUMO

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.


Assuntos
Glucose/metabolismo , Obesidade/metabolismo , Receptores de Orexina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Homeostase , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Resistência à Insulina , Fígado/metabolismo , Camundongos , Fibras Nervosas/metabolismo , Obesidade/etiologia , Receptores de Orexina/genética , Orexinas/metabolismo , Núcleos da Rafe/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais
4.
J Med Food ; 24(9): 978-986, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34524028

RESUMO

Epigenetic regulation by histone acetyltransferase (HAT) is associated with various biological processes and the progression of diseases, including nonalcoholic fatty liver disease (NAFLD). The objective of this study was to investigate whether the hypolipidemic properties of black mulberry (Morus atropurpurea Roxb.) fruit extract (BME) contribute toward protection against NAFLD by HAT inhibition. HepG2 cells were treated with oleic and palmitic acids to induce lipid accumulation, which was significantly attenuated by the treatment with BME at 50 and 100 µg/mL. BME also markedly reduced the expression of proteins associated with lipogenesis, which was attributed to the BME-mediated downregulation of lipogenic genes in HepG2 cells. BME significantly inhibited in vitro total HAT and p300 activities. In addition, BME suppressed total acetylated lysine as well as specific histone acetylation of proteins H3K14 and H3K27 in HepG2 cells. Mice were then fed with either a chow diet or western diet (WD), with or without BME (1%, w/w) supplementation, for 12 weeks to confirm hypolipidemic activity of BME. BME attenuated serum nonesterified fatty acids and low-density lipoprotein (LDL) cholesterol levels, which was likely associated with the downregulation of hepatic lipogenic gene expression in WD-fed obese mice. Taken together, the hypolipidemic activity of BME was observed in HepG2 cells treated with fatty acids as well as in livers of obese mice, and the hepatoprotection of BME is likely associated with the inhibition of acetylation. Further investigation is warranted to determine whether BME can be developed into an efficacious dietary intervention to attenuate the progression of NAFLD by epigenetic regulation in clinical settings.


Assuntos
Morus , Hepatopatia Gordurosa não Alcoólica , Acetilação , Animais , Dieta Hiperlipídica/efeitos adversos , Epigênese Genética , Frutas/metabolismo , Células Hep G2 , Histonas/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia
5.
Food Res Int ; 147: 110550, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399527

RESUMO

Type 2 diabetes mellitus (T2DM) is considered a rapidly growing chronic disease that threatens human health worldwide. Extracts of various seaweeds have been shown to have anti-diabetic activity. Sargarsum fusiforme, an edible brown seaweed, has been shown to possess anti-inflammatory, anti-diabetic and anti-obesity activities. In this study, we investigated the beneficial effect of an ethanol extract of S. fusiforme (EE) on type 2 diabetes in mice induced with high-fat diet (HFD) and streptozotocin (STZ). Administering EE to the diabetic mice significantly reduced food intake, water intake and fasting blood glucose (FBG), while improving glucose tolerance, lipid profile and ameliorating hepatic oxidative stress. Furthermore, these animals also exhibited significantly diminished epididymal fat deposition, as well as less pathological changes in the heart and liver tissues, while displaying some highly enriched benign gut bacteria (e.g., Intestinimonas, Oscillibacter, Lachnoclostridium, unidentified_Lachnospiraceae, Roseburia and Anaerotruncus) and a lower abundance of bacteria associated with diabetes or other metabolic diseases (e.g., Enterorhabdus and Romboutsia). Metabolomic analysis revealed reduced levels of branched-chain amino acids (BCAA), such as l-valine and l-isoleucine, aromatic amino acids (AAA), such as l-tyrosine and l-phenylalanine, and increased levels of 4-hydroxyphenylacetic acid (4-HPA) in the gut content, suggesting that EE may impact T2DM through modulation of these compounds in the gut of the animals. Taken together, the results implied that S. fusiforme may contain valuable active components other than polysaccharides that have potential benefit in alleviating T2DM.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hiperglicemia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Etanol , Hiperglicemia/tratamento farmacológico , Camundongos , Extratos Vegetais/farmacologia , Estreptozocina
6.
J Med Food ; 24(8): 841-851, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34342510

RESUMO

Obesity is a relevant health hazard characterized as a chronic noncommunicable disease, with severe comorbidities that cause mortality worldwide. Acrocomia aculeata is a Brazilian palm with edible fruits. Its pulp contains fibers, monounsaturated fatty acids (MUFAs), such as oleic acid and carotenoids. In this context, our study aimed to elucidate the protective effect of the lyophilized A. aculeata pulp added at the rates of 1%, 2%, and 4% to a high-fat (HF) diet (rich in saturated fats and cholesterol), for 90 days, in mice. The treatment with 4% pulp induced a significant increase in the biochemical parameters of serum cholesterol HDL-C (high-density lipoprotein) compared with the control. According to the evaluation of the epididymal tissue, the groups treated with A. aculeata pulp exhibited smaller fat deposits compared with the HF diet group. Therefore, we infer that the predominant components in A. aculeata, particularly fibers and MUFAs, promote beneficial effects on health parameters during simultaneous exposure to food rich in saturated fat and cholesterol, typical of the Western diet. This is the first study to correlate the presence of fatty acids from A. aculeata pulp in different proportions added in a HF diet with metabolic and histological parameters in Swiss mice.


Assuntos
Dieta Hiperlipídica , Gorduras na Dieta , Adipócitos , Animais , Colesterol , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Monoinsaturados , Hipertrofia , Lipoproteínas HDL , Camundongos
7.
Nat Commun ; 12(1): 4725, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354051

RESUMO

Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Antibacterianos/administração & dosagem , Ceco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Termogênese/fisiologia , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
8.
J Med Food ; 24(8): 873-882, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34406876

RESUMO

Ancient traditions showed that fermented enzyme foods have beneficial health effects on the body. However, only a few studies have reported on its impact on weight loss and metabolic syndrome. Therefore, it is necessary to verify whether diet supplementation with fermented enzyme foods can have a beneficial functional impact on the body. We examined the antiobesity properties of fermented mixed grain (FMG) with digestive enzymes (FMG) in diet-induced obese mice. Sixty C57BL/6J mice were randomly assigned to six dietary groups: (1) normal diet (ND), (2) high-fat diet (HFD), (3) Bacilus Coagulans, (4) steamed grain, (5) low-dose FMG (L-FMG), and (6) high-dose FMG (H-FMG) supplement for 12 weeks. The results showed that H-FMG supplement dramatically decreased body weight and fat mass with simultaneous decreases in plasma lipid contents. Furthermore, H-FMG significantly lowered fasting blood glucose concentrations and improved glucose tolerance compared with the HFD group. Also, the concentrations of inflammatory cytokines secreted from adipocytes in H-FMG-supplemented mice decreased dramatically. Taken together, our findings indicated that H-FMG can ameliorate HFD-induced obesity and its associated complications and could be used as a potential preventive intervention for obesity.


Assuntos
Dieta Hiperlipídica , Doenças Metabólicas , Adiposidade , Animais , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade
9.
Nat Commun ; 12(1): 4829, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376643

RESUMO

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Dioxóis/farmacologia , Glucose/metabolismo , Ácido Hialurônico/metabolismo , Lipólise/efeitos dos fármacos , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Intolerância à Glucose/metabolismo , Homeostase , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo
10.
Braz J Med Biol Res ; 54(10): e11391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34406209

RESUMO

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatosteatosis and steatohepatitis, is intrinsically related to obesity. Our previous study reported on the anti-obese activity of α,ß-amyrin (AMY), a pentacyclic triterpene isolated from Protium heptaphyllum. This study investigated its ability to prevent fatty liver and the underlying mechanism using the mouse model of NAFLD. NAFLD was induced in male Swiss mice fed a high fat diet (HFD) for 15 weeks. The controls were fed a normal chow diet (ND). The mice were simultaneously treated with AMY at 10 and 20 mg/kg or fenofibrate at 50 mg/kg. Lipid levels along with metabolic and inflammatory parameters were assessed in liver and serum. The liver sections were histologically examined using H&E staining. RT-qPCR and western blotting assays were performed to analyze signaling mechanisms. Mice fed HFD developed severe hepatic steatosis with elevated triglycerides and lipid droplets compared with ND controls. This was associated with a decrease in AMP-activated protein kinase (AMPK) activity, an increase of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and enhanced sterol regulatory element binding protein 1 (SREBP1) expression, which have roles in lipogenesis, inhibition of lipolysis, and inflammatory response. AMY treatment reversed these signaling activities and decreased the severity of hepatic steatosis and inflammatory response, evidenced by serum and liver parameters as well as histological findings. AMY-induced reduction in hepatic steatosis seemed to involve AMPK-mTORC1-SREBP1 signaling pathways, which supported its beneficial role in the prevention and treatment of NAFLD.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases Ativadas por AMP , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ácido Oleanólico/análogos & derivados , Proteína de Ligação a Elemento Regulador de Esterol 1
11.
Nutrients ; 13(8)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34444955

RESUMO

Diet and dietary components have profound effects on the composition of the gut microbiota and are among the most important contributors to the alteration in bacterial flora. This review examines the effects the "Western", "plant-based", "high-fat", "medical ketogenic", and "Mediterranean" diets have on the composition of the gut microbiota in both mice and human subjects. We show that specific dietary components that are commonly found in the "plant-based" and "Mediterranean" diet play a role in shifting the microbial composition. This review further evaluates the bacterial metabolites that are associated with diet, and their role in systemic inflammation and metabolic endotoxemia. Furthermore, the associations between diet/dietary components and altering bacterial composition, may lead to potential therapeutic targets for type II diabetes, obesity, and inflammatory diseases.


Assuntos
Dieta/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Fenômenos Fisiológicos da Nutrição , Animais , Dieta/métodos , Dieta Hiperlipídica/efeitos adversos , Dieta Cetogênica/efeitos adversos , Dieta Mediterrânea/efeitos adversos , Dieta Vegetariana/efeitos adversos , Dieta Ocidental/efeitos adversos , Endotoxemia/etiologia , Endotoxemia/microbiologia , Humanos , Inflamação/etiologia , Inflamação/microbiologia , Camundongos
12.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445045

RESUMO

In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring's brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype.


Assuntos
Depressão/genética , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Receptor CB1 de Canabinoide/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Epigênese Genética , Feminino , Expressão Gênica , Lactação/genética , Masculino , Gravidez , Ratos
13.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445047

RESUMO

Sargassum fusiforme alginate (SF-Alg) possess many pharmacological activities, including hypoglycemic and hypolipidemic. However, the hypoglycemic mechanisms of SF-Alg remain unclear due to its low bioavailability. In this study, we evaluated the therapeutic effect of SF-Alg on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. SF-Alg intervention was found to significantly reduce fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC), while increasing high-density lipoprotein cholesterol (HDL-c) and improving glucose tolerance. In addition, administrating SF-Alg to diabetic mice moderately attenuated pathological changes in adipose, hepatic, and heart tissues as well as skeletal muscle, and diminished oxidative stress. To probe the underlying mechanisms, we further analyzed the gut microbiota using 16S rRNA amplicon sequencing, as well as metabolites by non-targeted metabolomics. Here, SF-Alg significantly increased some benign bacteria (Lactobacillus, Bacteroides, Akkermansia Alloprevotella, Weissella and Enterorhabdus), and significantly decreased harmful bacteria (Turicibacter and Helicobacter). Meanwhile, SF-Alg dramatically decreased branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in the colon of T2D mice, suggesting a positive benefit of SF-Alg as an adjvant agent for T2D.


Assuntos
Alginatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Sargassum/química , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Camundongos , Estreptozocina , Triglicerídeos/sangue
14.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445634

RESUMO

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called "hunger" hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.


Assuntos
Corpo Estriado/patologia , Dieta Hiperlipídica/efeitos adversos , Grelina/metabolismo , Neurônios/patologia , Obesidade/patologia , Receptor CB2 de Canabinoide/metabolismo , Receptores de Grelina/metabolismo , Animais , Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Grelina/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB2 de Canabinoide/genética , Receptores de Grelina/genética , Transdução de Sinais , Regulação para Cima
15.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360761

RESUMO

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK-/- mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and ßMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.


Assuntos
Cardiomegalia/enzimologia , Diabetes Mellitus Experimental/enzimologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miocárdio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Volume Sistólico , Remodelação Ventricular
16.
Nutrients ; 13(7)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34371851

RESUMO

Diet-induced obesity reduces dopaminergic neurotransmission in the nucleus accumbens (NAc), and stressful weight loss interventions could promote cravings for palatable foods high in fat and sugar that stimulate dopamine. Activation of κ-opioid receptors (KORs) reduces synaptic dopamine, but contribution of KORs to lower dopamine tone after dietary changes is unknown. Therefore, the purpose of this study was to determine the function of KORs in C57BL/6 mice that consumed a 60% high-fat diet (HFD) for six weeks followed by replacement of HFD with a control 10% fat diet for one day or one week. HFD replacement induced voluntary caloric restriction and weight loss. However, fast-scan cyclic voltammetry revealed no differences in baseline dopamine parameters, whereas sex effects were revealed during KOR stimulation. NAc core dopamine release was reduced by KOR agonism after one day of HFD replacement in females but after one week of HFD replacement in males. Further, elevated plus-maze testing revealed no diet effects during HFD replacement on overt anxiety. These results suggest that KORs reduce NAc dopamine tone and increase food-related anxiety during dietary weight loss interventions that could subsequently promote palatable food cravings and inhibit weight loss.


Assuntos
Dieta com Restrição de Gorduras/métodos , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Obesidade/metabolismo , Receptores Opioides kappa/efeitos dos fármacos , Animais , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Transmissão Sináptica/efeitos dos fármacos
17.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360816

RESUMO

Hypothalamic dysfunction is an initial event following diet-induced obesity, primarily involving areas regulating energy balance such as arcuate nucleus (Arc) and median eminence (ME). To gain insights into the early hypothalamic diet-induced alterations, adult CD1 mice fed a high-fat diet (HFD) for 6 weeks were studied and compared with normo-fed controls. Transmission and scanning electron microscopy and histological staining were employed for morphological studies of the ME, while Raman spectroscopy was applied for the biochemical analysis of the Arc-ME complex. In HFD mice, ME ß2-tanycytes, glial cells dedicated to blood-liquor crosstalk, exhibited remarkable ultrastructural anomalies, including altered alignment, reduced junctions, degenerating organelles, and higher content of lipid droplets, lysosomes, and autophagosomes. Degenerating tanycytes also displayed an electron transparent cytoplasm filled with numerous vesicles, and they were surrounded by dilated extracellular spaces extending up to the subependymal layer. Consistently, Raman spectroscopy analysis of the Arc-ME complex revealed higher glycogen, collagen, and lipid bands in HFD mice compared with controls, and there was also a higher band corresponding to the cyanide group in the former compared to the last. Collectively, these data show that ME ß2-tanycytes exhibit early structural and chemical alterations due to HFD and reveal for the first-time hypothalamic cyanide presence following high dietary lipids consumption, which is a novel aspect with potential implications in the field of obesity.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Eminência Mediana/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/patologia , Metabolismo Energético , Masculino , Eminência Mediana/patologia , Camundongos , Obesidade/patologia
18.
Alzheimers Res Ther ; 13(1): 144, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454596

RESUMO

BACKGROUND: Epidemiological studies link vascular disease risk factors such as atherosclerosis, hypertension, and diabetes mellitus with Alzheimer's disease (AD). Whether there are direct links between these conditions to ß-amyloid (Aß) aggregation and tau pathology is uncertain. METHODS: To investigate the possible link between atherosclerosis and AD pathology, we subjected triple transgenic (3 × Tg) AD mice to a high-fat diet (HFD) at 3 months of age, which corresponds to early adulthood in humans. RESULTS: After 9 months of treatment, HFD-treated 3 × Tg mice exhibited worse memory deficits accompanied by blood hypercoagulation, thrombocytosis, and chronic platelet activation. Procoagulant platelets from HFD-treated 3 × Tg mice actively induced the conversion of soluble Aß40 into fibrillar Aß aggregates, associated with increased expression of integrin αIIbß3 and clusterin. At 9 months and older, platelet-associated fibrillar Aß aggregates were observed to obstruct the cerebral blood vessels in HFD-treated 3 × Tg mice. HFD-treated 3 × Tg mice exhibited a greater cerebral amyloid angiopathy (CAA) burden and increased cerebral vascular permeability, as well as more extensive neuroinflammation, tau hyperphosphorylation, and neuron loss. Disaggregation of preexisting platelet micro-clots with humanized GPIIIa49-66 scFv Ab (A11) significantly reduced platelet-associated fibrillar Aß aggregates in vitro and improved vascular permeability in vivo. CONCLUSIONS: These findings suggest that a major contribution of atherosclerosis to AD pathology is via its effects on blood coagulation and the formation of platelet-mediated Aß aggregates that compromise cerebral blood flow and therefore neuronal function. This leads to cognitive decline.


Assuntos
Doença de Alzheimer , Aterosclerose , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Aterosclerose/genética , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Ativação Plaquetária
19.
Life Sci ; 283: 119852, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34332979

RESUMO

Nonalcoholic fatty liver disease (NAFLD) occurs due to lipid metabolic disorders, which is associated with hepatic oxidative stress and inflammation. There is no definitive drug treatment for this disease. Accordingly, the present study aimed to evaluate the effects of dimethyl fumarate (DMF) as one of the superior effective drugs that induces a transcription factor of nuclear factor erythroid 2-related factor 2 (Nrf2) on development of NAFLD in mice. The metabolic disturbance in High-fat diet (HFD)-treated animals was associated with hyperlipidemia, increased activity levels of hepatic enzymes in serum, hyperglycemia, hyperinsulinemia, oxidative stress and inflammation. DMF supplementation had anti-inflammatory, antioxidant, anti-lipogenic and molecular compatibility effects induced by HFD in mice. In comparison to the HFD group, the DMF therapy could significantly suppress the sterol regulatory element binding protein-1 c (SREBP-1c) gene and protein levels, as well as upregulate the Nrf2 gene and protein levels. Additionally, the anti-inflammatory activity was observed for the DMF by inhibiting the nuclear factor kappa B (NF-κB) level. DMF reduces the development of NAFLD induced by HFD in mice through the modulation of transcription factors Nrf2, SREBP-1c and NF-κB. Thus, DMF can be considered as an effective candidate in the treatment of human NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
20.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445384

RESUMO

Diabetes is a predictor of nonalcoholic fatty liver disease (NAFLD). There are data suggesting that Tribulus terrestris (TT) saponins act as antidiabetic agents and protect against NAFLD. The effect of saponins may be increased by fermentable fibers such as inulin. The aim of the present study was to investigate the influence of TT saponins and TT saponins plus inulin on the plasma lipid profile and liver fatty acids of rats with induced diabetes mellitus type 2 (T2DM). The study was performed on 36 male Sprague-Dawley rats divided into two main groups: control and diabetic. Animals of the diabetic (DM) group were fed a high-fat diet and injected with streptozotocin (low doses). Animals of the control group (nDM) were on a regular diet and were injected with buffer. After the injections, the animals were split into subgroups: three non-diabetic (nDM): (i) control (c-C); (ii) saponin-treated rats (C-Sap); (iii) rats treated with saponins + inulin (C-Sap + IN), and three diabetic subgroups (DM): (iv) control (c-DM); (v) saponin-treated rats (DM-Sap); (vi) rats treated with saponins + inulin (DM-Sap + IN). Liver fatty acids were extracted and analyzed by gas chromatography, and plasma glucose and lipids were measured. The study showed significant changes in liver morphology, liver fatty acids, plasma lipid profile, and plasma glucose. In summary, supplementation with TT saponins or saponins with inulin for one month decreased the level of steatosis in rats with induced type 2 diabetes. Moreover, there were favorable effects on the plasma lipid profile in the rats. However, additional supplementation with inulin had a negative effect on liver morphology (with a microvesicular type of steatosis) in the non-diabetes group. Moreover, supplementation with inulin had a negative effect on plasma glucose in both diabetic and non-diabetic rats. These data show that a diet enriched with fermentable fibers reveals different effects in different organisms, and not all sources and forms of fiber are beneficial to health.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fígado Gorduroso/prevenção & controle , Inulina/administração & dosagem , Saponinas/administração & dosagem , Tribulus/química , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/análise , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Inulina/farmacologia , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Saponinas/farmacologia , Estreptozocina , Resultado do Tratamento
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