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1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(8): 892-900, 2020 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33053529

RESUMO

OBJECTIVES: To investigate the effects of environmental enrichment on cognitive behavior and the expression of adenosine triphosphate binding cassette transporter A7 (ABCA7) in hippocampus of the adolescent mice with high fat diet. METHODS: A total of healthy 3-week-old male C57BL/6J mice were randomly divided into 3 groups: a control (Con) group, a high fat diet (HFD) group, and a high fat diet+environmental enrichment (HFD+EE) group, with 10 mice in each group. The Con group was given normal diet. The HFD group was given high fat diet. The HFD+EE group was given high fat diet; at the same time, they treated by environmental enrichment. After 10 weeks, open field test was used to detect activity. Novel object recognition test and Y maze test were used to detect cognitive behavior. After the test, the brain was collected and used to detect the protein expression of ABCA7 in the hippocampus by immunohistochemistry and Western blotting. And quantitative RT-PCR (RT-qPCR) was used to detect the ABCA7 mRNA expression level in the hippocampus. RESULTS: There was no significant difference in the total movement distance in the mice among the 3 groups (P>0.05). In the novel object recognition test, the discrimination index of the HFD group was much lower than that of the Con group, and the difference was significant (P<0.01). The discrimination index of the HFD+EE group was higher than that of the HFD group, and the difference was significant (P<0.01). In the Y maze test, there was no significant difference in the percentage of time spent on the new arm among the mice in the 3 groups (P=0.1279). The percentage of entries in new arm in the HFD group was much lower than that in the Con group, and the difference was significant (P<0.01). The percentage of the entries in new arm in the HFD+EE group was significantly higher than that in the HFD group (P<0.05). The results of immunohistochemistry showed that ABCA7 was positively expressed in the cytoplasm of hippocampal neurons in the mice from these 3 groups, and the expression of ABCA7 in the hippocampus of the HFD group was lower than that of the Con group (CA1: P<0.01, CA3: P=0.06), while the expression of ABCA7 in hippocampus of HFD+EE group was higher than that of HFD group (CA1: P=0.23, CA3: P<0.05). Western blotting results showed that compared with the Con group, the protein level of ABCA7 in the hippocampus of the HFD group was significantly reduced (P<0.05), while compared with the Con group, the protein level of ABCA7 in the hippocampus of the HFD+EE group showed an upward trend (P=0.06). The results of RT-qPCR showed that the mRNA level of ABCA7 in the hippocampus of HFD group was significantly lower than that of the Con group (P<0.01), while the mRNA level of ABCA7 in the hippocampus of HFD+EE group was significantly higher than that of the HFD group (P<0.01). CONCLUSIONS: High fat diet in adolescent can impair cognitive function with a decrease in the expression of ABCA7 in hippocampus, which can be ameliorate by environmental enrichment.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Trifosfato de Adenosina , Dieta Hiperlipídica , Hipocampo , Animais , Cognição , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020469

RESUMO

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/metabolismo
3.
Wei Sheng Yan Jiu ; 49(5): 785-822, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070825

RESUMO

OBJECTIVE: Establish the prokaryotic expression system of Amuc_1100 protein from Akkermansia muciniphila, and analyze the effects of this protein on the body weight, blood glucose, intestinal barrier function and Akkermansia muciniphila abundance in rats fed with high-fat diet combined streptozotocin(STZ)injection. METHODS: PCR product of Amuc_1100 Gene(Gene ID: 34174504) was linked to the double enzyme-digested pET-26 b plasmid vector. The recombinant expression plasmid pET-26 b-Amuc_1100 then transformed into E. Coli BL21. The verified clones through sequence analysis were induced by the addition of IPTG. High-fat diet rats were interfered with the purified protein at high and low doses. The changes of body weight, blood glucose, intestinal barrier function and Akkermansia muciniphila abundance were analyzed. RESULTS: The recombinant expression plasmid pET-26 b-Amuc_1100 was successfully constructed. The sequencing result showed 100% similarity to the Amuc_1100 gene in GenBank. The molecular weight of the protein obtained was 42 kDa. The intervention of Amuc_1100 protein can reduce the weight of rats fed with high-fat diet combined STZ injection to some extent, improve barrier function and increase the abundance of Akkermansia muciniphila in intestine. CONCLUSION: The prokaryotic expression system of Amuc_1100 protein was successfully constructed, which has a certain regulatory effect on rats fed with high-fat diet combined STZ injection.


Assuntos
Dieta Hiperlipídica , Escherichia coli , Animais , Dieta Hiperlipídica/efeitos adversos , Escherichia coli/genética , Ratos , Estreptozocina/toxicidade , Verrucomicrobia
4.
Nat Commun ; 11(1): 4737, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968070

RESUMO

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Inflamassomos/efeitos dos fármacos , Resistência à Insulina , Inibidores da Transcriptase Reversa/farmacologia , Adipócitos/metabolismo , Animais , Sobrevivência Celular , RNA Helicases DEAD-box/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , HIV-1/efeitos dos fármacos , Hepatite B , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Musculares/metabolismo , Ribonuclease III/metabolismo
5.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907360

RESUMO

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Metformina/administração & dosagem , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo
6.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
7.
Nat Commun ; 11(1): 4765, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958780

RESUMO

Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.


Assuntos
Antígenos CD36/metabolismo , Endocitose/fisiologia , Ácidos Graxos/metabolismo , Lipoilação , Células 3T3-L1 , Aciltransferases/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/deficiência , Antígenos CD36/genética , Cavéolas/metabolismo , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Humanos , Gotículas Lipídicas/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Obesidade/tratamento farmacológico , Fosforilação , Transdução de Sinais , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Ganho de Peso/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
8.
PLoS One ; 15(8): e0238223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853260

RESUMO

Being delivered as a low birthweight (LBW) infant is a risk factor for elevated blood pressure and future problems with cardiovascular and cerebellar diseases. Although premature babies are reported to have low numbers of nephrons, some unclear questions remain about the mechanisms underlying elevated blood pressure in full-term LBW infants. We previously reported that glucocorticoids increased miR-449a expression, and increased miR-449a expression suppressed Crhr1 expression and caused negative glucocorticoid feedback. Therefore, we conducted this study to clarify the involvement of pituitary miR-449a in the increase in blood pressure caused by higher glucocorticoids in LBW rats. We generated a fetal low-carbohydrate and calorie-restricted model rat (60% of standard chow), and some individuals showed postnatal growth failure caused by growth hormone receptor expression. Using this model, we examined how a high-fat diet (lard-based 45kcal% fat)-induced mismatch between prenatal and postnatal environments could elevate blood pressure after growth. Although LBW rats fed standard chow had slightly higher blood pressure than control rats, their blood pressure was significantly higher than controls when exposed to a high-fat diet. Observation of glomeruli subjected to periodic acid methenamine silver (PAM) staining showed no difference in number or size. Aortic and cardiac angiotensin II receptor expression was altered with compensatory responses. Blood aldosterone levels were not different between control and LBW rats, but blood corticosterone levels were significantly higher in the latter with high-fat diet exposure. Administration of metyrapone, a steroid synthesis inhibitor, reduced blood pressure to levels comparable to controls. We showed that high-fat diet exposure causes impairment of the pituitary glucocorticoid negative feedback via miR-449a. These results clarify that LBW rats have increased blood pressure due to high glucocorticoid levels when they are exposed to a high-fat diet. These findings suggest a new therapeutic target for hypertension of LBW individuals.


Assuntos
Pressão Sanguínea/fisiologia , Retroalimentação Fisiológica/fisiologia , Glucocorticoides/sangue , Doenças da Hipófise/sangue , Doenças da Hipófise/fisiopatologia , Hipófise/fisiologia , Animais , Peso ao Nascer/efeitos dos fármacos , Peso ao Nascer/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Corticosterona/sangue , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Masculino , Metirapona/uso terapêutico , Doenças da Hipófise/tratamento farmacológico , Hipófise/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar
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.
Ecotoxicol Environ Saf ; 204: 111036, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32784013

RESUMO

Human exposure to methylmercury (MeHg) due to contaminated fish intake as part of a high-fat (HFD), high-carbohydrate diets is a reality today for many populations. HFD is associated with hypertension and hyperlipidemia, primary cardiovascular disease (CVD) risk factors. Some studies suggest that MeHg induces those risk factors. We evaluated the effect of MeHg exposure in mice fed with HFD or control diet for eight weeks. In the last experimental 15 days, the half group received a MeHg solution (20 mg/L) replacing water. Blood pressure (BP), heart rate, lipoprotein concentrations, and paraoxonase activity were evaluated. Liver cholesterol, triacylglycerol, and IBA-1+ cells, as well as transcriptional levels of genes related to lipid metabolism and inflammatory response, were also assessed. HFD and both MeHg groups presented increased BP and total cholesterol (TC). In the liver, HFD but not MeHg was related to an increase in TC. Also, MeHg intoxication reduced paraoxonase activity regardless of diet. MeHg intoxication and HFD increased steatosis and the number of IBA-1+ cells and modified some gene transcripts associated with lipid metabolism. In conclusion, we demonstrated that MeHg effects on CVD risk factors resemble those caused by HFD.


Assuntos
Pressão Arterial/efeitos dos fármacos , Aterosclerose/epidemiologia , Dieta Hiperlipídica/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Compostos de Metilmercúrio/efeitos adversos , Estado Nutricional , Animais , Aterosclerose/induzido quimicamente , Fígado Gorduroso/metabolismo , Feminino , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Lipoproteínas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco
11.
Life Sci ; 258: 118240, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781072

RESUMO

As a dicarboxylic acid with the structural formula HOOCCH (OH) COOH, tartronic acid is considered as an inhibitor of the transformation of carbohydrates into fat under fat-deficient diet conditions. However, the effect of tartronic acid on lipogenesis under high-fat diet conditions has yet to be established. In this work, we investigated the regulatory role of tartronic acid in lipogenesis in 3T3-L1 adipocytes and C57BL/6J mice. The results confirmed that tartronic acid promoted weight gain (without affecting food intake) and induced adipocyte hypertrophy in epididymal white adipose tissue and lipid accumulation in the livers of high-fat diet-induced obese mice. In vitro, tartronic acid promoted 3T3-L1 adipocyte differentiation by increasing the protein expression of FABP-4, PPARγ and SREBP-1. Moreover, the contents of both acetyl-CoA and malonyl-CoA were significantly upregulated by treatment with tartronic acid, while the protein expression of CPT-1ß were inhibited. In summary, we proved that tartronic acid promotes lipogenesis by serving as substrates for fatty acid synthesis and inhibiting CPT-1ß, providing a new perspective for the study of tartronic acid.


Assuntos
Acetilcoenzima A/biossíntese , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Lipogênese/efeitos dos fármacos , Malonil Coenzima A/biossíntese , Tartronatos/farmacologia , Regulação para Cima/efeitos dos fármacos , Células 3T3-L1 , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Lipogênese/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima/fisiologia
12.
PLoS One ; 15(8): e0234750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785220

RESUMO

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the underlying mechanism, we analyzed Bsep heterozygous knock-out (Bsep+/- mice) and wild-type (WT) C57BL/6J mice fed a high-fat diet (HFD) (32.0% animal fat) or normal diet. We examined histological changes, levels of hepatic lipids and hepatic bile acids, and expression of genes related to bile acid and cholesterol metabolism. HFD-fed Bsep+/- mice exhibited milder hepatic steatosis and less weight gain, compared to HFD-fed WT mice. The concentrations of total bile acid, triglycerides, and cholesterols were reduced in the liver of HFD-fed Bsep+/- mice. Regarding hepatic bile acid metabolism, the expression levels of Farnesoid X receptor (Fxr) and Multidrug resistance-associated protein 2 were significantly upregulated in HFD-fed Bsep+/- mice, compared to HFD-fed WT mice. Furthermore, several alterations were observed in upstream cholesterol metabolism in the liver. The expression levels of bile acid metabolism-related genes were also altered in the intestine of HFD-fed Bsep+/- mice. In conclusion, HFD-fed Bsep+/- mice exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in both the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the involvement of BSEP in the pathogenesis of NASH will provide greater insight and facilitate the development of novel therapeutic modalities.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Heterozigoto , Íleo/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/patologia
13.
Chem Biol Interact ; 330: 109199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32805210

RESUMO

Obesity is characterized by the deposition of excessive body fat, and is caused by energy imbalance, especially when consuming fat-rich diets. High fat diet (HFD)-associated obesity is greatly common in patients with non-alcoholic fatty liver disease (NAFLD) that is emerging as one of the most universal causes of liver disease worldwide, especially in Western countries. In spite of its high prevalence, only a small proportion of affected individuals will become inflamed, followed by fibrosis and chronic liver diseases, and most patients only show simple steatosis. In this case, the full comprehension of the mechanisms underlying the progression of NAFLD is of extreme significance; in spite of progress in this field, awareness on the development of NAFLD is still incomplete. Traditionally, liver steatosis is commonly connected with HFD, obesity, and insulin resistance (IR). Recently, various possible mechanisms have been put forward for liver damage, including endoplasmic reticulum stress, perturbation of autophagy, mitochondrial dysfunction, hepatocellular apoptosis, gut microbiota imbalance, dysregulation of microRNAs, and genetic/epigenetic risk factors, as well as an increase in inflammatory responses, among many others. Collectively, these proposed mechanisms allow for a variety of hits acting together on subjects to mediated NAFLD and will offer a more accurate explanation for progression of NAFLD. Therefore, this review summarizes the present information concerning NAFLD after HFD exposure, as well as discusses possible mechanisms through which it may arise.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações
14.
Nat Commun ; 11(1): 4313, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855402

RESUMO

It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.


Assuntos
Adipócitos Bege/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Obesidade/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Termogênese/genética , Animais , Calorimetria Indireta , Linhagem Celular , Temperatura Baixa/efeitos adversos , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético/genética , Regulação da Expressão Gênica/fisiologia , Células HEK293 , Humanos , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Knockout , Obesidade/etiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas/genética , RNA-Seq , Gordura Subcutânea/citologia , Gordura Subcutânea/metabolismo , Proteína Desacopladora 1/metabolismo
15.
PLoS One ; 15(6): e0234861, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603330

RESUMO

OBJECTIVE: To examine whether the cardiac, renal and uterine physiological hemodynamic changes during gestation are altered in rats with an early and prolonged exposure to a high fat diet (HFD). METHODS: Arterial pressure and cardiac, renal, uterine and radial arteries hemodynamic changes during gestation were examined in adult SD rats exposed to normal (13%) (n = 8) or high (60%) (n = 8) fat diets from weaning. Plethysmography, high-resolution high-frequency ultrasonography and clearance of an inulin analog were used to evaluate the arterial pressure and hemodynamic changes before and at days 7, 14 and 19 of gestation. RESULTS: Arterial pressure was higher (P<0.05) in rats with high than in those with normal (NFD) fat diet before pregnancy (123 ±3 and 110 ±3 mmHg, respectively) and only decreased at day 14 of gestation in rats with NFD (98±4 mmHg, P<0.05). A significant increment in stroke volume (42 ±10%) and cardiac output (51 ±12%) was found at day 19 of pregnancy in rats with NFD. The changes in stroke volume and cardiac output were similar in rats with NFD and HFD. When compared to the values obtained before pregnancy, a transitory elevation in renal blood flow was found at day 14 of pregnancy in both groups. However, glomerular filtration rate only increased (P<0.05) in rats with NFD at days 14 (20 ±7%) and 19 (27 ±8%) of gestation. The significant elevations of mean velocity, and velocity time integral throughout gestation in radial (127 ±26% and 111 ±23%, respectively) and uterine (91 ±16% and 111 ±25%, respectively) arteries of rats with NFD were not found in rats with an early and prolonged HFD. SUMMARY: This study reports novel findings showing that the early and prolonged exposure to a HFD leads to a significant impairment in the renal, uterine and radial arteries hemodynamic changes associated to gestation.


Assuntos
Artérias/fisiopatologia , Vasos Coronários/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Artérias/diagnóstico por imagem , Pressão Sanguínea/fisiologia , Vasos Coronários/diagnóstico por imagem , Feminino , Taxa de Filtração Glomerular/fisiologia , Rim/irrigação sanguínea , Modelos Animais , Gravidez , Ratos , Fluxo Sanguíneo Regional/fisiologia , Volume Sistólico/fisiologia , Ultrassonografia , Útero/irrigação sanguínea , Útero/diagnóstico por imagem
16.
Life Sci ; 257: 118028, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32615185

RESUMO

AIMS: Sertoli cells (SCs) play an important role in the process of spermatogenesis. SCs provide energy for germ cells (GCs) and themselves through glycolysis and fatty acid oxidation (FAO) respectively. High fat diet (HFD) impairs spermatogenesis by damaging function of SCs, however whether HFD disrupts energy metabolism in SCs remains unclear. MAIN METHODS: To explore this hypothesis, we built male Wistar rat model fed on HFD and cultured rats' primary SCs with palmitic acid (PA). Rats' fertility and sperm quality were evaluated in vivo. Glycolysis, lactate production and mitochondrial respiration were assessed by using extracellular flux analyzer, and the expression of enzymes involved in glucose and FAO was analyzed by Real-Time PCR or Western Blotting. KEY FINDINGS: The showed that the sperm concentration and pups per litter significantly decreased in rats fed on HFD compared to those rats fed on normal diet. There was an elevation of lactate levels in testicular tissue of rats fed on HFD and primary SCs exposed to PA. In vitro, PA increased glycolytic flux, and lactate production, and the levels of carnitine palmitoyltransferase I (CPT1) and long chain acyl-CoA dehydrogenase (LCAD) which were two key enzymes for fatty acid ß oxidation. Further analysis showed that mitochondrial respiration was impaired by PA, followed by the decrease in ATP turnover, maximal respiration and the increase in proton leak. SIGNIFICANCE: Taken together, the elevated lactate level, lipid metabolism disorder and mitochondrial dysfunction caused by HFD lead to SCs dysfunction, which ultimately leads to decreased sperm quality.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Células de Sertoli/metabolismo , Espermatogênese/fisiologia , Animais , Metabolismo Energético , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise , Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Oxirredução , Ácido Palmítico , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
17.
Am J Chin Med ; 48(5): 1073-1090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668968

RESUMO

Pro-inflammatory cytokines interfere with blood glucose homeostasis, which leads to hyperglycemia. Andrographis paniculata (AP) has been shown to possess anti-inflammatory activity and to reduce blood glucose levels in diabetes. The two major bioactive diterpenoids in AP, andrographolide (AND) and 14-deoxy-11,12-didehydroandrographolide (deAND), have potent anti-inflammatory activity. We studied whether APE (an ethanolic extract of AP), AND, and deAND could improve a high-fat diet (HFD)-induced hyperglycemia in vivo and TNF[Formula: see text]-induced impairment of insulin signaling in vitro. Male C57BL/6JNarl mice were fed a normal diet (ND) or the HFD, and the fatty mice were treated with APE, deAND, or AND for 16 weeks. 3T3-L1 cells were used to study the underlying mechanisms by which APE, deAND, or AND attenuated TNF[Formula: see text]-induced insulin resistance. The HFD significantly induced obesity, hyperglycemia, insulin resistance, and inflammation, whereas APE and deAND significantly ameliorated HFD-induced obesity, hyperglycemia, insulin resistance, and TNF[Formula: see text] production. The HFD significantly impaired insulin signaling by decreasing the protein expression of p-IRS1 tyr632 and p-AKT ser473, as well as the membrane translocation of GLUT4 in response to insulin stimulation in epididymal adipose tissue. HFD-impaired the membrane translocation of GLUT4 was significantly reversed by deAND and APE. In addition, deAND and APE markedly reversed the detrimental effect of TNF[Formula: see text] on the insulin signaling pathway and glucose uptake in 3T3-L1 cells. Despite no significant positive effect on p-AS160, a trend for recovery by deAND and APE was observed. These results suggest that deAND and APE protect against HFD-induced insulin resistance by ameliorating inflammation-driven impairment of insulin sensitivity.


Assuntos
Andrographis/química , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Células 3T3 , Animais , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Fitoterapia , Extratos Vegetais/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
18.
PLoS One ; 15(7): e0236741, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730300

RESUMO

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR's role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahrfl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahrfl/fl mice (control mice). The Pdgfrα-Cre Ahrfl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahrfl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Integrases/metabolismo , Obesidade/prevenção & controle , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/fisiologia , Receptores de Hidrocarboneto Arílico/fisiologia , Adiposidade , Animais , Metabolismo Energético , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia , Termogênese
19.
Nat Commun ; 11(1): 3766, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724076

RESUMO

Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans.


Assuntos
Doenças Cardiovasculares/imunologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inflamação/imunologia , Idoso , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Dieta Aterogênica/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dipeptidil Peptidase 4/imunologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Modelos Animais de Doenças , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Mediadores da Inflamação/análise , Mediadores da Inflamação/metabolismo , Masculino , Metformina/administração & dosagem , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/sangue , Isoformas de Proteínas/metabolismo , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos
20.
Environ Sci Pollut Res Int ; 27(32): 40525-40536, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32666453

RESUMO

Diabetes mellitus (DM) is one of the most dangerous incurable diseases that affects a large number of people worldwide. Artemisia species have various protective activities and are widely used for the control of diabetes in folkloric medicine. Therefore, the current study was designed to illustrate the protective effect of oral administration of Artemisia judaica extract (AjE) against hepatorenal damage in a high-fat diet/streptozotocin (HFD/STZ) rat model of hyperlipidemia and hyperglycemia. Animals were divided into five groups-control, AjE, HFD/STZ, HFD/STZ-AjE (300 mg/kg), and HFD/STZ-MET (100 mg/kg)-and treated daily for 28 days. The results revealed that STZ-injected rats showed marked hyperglycemia and hypoinsulinemia in addition to high levels of cholesterol, triglycerides, and low- and high-density lipoproteins compared to control rats. Significant elevations in hepatic (AST and ALT) and renal (urea, uric acid, and creatinine) function markers were observed in the serum of diabetic rats. Additionally, STZ injection caused remarkable elevations in lipid peroxidation and nitric oxide levels as well as suppression of antioxidant markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione). Marked elevations in TNF-α and Bax levels with a decline in Bcl-2 levels were detected after STZ injection. Furthermore, TGF-ß1 expression levels were significantly upregulated in the liver and kidney tissues. Rats that received AjE or MET showed significant improvement in most of the aforementioned parameters, and the protective efficacy was higher for AjE than for MET. Histopathological screening confirmed the biochemical findings. Conclusively, our results illustrated the antihyperglycemic, antihyperlipidemic, antioxidant, anti-inflammatory, and antiapoptotic activities of AjE against hepatorenal injury in HFD/STZ-induced diabetes.


Assuntos
Artemisia , Diabetes Mellitus Experimental , Metformina , Animais , Antioxidantes , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Fígado , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Estreptozocina
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