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1.
FASEB J ; 38(10): e23656, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38752523

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Obesity is a major risk factor for the development of COVID-19. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2. The receptor-binding domain of the S1 subunit (S1-RBD protein) in the SARS-CoV-2 spike glycoprotein binds to ACE2 on host cells, through which the virus enters several organs, including the lungs. Considering these findings, recombinant ACE2 might be utilized as a decoy protein to attenuate SARS-CoV-2 infection. Here, we examined whether obesity increases ACE2 expression in the lungs and whether recombinant ACE2 administration diminishes the entry of S1-RBD protein into lung cells. We observed that high-fat diet-induced obesity promoted ACE2 expression in the lungs by increasing serum levels of LPS derived from the intestine. S1-RBD protein entered the lungs specifically through ACE2 expressed in host lungs and that the administration of recombinant ACE2 attenuated this entry. We conclude that obesity makes hosts susceptible to recombinant SARS-CoV-2 spike proteins due to elevated ACE2 expression in lungs, and this model of administering S1-RBD protein can be applied to new COVID-19 treatments.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Dieta Hiperlipídica , Pulmão , Obesidade , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Dieta Hiperlipídica/efeitos adversos , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Pulmão/metabolismo , Pulmão/virologia , SARS-CoV-2/metabolismo , Obesidade/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Camundongos Endogâmicos C57BL , Internalização do Vírus , Masculino , Humanos , Camundongos Obesos , Proteínas Recombinantes/metabolismo
2.
FASEB J ; 38(10): e23669, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38747734

RESUMO

Amomum xanthioides (AX) has been used as an edible herbal medicine to treat digestive system disorders in Asia. Additionally, Lactobacillus casei is a well-known probiotic commonly used in fermentation processes as a starter. The current study aimed to investigate the potential of Lactobacillus casei-fermented Amomum xanthioides (LAX) in alleviating metabolic disorders induced by high-fat diet (HFD) in a mouse model. LAX significantly reduced the body and fat weight, outperforming AX, yet without suppressing appetite. LAX also markedly ameliorated excessive lipid accumulation and reduced inflammatory cytokine (IL-6) levels in serum superior to AX in association with UCP1 activation and adiponectin elevation. Furthermore, LAX noticeably improved the levels of fasting blood glucose, serum insulin, and HOMA-IR through positive regulation of glucose transporters (GLUT2, GLUT4), and insulin receptor gene expression. In conclusion, the fermentation of AX demonstrates a pronounced mitigation of overnutrition-induced metabolic dysfunction, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and obesity, compared to non-fermented AX. Consequently, we proposed that the fermentation of AX holds promise as a potential candidate for effectively ameliorating metabolic disorders.


Assuntos
Amomum , Dieta Hiperlipídica , Fermentação , Lacticaseibacillus casei , Obesidade , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos , Obesidade/metabolismo , Masculino , Lacticaseibacillus casei/metabolismo , Amomum/química , Camundongos Endogâmicos C57BL , Probióticos/farmacologia , Proteína Desacopladora 1/metabolismo , Resistência à Insulina , Camundongos Obesos , Adiponectina/metabolismo , Insulina/metabolismo , Insulina/sangue , Glicemia/metabolismo
3.
Respir Res ; 25(1): 213, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38762465

RESUMO

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.


Assuntos
Dieta Hiperlipídica , Inibidores de Hidroximetilglutaril-CoA Redutases , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade , Fibrose Pulmonar , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Camundongos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fibrose Pulmonar/prevenção & controle , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Inibidores de PCSK9 , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Camundongos Obesos , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertase 9/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Hiper-Reatividade Brônquica/prevenção & controle , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Anticorpos Monoclonais Humanizados
4.
J Appl Microbiol ; 135(5)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38740521

RESUMO

AIMS: The aim of this study was to evaluate the antiobesity effects of heat-killed Lactiplantibacillus plantarum Shinshu N-07 (N-07) isolated from fermented Brassica rapa L. METHODS AND RESULTS: Male mice were divided into three groups (n = 10/group); normal diet, western diet (WD), or WD + N-07 (N-07) group and administered each diet for 56 days. The N-07 group showed significant suppression of body weight gain and epididymal fat, perirenal fat, and liver weights compared with the WD group. Higher levels of fecal total cholesterol, triglyceride (TG), and free fatty acid (FFA) were observed in the N-07 group than in the WD group. The mRNA expression of the cholesterol transporter ATP-binding cassette transporter G5 (ABCG5) was significantly increased in the small intestine of N-07-fed mice compared with WD-fed mice. Moreover, N-07 supplementation significantly increased the mRNA expression of ABCG5 and ABCG8 in Caco-2 cells. Furthermore, the TG- and FFA-removal ability of N-07 was confirmed to evaluate its soybean oil- and oleic acid-binding capacities in in vitro experiments. CONCLUSIONS: The antiobesity effects of N-07 might be due to its ability to promote lipid excretion by regulating cholesterol transporter expression and lipid-binding ability.


Assuntos
Dieta Ocidental , Obesidade , Animais , Masculino , Camundongos , Obesidade/metabolismo , Humanos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Fármacos Antiobesidade/farmacologia , Lactobacillus plantarum , Camundongos Obesos , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Probióticos , Células CACO-2 , Brassica rapa/química , Temperatura Alta , Lipoproteínas/metabolismo , Triglicerídeos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL
5.
Commun Biol ; 7(1): 594, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760406

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.


Assuntos
Adenosina Desaminase , Dieta Hiperlipídica , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica , Proteínas de Ligação a RNA , Transdução de Sinais , Animais , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/deficiência , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Resistência à Insulina , Camundongos Obesos , Obesidade/metabolismo , Obesidade/genética , Camundongos Endogâmicos C57BL , Fígado/metabolismo
6.
Food Res Int ; 187: 114417, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38763667

RESUMO

Resistant starch serves as a prebiotic in the large intestine, aiding in the maintenance of a healthy intestinal environment and mitigating associated chronic illnesses. This study aimed to investigate the impact of resistant starch-enriched brown rice (RBR) on intestinal health and functionality. We assessed changes in resistant starch concentration, structural alterations, and branch chain length distribution throughout the digestion process using an in vitro model. The efficacy of RBR in the intestinal environment was evaluated through analyses of its prebiotic potential, effects on intestinal microbiota, and intestinal function-related proteins in obese animals fed a high-fat diet. RBR exhibited a higher yield of insoluble fraction in both the small and large intestines compared to white and brown rice. The total digestible starch content decreased, while the resistant starch content significantly increased during in vitro digestion. Furthermore, RBR notably enhanced the growth of four probiotic strains compared to white and brown rice, displaying higher proliferation activity than the positive control, FOS. Notably, consumption of RBR by high-fat diet-induced obese mice suppressed colon shortening, increased Bifidobacteria growth, and improved intestinal permeability. These findings underscore the potential prebiotic and gut health-promoting attributes of RBR, offering insights for the development of functional foods aimed at preventing gastrointestinal diseases.


Assuntos
Dieta Hiperlipídica , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Obesidade , Oryza , Prebióticos , Amido , Animais , Oryza/química , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Amido/metabolismo , Masculino , Obesidade/metabolismo , Camundongos Obesos , Amido Resistente , Probióticos , Digestão , Bifidobacterium/crescimento & desenvolvimento
7.
Biochim Biophys Acta Gene Regul Mech ; 1867(2): 195030, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38670485

RESUMO

Antiretroviral therapy-naive people living with HIV possess less fat than people without HIV. Previously, we found that HIV-1 transactivator of transcription (TAT) decreases fat in ob/ob mice. The TAT38 (a.a. 20-57) is important in the inhibition of adipogenesis and contains three functional domains: Cys-ZF domain (a.a. 20-35 TACTNCYCAKCCFQVC), core-domain (a.a. 36-46, FITKALGISYG), and protein transduction domain (PTD)(a.a. 47-57, RAKRRQRRR). Interestingly, the TAT38 region interacts with the Cyclin T1 of the P-TEFb complex, of which expression increases during adipogenesis. The X-ray crystallographic structure of the complex showed that the Cys-ZF and the core domain bind to the Cyclin T1 via hydrophobic interactions. To prepare TAT38 mimics with structural and functional similarities to TAT38, we replaced the core domain with a hydrophobic aliphatic amino acid (from carbon numbers 5 to 8). The TAT38 mimics with 6-hexanoic amino acid (TAT38 Ahx (C6)) and 7-heptanoic amino acid (TAT38 Ahp (C7)) inhibited adipogenesis of 3T3-L1 potently, reduced cellular triglyceride content, and decreased body weight of diet-induced obese (DIO) mice by 10.4-11 % in two weeks. The TAT38 and the TAT38 mimics potently repressed the adipogenic transcription factors genes, C/EBPα, PPARγ, and SREBP1. Also, they inhibit the phosphorylation of PPARγ. The TAT peptides may be promising candidates for development into a drug against obesity or diabetes.


Assuntos
Adipogenia , PPAR gama , Proteína de Ligação a Elemento Regulador de Esterol 1 , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Animais , PPAR gama/metabolismo , Adipogenia/efeitos dos fármacos , Camundongos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Células 3T3-L1 , Humanos , Regulação da Expressão Gênica , Camundongos Obesos , Masculino , Ciclina T/metabolismo , Obesidade/metabolismo , Adipócitos/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Estimuladoras de Ligação a CCAAT
8.
J Agric Food Chem ; 72(18): 10391-10405, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38669300

RESUMO

Metabolic-associated fatty liver disease (MAFLD) is witnessing a global surge; however, it still lacks effective pharmacological interventions. Fucoxanthin, a natural bioactive metabolite derived from marine brown algae, exhibits promising pharmacological functions, particularly in ameliorating metabolic disorders. However, the mechanisms underlying its therapeutic efficacy in addressing MAFLD remain elusive. Our present findings indicated that fucoxanthin significantly alleviated palmitic acid (PA)-induced hepatic lipid deposition in vitro and obesity-induced hepatic steatosis in ob/ob mice. Moreover, at both the protein and transcriptional levels, fucoxanthin effectively increased the expression of PPARα and CPT1 (involved in fatty acid oxidation) and suppressed FASN and SREBP1c (associated with lipogenesis) in both PA-induced HepG2 cells and hepatic tissues in ob/ob mice. This modulation was accompanied by the activation of AMPK. The capacity of fucoxanthin to improve hepatic lipid deposition was significantly attenuated when utilizing the AMPK inhibitor or siRNA-mediated AMPK silencing. Mechanistically, fucoxanthin activates AMPK, subsequently regulating the KEAP1/Nrf2/ARE signaling pathway to exert antioxidative effects and stimulating the PGC1α/NRF1 axis to enhance mitochondrial biogenesis. These collective actions contribute to fucoxanthin's amelioration of hepatic steatosis induced by metabolic perturbations. These findings offer valuable insights into the prospective utilization of fucoxanthin as a therapeutic strategy for managing MAFLD.


Assuntos
Fígado , Camundongos Endogâmicos C57BL , Xantofilas , Xantofilas/farmacologia , Animais , Humanos , Camundongos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Células Hep G2 , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR alfa/metabolismo , PPAR alfa/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Obesidade/genética , Lipogênese/efeitos dos fármacos , Camundongos Obesos
9.
Mol Nutr Food Res ; 68(8): e2300720, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38581348

RESUMO

SCOPE: The global prevalence of obesity has significantly increased, presenting a major health challenge. High-fat diet (HFD)-induced obesity is closely related to the disease severity of psoriasis, but the mechanism is not fully understood. METHODS AND RESULTS: The study utilizes the HFD-induced obesity model along with an imiquimod (IMQ)-induced psoriasis-like mouse model (HFD-IMQ) to conduct transcriptomics and metabolomic analyses. HFD-induced obese mice exhibits more severe psoriasis-like lesions compared to normal diet (ND)-IMQ mice. The expression of genes of the IL-17 signaling pathway (IL-17A, IL-17F, S100A9, CCL20, CXCL1) is significantly upregulated, leading to an accumulation of T cells and neutrophils in the skin. Moreover, the study finds that there is an inhibition of the branched-chain amino acids (BCAAs) catabolism pathway, and the key gene branched-chain amino transferase 2 (Bcat2) is significantly downregulated, and the levels of leucine, isoleucine, and valine are elevated in the HFD-IMQ mice. Furthermore, the study finds that the peroxisome proliferator-activated receptor gamma (PPAR γ) is inhibited, while STAT3 activity is promoted in HFD-IMQ mice. CONCLUSION: HFD-induced obesity significantly amplifies IL-17 signaling and exacerbates psoriasis, with a potential role played by Bcat2-mediated BCAAs metabolism. The study suggests that BCAA catabolism and PPAR γ-STAT3 exacerbate inflammation in psoriasis with obesity.


Assuntos
Aminoácidos de Cadeia Ramificada , Dieta Hiperlipídica , Obesidade , Psoríase , Transaminases , Animais , Masculino , Camundongos , Aminoácidos de Cadeia Ramificada/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Imiquimode , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-17/genética , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Obesidade/complicações , PPAR gama/metabolismo , PPAR gama/genética , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais , Pele/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Transaminases/metabolismo
10.
Mol Nutr Food Res ; 68(9): e2300758, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38639319

RESUMO

SCOPE: Obesity and metabolic diseases are closely associated, and individuals who become obese are also prone to type 2 diabetes and cardiovascular disorders. Gut microbiota is mediated by diet and can influence host metabolism and the incidence of metabolic disorders. Recent studies have suggested that improving gut microbiota through a fructooligosaccharide (FOS)-supplemented diet may ameliorate obesity and other metabolic disorders. Although accumulating evidence supports the notion of the developmental origins of health and disease, the underlying mechanisms remain obscure. METHODS AND RESULTS: ICR mice are fed AIN-93G formula-based cellulose -, FOS-, acetate-, or propionate-supplemented diets during pregnancy. Offspring are reared by conventional ICR foster mothers for 4 weeks; weaned mice are fed high fat diet for 12 weeks and housed individually. The FOS and propionate offspring contribute to suppressing obesity and improving glucose intolerance. Gut microbial compositions in FOS-fed mothers and their offspring are markedly changed. However, the beneficial effect of FOS diet on the offspring is abolished when antibiotics are administered to pregnant mice. CONCLUSION: The findings highlight the link between the maternal gut environment and the developmental origin of metabolic syndrome in offspring. These results open novel research avenues into preemptive therapies for metabolic disorders by targeting the maternal gut microbiota.


Assuntos
Dieta Hiperlipídica , Microbioma Gastrointestinal , Camundongos Endogâmicos ICR , Obesidade , Oligossacarídeos , Animais , Gravidez , Oligossacarídeos/farmacologia , Oligossacarídeos/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos Obesos , Camundongos , Efeitos Tardios da Exposição Pré-Natal , Fenótipo , Fenômenos Fisiológicos da Nutrição Materna , Suplementos Nutricionais
11.
Arterioscler Thromb Vasc Biol ; 44(6): 1283-1301, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38572646

RESUMO

BACKGROUND: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. METHODS: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. RESULTS: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05). CONCLUSIONS: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.


Assuntos
Plaquetas , Diacilglicerol Quinase , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Trombose , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/metabolismo , Trombose/prevenção & controle , Trombose/sangue , Trombose/enzimologia , Trombose/tratamento farmacológico , Humanos , Masculino , Diacilglicerol Quinase/antagonistas & inibidores , Diacilglicerol Quinase/metabolismo , Camundongos , Ativação Plaquetária/efeitos dos fármacos , Feminino , Agregação Plaquetária/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Pessoa de Meia-Idade , Fibrinolíticos/farmacologia , Estudos de Casos e Controles , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Obesidade/sangue , Inibidores da Agregação Plaquetária/farmacologia
12.
Am J Physiol Cell Physiol ; 326(5): C1543-C1555, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38586877

RESUMO

Obesity imposes deficits on adipose tissue and vascular endothelium, yet the role that distinct adipose depots play in mediating endothelial dysfunction in local arteries remains unresolved. We recently showed that obesity impairs endothelial Kir2.1 channels, mediators of nitric oxide production, in arteries of visceral adipose tissue (VAT), while Kir2.1 function in subcutaneous adipose tissue (SAT) endothelium remains intact. Therefore, we determined if VAT versus SAT from lean or diet-induced obese mice affected Kir2.1 channel function in vitro. We found that VAT from obese mice reduces Kir2.1 function without altering channel expression whereas AT from lean mice and SAT from obese mice had no effect on Kir2.1 function as compared to untreated control cells. As Kir2.1 is well known to be inhibited by fatty acid derivatives and obesity is strongly associated with elevated circulating fatty acids, we next tested the role of the fatty acid translocase CD36 in mediating VAT-induced Kir2.1 dysfunction. We found that the downregulation of CD36 restored Kir2.1 currents in endothelial cells exposed to VAT from obese mice. In addition, endothelial cells exposed to VAT from obese mice exhibited a significant increase in CD36-mediated fatty acid uptake. The importance of CD36 in obesity-induced endothelial dysfunction of VAT arteries was further supported in ex vivo pressure myography studies where CD36 ablation rescued the endothelium-dependent response to flow via restoring Kir2.1 and endothelial nitric oxide synthase function. These findings provide new insight into the role of VAT in mediating obesity-induced endothelial dysfunction and suggest a novel role for CD36 as a mediator of endothelial Kir2.1 impairment.NEW & NOTEWORTHY Our findings suggest a role for visceral adipose tissue (VAT) in the dysfunction of endothelial Kir2.1 in obesity. We further reveal a role for CD36 as a major contributor to VAT-mediated Kir2.1 and endothelial dysfunction, suggesting that CD36 offers a potential target for preventing the early development of obesity-associated cardiovascular disease.


Assuntos
Antígenos CD36 , Células Endoteliais , Gordura Intra-Abdominal , Camundongos Endogâmicos C57BL , Obesidade , Canais de Potássio Corretores do Fluxo de Internalização , Animais , Antígenos CD36/metabolismo , Antígenos CD36/genética , Gordura Intra-Abdominal/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Obesidade/metabolismo , Camundongos , Masculino , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Camundongos Obesos , Gordura Subcutânea/metabolismo , Dieta Hiperlipídica
13.
Diabetes Obes Metab ; 26(6): 2368-2378, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38560764

RESUMO

AIM: To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon-like peptide-1 receptor (GLP-1R) agonists for in-depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. MATERIALS AND METHODS: Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)-K1 cells stably expressing human GCGR and GLP-1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP-1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP-1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor-21 (FGF21) and liver nicotinamide N-methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight- and glucose-lowering efficacies were investigated in diet-induced obese (DIO) mice and diabetic db/db mice, respectively. RESULTS: Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP-1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP-1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in-depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15- to 17-fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight-lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%-0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). CONCLUSIONS: Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, engaging the GCGR for robust body weight-lowering efficacy exceeding that of selective GLP-1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP-1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity.


Assuntos
Cricetulus , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Receptores de Glucagon , Animais , Receptores de Glucagon/agonistas , Receptores de Glucagon/genética , Camundongos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Células CHO , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Humanos , Biomarcadores/sangue , Masculino , Ratos , Camundongos Obesos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico
14.
Biomed Pharmacother ; 174: 116531, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574624

RESUMO

N-acylethanolamines (NAEs) are endogenous lipid-signalling molecules involved in inflammation and energy metabolism. The potential pharmacological effect of NAE association in managing inflammation-based metabolic disorders is unexplored. To date, targeting liver-adipose axis can be considered a therapeutic approach for the treatment of obesity and related dysfunctions. Here, we investigated the metabolic effect of OLALIAMID® (OLA), an olive oil-derived NAE mixture, in limiting liver and adipose tissue (AT) dysfunction of high-fat diet (HFD)-fed mice. OLA reduced body weight and fat mass in obese mice, decreasing insulin resistance (IR), as shown by homeostasis model assessment index, and leptin/adiponectin ratio, a marker of adipocyte dysfunction. OLA improved serum lipid and hepatic profile and the immune/inflammatory pattern of metainflammation. In liver of HFD mice, OLA treatment counteracted glucose and lipid dysmetabolism, restoring insulin signalling (phosphorylation of AKT and AMPK), and reducing mRNAs of key markers of fatty acid accumulation. Furthermore, OLA positively affected AT function deeply altered by HFD by reprogramming of genes involved in thermogenesis of interscapular brown AT (iBAT) and subcutaneous white AT (scWAT), and inducing the beigeing of scWAT. Notably, the NAE mixture reduced inflammation in iBAT and promoted M1-to-M2 macrophage shift in scWAT of obese mice. The tissue and systemic anti-inflammatory effects of OLA and the increased expression of glucose transporter 4 in scWAT contributed to the improvement of gluco-lipid toxicity and insulin sensitivity. In conclusion, we demonstrated that this olive oil-derived NAE mixture is a valid nutritional strategy to counteract IR and obesity acting on liver-AT crosstalk, restoring both hepatic and AT function and metabolism.


Assuntos
Adipócitos , Tecido Adiposo , Dieta Hiperlipídica , Etanolaminas , Resistência à Insulina , Fígado , Camundongos Endogâmicos C57BL , Obesidade , Animais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Etanolaminas/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Camundongos , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Camundongos Obesos , Metabolismo dos Lipídeos/efeitos dos fármacos
15.
Biomed Pharmacother ; 174: 116564, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38608525

RESUMO

During resolution of inflammation, specialized proresolving mediators (SPMs), including resolvins, are produced to restore tissue homeostasis. We hypothesized that there might be a dysregulation of SPMs pathways in pathological vascular remodeling and that resolvin D2 (RvD2) might prevent vascular remodeling and contractile and endothelial dysfunction in a model of obesity and hypertension. In aortic samples of patients with or without abdominal aortic aneurysms (AAA), we evaluated gene expression of enzymes involved in SPMs synthesis (ALOXs), SPMs receptors and pro-inflammatory genes. In an experimental model of aortic dilation induced by high fat diet (HFD, 60%, eighteen weeks) and angiotensin II (AngII) infusion (four weeks), we studied the effect of RvD2 administration in aorta and small mesenteric arteries structure and function and markers of inflammation. In human macrophages we evaluated the effects of AngII and RvD2 in macrophages function and SPMs profile. In patients, we found positive correlations between AAA and obesity, and between AAA and expression of ALOX15, RvD2 receptor GPR18, and pro-inflammatory genes. There was an inverse correlation between the expression of aortic ALOX15 and AAA growth rate. In the mice model, RvD2 partially prevented the HFD plus AngII-induced obesity and adipose tissue inflammation, hypertension, aortic and mesenteric arteries remodeling, hypercontratility and endothelial dysfunction, and the expression of vascular proinflammatory markers and cell apoptosis. In human macrophages, RvD2 prevented AngII-induced impaired efferocytosis and switched SPMs profile. RvD2 might represent a novel protective strategy in preventing vascular damage associated to hypertension and obesity likely through effects in vascular and immune cells.


Assuntos
Ácidos Docosa-Hexaenoicos , Hipertensão , Camundongos Endogâmicos C57BL , Obesidade , Remodelação Vascular , Animais , Masculino , Humanos , Ácidos Docosa-Hexaenoicos/farmacologia , Hipertensão/metabolismo , Hipertensão/tratamento farmacológico , Obesidade/complicações , Obesidade/metabolismo , Remodelação Vascular/efeitos dos fármacos , Camundongos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Dieta Hiperlipídica/efeitos adversos , Angiotensina II , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Camundongos Obesos , Vasoconstrição/efeitos dos fármacos , Inflamação/patologia , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Animais de Doenças
16.
World J Microbiol Biotechnol ; 40(6): 168, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630156

RESUMO

Obesity is a growing epidemic worldwide. Several pharmacologic drugs are being used to treat obesity but these medicines exhibit side effects. To find out the alternatives of these drugs, we aimed to assess the probiotic properties and anti-obesity potentiality of a lactic acid bacterium E2_MCCKT, isolated from a traditional fermented rice beverage, haria. Based on the 16S rRNA sequencing, the bacterium was identified as Lactiplantibacillus plantarum E2_MCCKT. The bacterium exhibited in vitro probiotic activity in terms of high survivability in an acidic environment and 2% bile salt, moderate auto-aggregation, and hydrophobicity. Later, E2_MCCKT was applied to obese mice to prove its anti-obesity potentiality. Adult male mice (15.39 ± 0.19 g) were randomly divided into three groups (n = 5) according to the type of diet: normal diet (ND), high-fat diet (HFD), and HFD supplemented with E2_MCCKT (HFT). After four weeks of bacterial treatment on the obese mice, a significant reduction of body weight, triglyceride, and cholesterol levels, whereas, improvements in serum glucose levels were observed. The bacterial therapy led to mRNA up-regulation of lipolytic transcription factors such as peroxisome proliferator-activated receptor-α which may increase the expression of fatty acid oxidation-related genes such as acyl-CoA oxidase and carnitine palmitoyl-transferase-1. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol-regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase genes. In protein expression study, E2_MCCKT significantly increased IL-10 expression while decreasing pro-inflammatory cytokine (IL-1Ra and TNF-α) expression. In conclusion, the probiotic Lp. plantarum E2_MCCKT might have significant anti-obesity effects on mice.


Assuntos
Dieta Hiperlipídica , Obesidade , Masculino , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Camundongos Obesos , RNA Ribossômico 16S/genética , Ácidos Graxos
17.
Elife ; 122024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564479

RESUMO

Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Células Estreladas do Fígado , Fígado/metabolismo , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , RNA Interferente Pequeno/metabolismo
18.
FASEB J ; 38(7): e23579, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38568838

RESUMO

Lifestyle interventions remain the treatment of choice for patients with obesity and metabolic complications, yet are difficult to maintain and often lead to cycles of weight loss and regain (weight cycling). Literature on weight cycling remains controversial and we therefore investigated the association between weight cycling and metabolic complications using preexistent obese mice. Ldlr-/-.Leiden mice received a high-fat diet (HFD) for 20 weeks to induce obesity. Subsequently, weight-cycled mice were switched between the healthy chow diet and HFD for four 2-week periods and compared to mice that received HFD for the total study period. Repeated weight cycling tended to decrease body weight and significantly reduced fat mass, whereas adipose tissue inflammation was similar relative to HFD controls. Weight cycling did not significantly affect blood glucose or plasma insulin levels yet significantly reduced plasma free fatty acid and alanine transaminase/aspartate transaminase levels. Hepatic macrovesicular steatosis was similar and microvesicular steatosis tended to be increased upon weight cycling. Weight cycling resulted in a robust decrease in hepatic inflammation compared to HFD controls while hepatic fibrosis and atherosclerosis development were not affected. These results argue against the postulate that repeated weight cycling leads to unfavorable metabolic effects, when compared to a continuous unhealthy lifestyle, and in fact revealed beneficial effects on hepatic inflammation, an important hallmark of non-alcoholic steatohepatitis.


Assuntos
Fígado , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Fígado/metabolismo , Camundongos Obesos , Ciclo de Peso , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Inflamação/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL
19.
PLoS One ; 19(4): e0300705, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38603672

RESUMO

Obesity is a major independent risk factor for chronic kidney disease and can activate renal oxidative stress injury. Ascorbate and aldarate metabolism is an important carbohydrate metabolic pathway that protects cells from oxidative damage. However the effect of oxidative stress on this pathway is still unclear. Therefore, the primary objective of this study was to investigate the ascorbate and aldarate metabolism pathway in the kidneys of high-fat diet-fed obese mice and determine the effects of oxidative stress. Male C57BL/6J mice were fed on a high-fat diet for 12 weeks to induce obesity. Subsequently, non-targeted metabolomics profiling was used to identify metabolites in the kidney tissues of the obese mice, followed by RNA sequencing using transcriptomic methods. The integrated analysis of metabolomics and transcriptomics revealed the alterations in the ascorbate and aldarate metabolic pathway in the kidneys of these high-fat diet-fed obese mice. The high-fat diet-induced obesity resulted in notable changes, including thinning of the glomerular basement membrane, alterations in podocyte morphology, and an increase in oxidative stress. Metabolomics analysis revealed 649 metabolites in the positive-ion mode, and 470 metabolites in the negative-ion mode. Additionally, 659 differentially expressed genes (DEGs) were identified in the obese mice, of which 34 were upregulated and 625 downregulated. Integrated metabolomics and transcriptomics analyses revealed two DEGs and 13 differential metabolites in the ascorbate and aldarate metabolic pathway. The expression levels of ugt1a9 and ugt2b1 were downregulated, and the ascorbate level in kidney tissue of obese mice was reduced. Thus, renal oxidative stress injury induced by high-fat diet affects metabolic regulation of ascorbate and aldarate metabolism in obese mice. Ascorbate emerged as a potential marker for predicting kidney damage due to high-fat diet-induced obesity.


Assuntos
Dieta Hiperlipídica , Rim , Animais , Camundongos , Masculino , Dieta Hiperlipídica/efeitos adversos , Camundongos Obesos , Camundongos Endogâmicos C57BL , Rim/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Metabolômica , Perfilação da Expressão Gênica
20.
PLoS One ; 19(4): e0301496, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38635745

RESUMO

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Resistência à Insulina , Humanos , Camundongos , Masculino , Ratos , Animais , Camundongos Obesos , Antagonistas dos Receptores de Dopamina D2 , Prolactina , Receptores da Prolactina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Sulpirida/farmacologia , Sulpirida/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/etiologia , Dieta Hiperlipídica/efeitos adversos , Hiperglicemia/tratamento farmacológico , Hipertrofia , Insulina/metabolismo
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