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1.
Life Sci ; 258: 118196, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763295

RESUMO

AIM: The pharmacological properties of pentoxifylline have been re-evaluated, particularly in chronic kidney disease in diabetes, favored by its anti-inflammatory action. Definitive evidences of renal outcomes are lacking, which indicates the need for investigation of novel mechanisms of action of pentoxifylline. We postulated that components associated with the metabolism of advanced glycation end products (AGEs) may be modulated by pentoxifylline, which consequently decreases the detrimental effects of obesity on kidneys. MAIN METHODS: C57BL-6J mice were fed a high-fat diet for 14 weeks and treated with 50 mg/kg pentoxifylline during the last 7 weeks. Changes in the renal levels of AGE metabolism-associated components were investigated, with particular focus on the receptor for AGEs (RAGE), its downstream components, and components related to AGE detoxification, including glyoxalase 1 (GLO 1). KEY FINDINGS: Pentoxifylline reduced body weight gain, improved insulin sensitivity and glucose tolerance, downregulated biomarkers of glycoxidative stress, and enhanced plasma paraoxonase 1 activity. In the kidneys, pentoxifylline inhibited glomerular expansion, lipid deposition, reduced pro-inflammatory cytokine levels, and induced the activation of AMP-activated protein kinase. Pentoxifylline inhibited the renal accumulation of AGEs and reduced the levels of RAGE and its downstream components, and consequently mitigated oxidative stress and apoptosis. Pentoxifylline also increased the renal levels of GLO 1 and the activities of antioxidant enzymes. Urinary albumin levels were observed to be lowered, which reconfirmed the antialbuminuric effects of pentoxifylline. SIGNIFICANCE: The novel mechanisms of action help explain the renoprotective effects of pentoxifylline and the attenuation of obesity-associated renal complications related to glycoxidative stress.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Glicólise/efeitos dos fármacos , Rim/patologia , Lactoilglutationa Liase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pentoxifilina/farmacologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Rim/efeitos dos fármacos , Camundongos Obesos , Transdução de Sinais/efeitos dos fármacos
2.
Nat Commun ; 11(1): 1822, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286278

RESUMO

B cell dysfunction due to obesity can be associated with alterations in the levels of micro-RNAs (miRNAs). However, the role of miRNAs in these processes remains elusive. Here, we show that miR-802 is increased in the pancreatic islets of obese mouse models and demonstrate that inducible transgenic overexpression of miR-802 in mice causes impaired insulin transcription and secretion. We identify Foxo1 as a transcription factor of miR-802 promoting its transcription, and NeuroD1 and Fzd5 as targets of miR-802-dependent silencing. Repression of NeuroD1 in ß cell and primary islets impairs insulin transcription and reduction of Fzd5 in ß cell, which, in turn, impairs Ca2+ signaling, thereby repressing calcium influx and decreasing insulin secretion. We functionally create a novel network between obesity and ß cell dysfunction via miR-802 regulation. Elucidation of the impact of obesity on microRNA expression can broaden our understanding of pathophysiological development of diabetes.


Assuntos
Secreção de Insulina/genética , Insulina/genética , MicroRNAs/metabolismo , Obesidade/genética , Transcrição Genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Proteína Forkhead Box O1/metabolismo , Receptores Frizzled/metabolismo , Deleção de Genes , Inativação Gênica , Insulina/metabolismo , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , MicroRNAs/genética , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Regulação para Cima/genética
3.
Life Sci ; 253: 117651, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304764

RESUMO

AIMS: To investigate the combination of dimerization and PEGylation to enhance the receptor activation and in vivo stability of Oxyntomodulin (OXM). MAIN METHODS: All LDM peptides were produced by using standard method of solid phase synthesis. The in vitro effects of LDM peptides were assessed by glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GcgR) binding test and Proteolytic stability test. Subsequently, saline, Liraglutide and three doses of LDM-3 treated groups were subjected to the evaluation of aute and long-term efficacy. KEY FINDINGS: Five long-acting OXM conjugates, termed LDM-1 to LDM-5, were designed using cysteine (Cys)-specific modification reaction including the activated PEG, bisMal-NH2, and OXM-Cys, and all prepared with high purity. LDM-3 exhibited greater GLP-1R and GcgR activation and ameliorative serum stability. In addition, LDM-3 was identified with enhanced insulinotropic and glycemic abilities in the gene knockout mice. The prolonged glucose-lowering effects of the LDM-3 were proved by hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diet-induced obesity (DIO) mice. Furthermore, the pharmacokinetic tests in Sprague Dawley (SD) rat and cynomolgus monkey exhibited the lifespans of LDM-3 at 90 nmol·kg-1 were 101.5 h and 119.4 h, respectively. Nevertheless, consecutive 8-week administration of LDM-3 improved the cumulative body weight gain, food intake, % HbA1c, glucose tolerance and the pancreatic of the obese mice. SIGNIFICANCE: LDM-3, as a dual GLP-1R and GcgR agonist, holds potential to be developed as a promising therapeutic candidate for both diabetes and obesity.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipoglicemiantes/química , Oxintomodulina/química , Receptores de Glucagon/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Dimerização , Glucagon/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Obesidade/metabolismo , Oxintomodulina/farmacocinética , Polietilenoglicóis/química , Ratos Sprague-Dawley , Técnicas de Síntese em Fase Sólida , Perda de Peso/efeitos dos fármacos
4.
Obesity (Silver Spring) ; 28(6): 1075-1085, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32348021

RESUMO

OBJECTIVE: Identifying novel approaches to combat obesity is important to improve health span. It was hypothesized that methionine restriction (MR) will induce weight loss in obese mice by reducing adipose tissue mass caused by increased energy expenditure and reprogramming of adipose tissue homeostasis. The roles of adiponectin (ADIPOQ) and fibroblast growth factor 21 (FGF21) during weight loss in MR mice were also tested. METHODS: Diet-induced obese (DIO) male C57BL/6J (wild type), Adipoq-deficient (Adipoq knockout [KO]), Fgf21-KO, and Adipoq-Fgf21 double-KO mice were used. Following a switch to high-fat control (DIO-CF, 60% fat/0.86% methionine) or MR (DIO-MR, 60% fat/0.12% methionine) diet, physiological parameters were measured, and inguinal and perigonadal adipose tissues were examined. RESULTS: Obese mice subjected to MR showed loss of body weight and adiposity, increased energy expenditure, and improved glucose tolerance that were independent of the actions of ADIPOQ and FGF21. MR induced reduction of circulating lipids, glucose, insulin, leptin, and insulin like growth factor 1 and increased ß-hydroxybutyrate, ADIPOQ, and FGF21 concentrations. In fat, MR upregulated protein levels of adipose triglyceride lipase, apoptosis-inducing factor, lysosomal-associated membrane proteins 1 and 2, autophagy-related protein 5, beclin-1, and light chain 3B I and II. CONCLUSIONS: MR reduction of adipose tissue mass in obese mice is associated with elevated lipolysis, apoptosis, and autophagy and occurs independently of the actions of ADIPOQ and FGF21.


Assuntos
Adiponectina/metabolismo , Adiposidade/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Metionina/metabolismo , Camundongos Obesos/genética , Perda de Peso/fisiologia , Animais , Masculino , Camundongos
5.
Food Chem ; 320: 126648, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32234657

RESUMO

High circulating branched-chain amino acid (BCAA) levels can be diagnosis indicators for obesity. Luffa cylindrica (luffa) is one of vegetables against obesity. However, whether the anti-obesity of luffa is associated with BCAA metabolism and gut microbiota remains unknown. Here, we used conventionally raised diet-induced obese (DIO) mice to prove dietary luffa could reduce higher circulating BCAA levels and upregulate the tissue-specific expressions of BCAA-catabolizing enzymes. Meanwhile, dietary luffa selectively decreased the relative abundances of g_Enterortabdus, g_Eubacterium_xylanophilum_group and g_Butyricicoccus that exhibited significantly positive correlations with BCAA levels, BMI and HOMA-IR. Bacterial functionality prediction indicated dietary luffa potentially inhibited bacterial BCAA biosynthesis for reducing BCAAs supplementation. More importantly, dietary luffa had no impacts on BCAA catabolism in germ-free-mimic DIO mice. Thus, dietary luffa improved BCAA dysfunction via gut microbiota to attenuate obesity. This study offers a novel insight into dietary intervention against obesity from the aspect of gut microbiota-amino acid metabolism.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Fármacos Antiobesidade/farmacologia , Microbioma Gastrointestinal/fisiologia , Luffa , Obesidade/dietoterapia , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia
6.
Obesity (Silver Spring) ; 28(6): 1086-1097, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32281747

RESUMO

OBJECTIVE: Weight regain after weight loss is common, and there is evidence to suggest negative effects on health because of weight cycling. This study sought to investigate the impact of weight regain in formerly obese mice on adipose tissue architecture and stromal cell function. METHODS: A diet-switch model was employed for obesity induction, weight loss, and weight regain in mice. Flow cytometry quantified adipose tissue leukocytes in adipose tissue. Liver and adipose tissue depots were compared to determine tissue-specific effects of weight cycling. RESULTS: Epididymal white adipose tissue of formerly obese mice failed to expand in response to repeat exposure to high-fat diet and retained elevated numbers of macrophages and T cells. Weight regain was associated with disproportionally elevated liver mass, hepatic triglyceride content, serum insulin concentration, and serum transaminase concentration. These effects occurred despite an extended 6-month weight loss cycle and they demonstrate that formerly obese mice maintain durable alterations in their physiological response to weight regain. Conditioned media from epididymal adipose tissue of formerly obese mice inhibited adipogenesis of 3T3-L1 preadipocytes, suggesting a potential mechanism to explain failed epididymal adipose tissue expansion during weight regain. CONCLUSIONS: Metabolic abnormalities related to defects in adipose tissue expansion and ongoing dysfunction manifest in formerly obese mice during weight regain.


Assuntos
Tecido Adiposo/metabolismo , Fígado Gorduroso/metabolismo , Obesidade/metabolismo , Ganho de Peso/fisiologia , Animais , Dieta Hiperlipídica , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos
7.
Obesity (Silver Spring) ; 28(4): 756-764, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32144880

RESUMO

OBJECTIVE: The aim of this study was to investigate the effect of Von Willebrand factor (VWF) on high-fat diet (HFD)-induced hepatic steatosis, insulin resistance, and inflammation in mice. METHODS: The expression of VWF was detected in obese mice. Wild-type and VWF knockout mice were fed a normal chow diet or an HFD, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations. Inflammatory cytokine levels and the number of hepatic macrophages were determined in these mice fed an HFD. RESULTS: VWF expression was significantly increased in obese mice. VWF-/- mice were less obese and had improved hepatic steatosis, balance of lipid metabolism, and insulin resistance in response to HFD. Furthermore, VWF deficiency attenuated HFD-induced systemic and hepatic inflammation. In addition, VWF deficiency rescued the abnormal accumulation of hepatic macrophages. CONCLUSIONS: These data demonstrated VWF deficiency improves hepatic steatosis, insulin resistance, and inflammation. Furthermore, the protective effects are mediated via regulation of hepatic macrophages.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Inflamação/terapia , Resistência à Insulina/fisiologia , Fator de von Willebrand/uso terapêutico , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fator de von Willebrand/farmacologia
8.
Exerc Immunol Rev ; 26: 10-22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32139355

RESUMO

Moderate aerobic training may be therapeutic for chronic low-grade inflammatory diseases due to the associated anti-inflammatory response that is mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPARγ) regulates the M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Against this background, the present study seeks to clarify whether the conditional deletion of PPARγ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic training. To test this hypothesis, two mice strains were used: PPARγ LyzCre+/+ (KO) and littermates control animals (WT). Each genotype was divided into 1) sedentary high-fat diet (HF) and 2) high-fat diet and moderate aerobic training (HFT) (n = 5-8 per group). The experimental protocol lasted for 12 weeks, comprising 4 weeks of HF diet only and 8 weeks of HF diet and aerobic training (5 times/week, 50-60 minutes/day at 60% of maximum speed). Metabolic analyses were carried out on the serum glucose homeostase, adipose tissue morphology and cytokine content, and macrophage cytokine production.Immunophenotyping and gene expression were also performed. KO male mice were more prone to hypertrophy in the subcutaneous adipose tissue, though only the IL-1ß (p = 0.0049) was higher compared to the values observed in WT animals. Peritoneal macrophages from KO animals exhibited a marked inflammatory environment with an increase in TNF-α (p = 0.0008), IL- 1ß (p = 0.0017), and IL-6 (p < 0.0001) after lipopolysaccharide stimulation. The moderate aerobic training protected both genotypes from weight gain and reduced the caloric intake in the KO animals. Despite the attenuation of the M2 marker CD206 (p < 0.001) in the absence of PPAR-γ, the aerobic training modulated cytokine production in LPS stimulated peritoneal macrophages from both genotypes, reducing proinflammatory cytokines such as TNF-α (p = 0.0002) and IL-6 (p < 0.0001). Overall, our findings demonstrate the essential role of PPARγ in macrophage immunophenotypes. However, the deletion of PPARγ did not inhibit the exercise-mediated anti-inflammatory effect, underscoring the important role of exercise in modulating inflammation.


Assuntos
Inflamação/imunologia , Macrófagos Peritoneais/imunologia , PPAR gama/imunologia , Condicionamento Físico Animal , Animais , Dieta Hiperlipídica , Imunofenotipagem , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fator de Necrose Tumoral alfa/imunologia
9.
PLoS Biol ; 18(3): e3000688, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32218572

RESUMO

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fármacos Antiobesidade/uso terapêutico , Cumarínicos/uso terapêutico , Obesidade/prevenção & controle , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Reação de Maillard , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Propiltiouracila/toxicidade , Termogênese , Tri-Iodotironina/antagonistas & inibidores , Tri-Iodotironina/metabolismo , Ganho de Peso/efeitos dos fármacos
10.
Metabolism ; 106: 154191, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32112822

RESUMO

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) plays a key role in fatty acid metabolism and glucose homeostasis. In the context of dyslipemia, LRP1 is upregulated in the heart. Our aim was to evaluate the impact of cardiomyocyte LRP1 deficiency on high fat diet (HFD)-induced cardiac and metabolic alterations, and to explore the potential mechanisms involved. METHODS: We used TnT-iCre transgenic mice with thoroughly tested suitability to delete genes exclusively in cardiomyocytes to generate an experimental mouse model with conditional Lrp1 deficiency in cardiomyocytes (TNT-iCre+-LRP1flox/flox). FINDINGS: Mice with Lrp1-deficient cardiomyocytes (cm-Lrp1-/-) have a normal cardiac function combined with a favorable metabolic phenotype against HFD-induced glucose intolerance and obesity. Glucose intolerance protection was linked to higher hepatic fatty acid oxidation (FAO), lower liver steatosis and increased whole-body energy expenditure. Proteomic studies of the heart revealed decreased levels of cardiac pro-atrial natriuretic peptide (pro-ANP), which was parallel to higher ANP circulating levels. cm-Lrp1-/- mice showed ANP signaling activation that was linked to increased fatty acid (FA) uptake and increased AMPK/ ACC phosphorylation in the liver. Natriuretic peptide receptor A (NPR-A) antagonist completely abolished ANP signaling and metabolic protection in cm-Lrp1-/- mice. CONCLUSIONS: These results indicate that an ANP-dependent axis controlled by cardiac LRP1 levels modulates AMPK activity in the liver, energy homeostasis and whole-body metabolism.


Assuntos
Resistência à Insulina/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Miócitos Cardíacos/metabolismo , Obesidade/genética , Adenilato Quinase/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Metabolismo dos Lipídeos/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Obesidade/metabolismo , Obesidade/patologia
11.
PLoS One ; 15(3): e0229397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191726

RESUMO

Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2Δpodocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2Δpodocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2Δpodocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)-unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2Δpodocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.


Assuntos
Autofagia , Glomerulosclerose Segmentar e Focal/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Obesidade/complicações , Podócitos/patologia , Insuficiência Renal Crônica/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Podócitos/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/fisiologia
12.
Ann Rheum Dis ; 79(5): 635-645, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32156705

RESUMO

OBJECTIVES: In this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression. METHODS: Destabilisation of the medial meniscus (DMM) surgery was performed in 10-week-old wild type and AMP-activated protein kinase (AMPK)α1 knockout (KO) mice. Metformin (4 mg/day in drinking water) was given, commencing either 2 weeks before or 2 weeks after DMM surgery. Mice were sacrificed 6 and 12 weeks after DMM surgery. OA phenotype was analysed by micro-computerised tomography (µCT), histology and pain-related behaviour tests. AMPKα1 (catalytic alpha subunit of AMPK) expression was examined by immunohistochemistry and immunofluorescence analyses. The OA phenotype was also determined by µCT and MRI in non-human primates. RESULTS: Metformin upregulated phosphorylated and total AMPK expression in articular cartilage tissue. Mild and more severe cartilage degeneration was observed at 6 and 12 weeks after DMM surgery, evidenced by markedly increased Osteoarthritis Research Society International scores, as well as reduced cartilage areas. The administration of metformin, commencing either before or after DMM surgery, caused significant reduction in cartilage degradation. Prominent synovial hyperplasia and osteophyte formation were observed at both 6 and 12 weeks after DMM surgery; these were significantly inhibited by treatment with metformin either before or after DMM surgery. The protective effects of metformin on OA development were not observed in AMPKα1 KO mice, suggesting that the chondroprotective effect of metformin is mediated by AMPK signalling. In addition, we demonstrated that treatment with metformin could also protect from OA progression in a partial medial meniscectomy animal model in non-human primates. CONCLUSIONS: The present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Cartilagem Articular/efeitos dos fármacos , Metformina/farmacologia , Osteoartrite/tratamento farmacológico , Regulação para Cima/genética , Animais , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Hipoglicemiantes/farmacologia , Meniscos Tibiais/patologia , Meniscos Tibiais/cirurgia , Camundongos , Camundongos Knockout , Camundongos Obesos , Osteoartrite/patologia , Distribuição Aleatória , Sensibilidade e Especificidade , Transdução de Sinais/genética
13.
Obesity (Silver Spring) ; 28(3): 590-600, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32034895

RESUMO

OBJECTIVE: Previous studies have revealed decreased mitochondrial respiration in adipocytes of obese mice. This study aimed to identify the molecular underpinnings of altered mitochondrial metabolism in adipocytes. METHODS: Untargeted proteomics of mitochondria isolated from adipocytes and metabolite profiling of adipose tissues were conducted in diet-induced obese (DIO) and lean mice. Subcutaneous and intra-abdominal adipose tissues were studied to depict depot-specific alterations. RESULTS: In subcutaneous adipocytes of DIO mice, changes in proteins related to mitochondrial structure and function were observed. Mitochondrial proteins of the inner and outer membrane were strongly reduced, whereas proteins of key matrix metabolic pathways were increased in the obese versus lean state, as further substantiated by metabolite profiling. A pronounced decrease in the oxidative phosphorylation (OXPHOS) enzymatic equipment and cristae density of the inner membrane was identified. In intra-abdominal adipocytes, similar systematic downregulation of the OXPHOS machinery in obesity occurred, but there was no regulation of outer membrane or matrix proteins. CONCLUSIONS: Protein components of the OXPHOS machinery are systematically downregulated in adipose tissues of DIO mice compared with lean mice. Loss of the mitochondrial OXPHOS capacity in adipocytes may aggravate the development of metabolic disease.


Assuntos
Adipócitos/metabolismo , Mitocôndrias/metabolismo , Obesidade/genética , Proteômica/métodos , Animais , Metabolismo Energético , Humanos , Masculino , Camundongos , Camundongos Obesos , Obesidade/metabolismo
14.
Metabolism ; 105: 154171, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32006557

RESUMO

BACKGROUND: Based on the metabolic effect of exogenous ATPase inhibitory factor 1 (IF1) on glucose metabolism, we tested whether IF1 treatment is effective in ameliorating weight gain and whether its effects are sex specific. METHODS: HFD-fed C57BL/6 mice were treated with IF1 (5 mg/kg body weight, injected intraperitoneally). The underlying mechanisms of effect of IF1 on body weight were investigated in vitro and in vivo. Associations between genotypes of IF1 and obesity and relevant phenotype were further tested at the population level. RESULTS: Chronic treatment with IF1 significantly decreased body weight gain by regulating food intake of HFD-fed male mice. IF1 activated the AKT/mTORC pathway and modulated the expression of appetite genes in the hypothalamus of HFD-fed male mice and its effect was confirmed in hypothalamic cell lines as well as hypothalamic primary cells. This required the interaction of IF1 with ß-F1-ATPase on the plasma membrane of hypothalamic cells, which led to an increase in extracellular ATP production. In addition, IF1 treatment showed sympathetic nerve activation as measured by serum norepinephrine levels and UCP-1 expression in the subcutaneous fat of HFD-fed male mice. Notably, administration of recombinant IF1 to HFD-fed ovariectomized female mice showed remarkable reductions in food intake as well as body weight, which was not observed in wild-type 5-week female mice. Lastly, sex-specific genotype associations of IF1 with obesity prevalence and metabolic traits were demonstrated at the population level in humans. IF1 genetic variant (rs3767303) was significantly associated with lower prevalence of obesity and lower levels of body mass index, waist circumference, hemoglobin A1c, and glucose response area only in male participants. CONCLUSION: IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner.


Assuntos
Peso Corporal/efeitos dos fármacos , Obesidade/genética , Proteínas/genética , Proteínas/farmacologia , Animais , Apetite/genética , Dieta Hiperlipídica , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/epidemiologia , Ovariectomia , Prevalência , Caracteres Sexuais , Ganho de Peso/efeitos dos fármacos
15.
Nat Commun ; 11(1): 807, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042044

RESUMO

Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.


Assuntos
Autofagia/genética , Jejum/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fígado/metabolismo , Animais , Autofagia/efeitos dos fármacos , Epigênese Genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/deficiência , Hepatócitos/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lipólise , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , PPAR alfa/metabolismo , Fosforilação , Ligação Proteica , Transdução de Sinais , Regulação para Cima
16.
PLoS Biol ; 18(2): e3000603, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32092075

RESUMO

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic ß cell failure. ß cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of ß-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in ß cells not only modulates insulin secretion and ß cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in ß cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in ß cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and ß cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of ß cells and offer opportunities for the treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , MicroRNAs/metabolismo , Animais , Proliferação de Células , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Exossomos/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperinsulinismo/prevenção & controle , Hiperplasia/prevenção & controle , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , MicroRNAs/sangue , MicroRNAs/genética , Comunicação Parácrina , Transdução de Sinais
17.
Am J Physiol Endocrinol Metab ; 318(4): E579-E585, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101030

RESUMO

Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose-lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in nonhematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that were evident during a glucose tolerance test (GTT) in high-fat diet (HFD)-fed wild-type (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in nonhematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance but NOD2 activation in nonhematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.


Assuntos
Glicemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Microbiota , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Ativação Metabólica , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética
18.
Oxid Med Cell Longev ; 2020: 3071658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082477

RESUMO

This study is aimed at investigating the effect of different exercise loads on the reproductive function of obese male mice and the underlying mechanisms. Male mice with high-fat diet-induced obesity were divided into obesity control (OC), obesity moderate-load exercise (OME), and obesity high-load exercise (OHE) groups. The OME and OHE groups were subjected to swimming exercise 5 days per week over a duration of 8 weeks, with the exercise load progressively increased to 2 h per day in the OME group and 2 h twice per day in the OHE group. In the OC group mice without exercise regimen, we observed a decrease in mRNA expression of antioxidant enzymes, increase in free radical products, upregulation of mRNA and protein expression of nuclear factor-κB and proinflammatory cytokines, inhibition of mRNA and protein expression of testosterone synthases, decrease in the serum testosterone level and sperm quality, and increase in sperm apoptosis. Although both moderate-load exercise and high-load exercise reduced body fat, only moderate-load exercise effectively alleviated obesity-induced oxidative stress, downregulated the expression of nuclear factor-κB and proinflammatory cytokines, and reversed the decrease in mRNA and protein expression of testosterone synthases, serum testosterone level, and sperm quality. These changes were not observed in the OHE group mice. Obesity-induced testicular oxidative stress and inflammatory response decreased testosterone synthesis and sperm quality. Moderate-load exercise alleviated the negative effect of obesity on male reproductive function by decreasing testicular oxidative stress and inflammatory responses. Although high-load exercise effectively reduced body fat, its effects on alleviating oxidative stress and improving male reproductive function were limited.


Assuntos
Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Espermatozoides/metabolismo , Testículo/metabolismo , Testosterona/sangue , Animais , Apoptose/fisiologia , Peso Corporal/fisiologia , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glutationa Peroxidase/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , NF-kappa B/metabolismo , Obesidade/enzimologia , Obesidade/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Reprodução/fisiologia , Superóxido Dismutase-1/metabolismo , Natação
19.
Biochem Biophys Res Commun ; 524(3): 716-722, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035613

RESUMO

MicroRNAs are well acknowledged as key mediators in the development of chronic metabolic diseases, including NAFLD. However, their roles in hepatic lipid metabolism and fatty liver still remain well elucidated. Here, we found that miR-103 represses de novo lipogenesis (DNL) and dampens the development of obesity/diet-induced fatty liver through targeting at Fasn and Scd1 in mouse liver. miR-103, robustly amplified in obese livers, inhibits the expression of Fasn and Scd1 via directly interacting with their mRNA 3' untranslated regions. Upregulated miR-103 sufficiently reduces the expression of Fasn and Scd1 and blocks the lipid accumulation in oleate-incubated hepatocytes. Furthermore, specifically overexpressing miR-103 in mouse liver by adenovirus significantly inhibits hepatic DNL to repress HCD-promoted hepatic lipid contents as well as NAFLD development. Meanwhile, enforced expression of hepatic miR-103 also alleviates obesity-associated fatty liver via reducing Fasn and Scd1 in db/db mice. Together, our study reveals a critical role of miR-103 in lipid homeostasis of liver and pathogenesis of NAFLD.


Assuntos
Ácido Graxo Sintases/metabolismo , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Sequência de Bases , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/genética
20.
Environ Toxicol ; 35(6): 707-713, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32023008

RESUMO

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD-induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac-damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro-apoptotic proteins and decrease in the proteins of IGF-1R-survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Dieta Hiperlipídica/efeitos adversos , Diterpenos/farmacologia , Coração/efeitos dos fármacos , Obesidade/patologia , Andrographis/química , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Fármacos Cardiovasculares/isolamento & purificação , Diterpenos/isolamento & purificação , Masculino , Camundongos , Camundongos Obesos , Miocárdio/metabolismo , Miocárdio/patologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Transdução de Sinais
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