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1.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203825

RESUMO

Obesity is closely related to insulin resistance and type 2 diabetes genesis. The liver is a key organ to glucose homeostasis since insulin resistance in this organ increases hepatic glucose production (HGP) and fasting hyperglycemia. The protein-tyrosine phosphatase 1B (PTP1B) may dephosphorylate the IR and IRS, contributing to insulin resistance in this organ. Aerobic exercise is a great strategy to increase insulin action in the liver by reducing the PTP1B content. In contrast, no study has shown the direct effects of strength training on the hepatic metabolism of PTP1B. Therefore, this study aims to investigate the effects of short-term strength exercise (STSE) on hepatic insulin sensitivity and PTP1B content in obese mice, regardless of body weight change. To achieve this goal, obese Swiss mice were submitted to a strength exercise protocol lasting 15 days. The results showed that STSE increased Akt phosphorylation in the liver and enhanced the control of HGP during the pyruvate tolerance test. Furthermore, sedentary obese animals increased PTP1B content and decreased IRS-1/2 tyrosine phosphorylation; however, STSE was able to reverse this scenario. Therefore, we conclude that STSE is an important strategy to improve the hepatic insulin sensitivity and HGP by reducing the PTP1B content in the liver of obese mice, regardless of changes in body weight.


Assuntos
Peso Corporal , Resistência à Insulina , Condicionamento Físico Animal , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Adiposidade , Animais , Regulação para Baixo , Glucose/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Camundongos Obesos , Treinamento de Força , Transdução de Sinais
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206460

RESUMO

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.


Assuntos
Cromo/deficiência , Clozapina/farmacologia , Intolerância à Glucose/metabolismo , Nefropatias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Doenças Retinianas/metabolismo , Adipócitos/metabolismo , Animais , Biomarcadores , Pesos e Medidas Corporais , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/genética , Imunofluorescência , Expressão Gênica , Regulação da Expressão Gênica , Imuno-Histoquímica , Insulina/metabolismo , Nefropatias/etiologia , Fígado/metabolismo , Camundongos , Camundongos Obesos , Óxido Nítrico Sintase Tipo II , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Retinianas/etiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
4.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207032

RESUMO

The gastrointestinal tract is a heterogeneous ecosystem with distinct, stratified environments, which leads to different microbial composition in different intestinal segments. The regional heterogeneity of intestinal microbiota complicates the relationship between diet and microbiota. Few studies have focused on the effects of different diets on microbiota in different intestinal segments. This study aimed to investigate the effects of functional fiber on the microbial composition in multiple intestinal segments from a high-fat diet compared with a normal chow diet. We found that the response of microbiota from different intestinal segments to diet was related to the intestinal physiologic function and the physicochemical properties of dietary nutrients. A high-fat diet drove changes in the microbial composition in the hindgut, possibly by affecting the digestive environment of the foregut, and increased the regional heterogeneity of the whole intestinal microbiota. The supplementation of functional fiber promoted the microbial transfer and colonization from the anterior to the posterior intestinal segments, and increased the regional similarity of intestinal microbiota accordingly, particularly within the hindgut. The gut fermentation of the functional fiber, which mainly occurred in the hindgut, resulted in a significant change in the microbial composition and metabolism in the cecum and colon, with richer carbohydrate metabolism-related bacteria, including Mucispirillum, Prevotella, Anaerostipes, Oscillospira, Ruminococcus, Bacteroides, Coprococcus, Ruminococcus (Lachnospiraceae), and Allobaculum, and higher production of acetate and butyrate. We concluded that multiple regulatory mechanisms of diets which affect microbiota composition exist, including microbial metabolism, microbial migration, and the regulation of the intestinal environment.


Assuntos
Fibras na Dieta , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Obesidade/etiologia , Obesidade/metabolismo , Animais , Biodiversidade , Ceco/metabolismo , Ceco/microbiologia , Colo/metabolismo , Colo/microbiologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Camundongos , Camundongos Obesos , Especificidade de Órgãos
5.
FASEB J ; 35(7): e21730, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34110631

RESUMO

Adipose tissue macrophages (ATMs) represent the most abundant leukocytes in adipose tissue (AT). An increase in number and a phenotypical switch of ATMs during the development of obesity contribute to chronic inflammation and metabolic disorders, which have been regarded as potential therapeutic targets to restore AT homeostasis. Emodin has been shown to exert strong anti-inflammatory property via acting on macrophages in a range of disease models. However, whether emodin exerts a beneficial effect on obesity via modulating ATMs has not been reported. In high-fat diet (HFD)-induced obese mice, emodin significantly inhibited the increase of body weight and lipid accumulation in ATs. Emodin apparently reduced glucose and insulin levels and ameliorated serum lipid profiles in HFD-fed mice. Moreover, the local and systemic inflammation was dramatically alleviated by emodin. We next discovered that M2 macrophage percentage was greatly increased by emodin although total ATMs was not altered, which resulted in a net increase of M2 macrophages in AT. In vitro studies confirmed that emodin promoted the polarization of macrophages towards M2. Gene ontology (GO) analysis showed that myeloid leukocyte differentiation and activation were among the most significant biological processes in emodin-treated ATMs. We further identified that TREM2 was the most dramatically upregulated molecule by emodin and emodin-induced M2 macrophage polarization was dependent on TREM2. Furthermore, silencing TREM2 apparently abrogated the effect of emodin on AT inflammation and adipogenesis. We, for the first time, disclosed that emodin inhibited obesity by promoting M2 macrophage polarization via TREM2, suggesting that emodin may be explored as a clinical and translational candidate in preventing obesity and its related metabolic diseases.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Emodina/farmacologia , Inflamação/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/fisiologia , Macrófagos/efeitos dos fármacos , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Linhagem Celular , Dieta Hiperlipídica , Inflamação/metabolismo , Insulina/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo
6.
FASEB J ; 35(7): e21734, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143451

RESUMO

Impaired glucose homeostasis in obesity is mitigated by enhancing the glucoregulatory actions of glucagon-like peptide 1 (GLP-1), and thus, strategies that improve GLP-1 sensitivity and secretion have therapeutic potential for the treatment of type 2 diabetes. This study shows that Holdemanella biformis, isolated from the feces of a metabolically healthy volunteer, ameliorates hyperglycemia, improves oral glucose tolerance and restores gluconeogenesis and insulin signaling in the liver of obese mice. These effects were associated with the ability of H. biformis to restore GLP-1 levels, enhancing GLP-1 neural signaling in the proximal and distal small intestine and GLP-1 sensitivity of vagal sensory neurons, and to modify the cecal abundance of unsaturated fatty acids and the bacterial species associated with metabolic health. Our findings overall suggest the potential use of H biformis in the management of type 2 diabetes in obesity to optimize the sensitivity and function of the GLP-1 system, through direct and indirect mechanisms.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Firmicutes/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Camundongos Obesos/metabolismo , Camundongos Obesos/microbiologia , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Gluconeogênese/fisiologia , Glucose/metabolismo , Teste de Tolerância a Glucose/métodos , Hiperglicemia/metabolismo , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia
7.
In Vivo ; 35(4): 2107-2114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34182486

RESUMO

BACKGROUND/AIM: Οverweight and obesity are risk factors for chronic diseases. Dietary calcium has been reported to exert anti-obesity effects. However, the complex modulating effects of calcium intake on obese mice have not been clarified. MATERIALS AND METHODS: The effects of calcium intake on body weight/visceral fat mass were examined in the obese mouse model, KK-Ay Results: Body weight gain decreased in mice fed a diet containing 0.4 to 3.2% calcium at the age of 11 and 13 weeks, but not at 12 weeks after normalization for food intake. Calcium intake also decreased serum insulin levels and increased the amount of feces excreted. Fecal deoxycholate levels were lower in the high-calcium group than in the normal diet control group. Furthermore, the ratio of the deoxycholate-producing microbiome in feces decreased. CONCLUSION: Dietary calcium has anti-obesity effects in obese KK-Ay mice. Inhibition of insulin production and an increased amount of feces excreted with calcium intake may affect body weight.


Assuntos
Cálcio na Dieta , Obesidade , Animais , Peso Corporal , Dieta , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia
8.
Stem Cell Res Ther ; 12(1): 364, 2021 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174964

RESUMO

BACKGROUND: Obesity is a metabolic disorder syndrome characterized by excessive fat accumulation that is related to many diseases. Human amniotic mesenchymal stem cells (hAMSCs) have a great potential for cell-based therapy due to their characteristics such as pluripotency, low immunogenicity, no tumorigenicity, potent paracrine effects, and no ethical concern. Recently, we observed that both hAMSCs and their conditioned medium (hAMSCs-CM) efficiently repaired skin injury, inhibited hepatocellular carcinoma, and alleviated high-fat diet (HFD)-induced diabetes. However, the effects and the underlying mechanisms of hAMSCs-CM on high-fat diet (HFD)-induced obesity were not explored. METHODS: The characteristics of hAMSCs were confirmed by flow cytometry, RT-PCR, and immunofluorescence. Obese mice were induced by administrating HFD for 15 weeks and simultaneously, the mice were intraperitoneally injected with hAMSCs-CM weekly to evaluate the effects of hAMSCs-CM on HFD-induced obesity. GTT and ITT assays were used to assess the effects of hAMSCs-CM on HFD-induced glucose tolerance and insulin resistance. The lipid accumulation and adipocytes hypertrophy in mouse adipose tissues were determined by histological staining, in which the alterations of blood lipid, liver, and kidney function were also examined. The role of hAMSCs-CM in energy homeostasis was monitored by examining the oxygen consumption (VO2), carbon dioxide production (VCO2), and food and water intake in mice. Furthermore, the expressions of the genes related to glucose metabolism, fatty acid ß oxidation, thermogenesis, adipogenesis, and inflammation were determined by western blot analysis, RT-PCR, and immunofluorescence staining. The roles of hAMSCs-CM in adipogenesis and M1/M2 macrophage polarization were investigated with 3T3-L1 preadipocytes or RAW264.7 cells in vitro. RESULTS: hAMSCs-CM significantly restrained HFD-induced obesity in mice by inhibiting adipogenesis and lipogenesis, promoting energy expenditure, and reducing inflammation. The underlying mechanisms of the anti-obesity of hAMSCs-CM might be involved in inhibiting PPARγ and C/EBPα-mediated lipid synthesis and adipogenesis, promoting GLUT4-mediated glucose metabolism, elevating UCP1/PPARα/PGC1α-regulated energy expenditure, and enhancing STAT3-ARG1-mediated M2-type macrophage polarization. CONCLUSION: Our studies demonstrated that hAMSCs significantly alleviated HFD-induced obesity through their paracrine effects. Obviously, our results open up an attractive therapeutic modality for the prevention and treatment of obesity and other metabolic disorders clinically. The cytokines, exosomes, or micro-vesicles secreted from hAMSCs significantly inhibited HFD-induced obesity in mice by inhibiting lipid production and adipogenesis, promoting energy consumption, and reducing inflammation.


Assuntos
Dieta Hiperlipídica , Células-Tronco Mesenquimais , Células 3T3-L1 , Adipogenia , Animais , Meios de Cultivo Condicionados/farmacologia , Dieta Hiperlipídica/efeitos adversos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/terapia
9.
Microbiome ; 9(1): 147, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183063

RESUMO

BACKGROUND: Leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although ob/ob and db/db mice are similarly gaining weight and developing massive obesity, db/db mice are more diabetic than ob/ob mice. It remains still unclear why targeting the same pathway-leptin signaling-leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in ob/ob and db/db mice. RESULTS: Six-week-old ob/ob and db/db mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between ob/ob and db/db mice. Strikingly, the fat distribution was different, with db/db mice having more subcutaneous and ob/ob mice having more epididymal fat. In addition, liver steatosis was more pronounced in the ob/ob mice than in db/db mice. We also found very distinct inflammatory profiles between ob/ob and db/db mice, with a more pronounced inflammatory tone in the liver for ob/ob mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for db/db mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes. CONCLUSION: Taken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition. Video abstract.


Assuntos
Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Tipo 2/genética , Leptina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade
10.
J Food Biochem ; 45(7): e13808, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34075620

RESUMO

Vaccinium bracteatum Thunb. fruits have been used as traditional food. This study investigated the effects of a polyphenol-rich Vaccinium bracteatum Thunb. fruit extract (VBTE) on obesity and obesity-related diseases in mice, and the potential role of the gut microbiota in the bioactivity of VBTE was also determined. Chemical constituents of the VBTE were analyzed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS). C57BL/6J mice (weighing 17.8-21.6 g) were fed a low-fat diet (LFD) or high-fat diet (HFD) with or without VBTE treatment for 14 weeks. The gut microbial changes were determined using 16S rRNA sequencing. Our results showed that VBTE mainly contains 36 kinds of polyphenols. VBTE reduced HFD-induced body weight gain by 33.42% (p < .05), steatosis scores by 56.25% (p < .05), and insulin resistance index by 51.49% (p < .05). Moreover, VBTE altered the composition of the gut microbiota. The correlation analysis indicated that Akkermansia, Alistipes, Bacteroides, Alloprevotella, Ruminiclostridium, Ruminiclostridium_9, and Rikenellaceae_RC9_gut_group were negatively correlated with serum lipids, glucose, and insulin, while Escherichia-Shigella was positively associated with these clinical indicators. In conclusion, VBTE supplement could reduce obesity and be a treatment option for obesity-related diseases by influencing the gut microbiota in mice. PRACTICAL APPLICATIONS: Plant extracts are widely used to treat obesity and related metabolic disorders. Polyphenols, the well-known natural antioxidants present in fruits, are consumed as a dietary supplement to prevent many diseases. Recent pharmacological studies have reported that Vaccinium bracteatum Thunb. fruits have many physiological functions, such as anti-proliferative, anti-inflammatory, and antidepressant-like effects. Despite these properties of Vaccinium bracteatum Thunb. fruits, their anti-obesity effect has not been studied to date. The findings of this study will support VBTE could be used as an important therapeutic application for preventing obesity and related metabolic diseases by modulating the gut microbiota.


Assuntos
Microbioma Gastrointestinal , Vaccinium myrtillus , Animais , Dieta Hiperlipídica/efeitos adversos , Frutas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Extratos Vegetais/farmacologia , RNA Ribossômico 16S/genética , Espectrometria de Massas em Tandem
11.
Nat Commun ; 12(1): 3997, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183666

RESUMO

Despite obesity being a predisposing factor for pancreatic ß-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood. In this study, we identify an islet-enriched long non-coding RNA (lncRNA), which we name ß-cell function and apoptosis regulator (ßFaar). ßFaar is dramatically downregulated in the islets of the obese mice, and a low level of ßFaar is necessary for the development of obesity-associated ß-cell dysfunction and apoptosis. Mechanistically, ßFaar promote the synthesis and secretion of insulin by upregulating islet-specific genes Ins2, NeuroD1, and Creb1 through sponging miR-138-5p. In addition, using quantitative mass spectrometry, we identify TRAF3IP2 and SMURF1 as interacting proteins that are specifically associated with ßFaar. We demonstrate that SMURF1 ubiquitin ligase activity is essential for TRAF3IP2 ubiquitination and activation of NF-κB-mediate ß-cell apoptosis. Our experiments provide direct evidence that dysregulated ßFaar contributes to the development of obesity-induced ß-cell injury and apoptosis.


Assuntos
Apoptose/genética , Células Secretoras de Insulina/metabolismo , Insulina/biossíntese , Obesidade/patologia , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/genética , Secreção de Insulina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/genética , NF-kappa B/metabolismo , Obesidade/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia
12.
J Med Food ; 24(6): 666-669, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34077672

RESUMO

Obesity is defined as excess adipose mass that causes serious health problems. Phenethyl isothiocyanate (PEITC) is a major and relatively nontoxic compound of the isothiocyanates. Although many studies have demonstrated that PEITC is a potent substance with physiological activities, such as anticancer activity, the precise mechanism for the effects of PEITC on inflammation and lipid metabolism in adipose tissue is not clear. Our study aimed to clarify the effects of PEITC supplements on the adipose tissue in obesity induced with a high-fat/cholesterol diet, and the underlying mechanisms. We induced obesity by feeding the mice with high fat with 1% cholesterol diet (HFCD) for 13 weeks. Mice were divided into five groups: normal diet (CON), HFCD, HFCD with 3 mg/(kg·d) gallic acid (HFCD+G), and HFCD with 30 and 75 mg/(kg·d) PEITC (HFCD+P30 and HFCD+P75, respectively). Using western blotting and quantitative polymerase chain reaction (qPCR) analysis of the adipose tissue, we determined the expression of lipid metabolism-related genes and inflammation-related genes. In the HFCD, the expression level of nuclear factor-κB (NF-κB), lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), and cyclooxygenase-2 (COX-2), was higher compared with that in the CON. Moreover, in the HFCD, the expression of p-mechanical targets of the rapamycin (mTOR) was increased, whereas that of p-AMP-activated protein kinase (AMPK) was decreased compared with that in the CON. Nevertheless, these decreased expression levels of p-AMPK and increased levels of LOX-1, p-mTOR, peroxisome proliferator-activated receptor gamma (PPARγ), NF-κB, and COX-2, were alleviated by PEITC supplementation. Therefore, we suggest that PEITC might be a potential preventive agent for ameliorating obesity-induced inflammation and adipogenesis by modulating the mTOR/AMPK/PPARγ pathway.


Assuntos
Metabolismo dos Lipídeos , PPAR gama , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Inflamação/genética , Inflamação/metabolismo , Isotiocianatos/metabolismo , Camundongos , Camundongos Obesos , PPAR gama/genética , PPAR gama/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
13.
Nat Commun ; 12(1): 3388, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099676

RESUMO

Wearable smart electronic devices, such as smart watches, are generally equipped with green-light-emitting diodes, which are used for photoplethysmography to monitor a panoply of physical health parameters. Here, we present a traceless, green-light-operated, smart-watch-controlled mammalian gene switch (Glow Control), composed of an engineered membrane-tethered green-light-sensitive cobalamin-binding domain of Thermus thermophilus (TtCBD) CarH protein in combination with a synthetic cytosolic TtCBD-transactivator fusion protein, which manage translocation of TtCBD-transactivator into the nucleus to trigger expression of transgenes upon illumination. We show that Apple-Watch-programmed percutaneous remote control of implanted Glow-controlled engineered human cells can effectively treat experimental type-2 diabetes by producing and releasing human glucagon-like peptide-1 on demand. Directly interfacing wearable smart electronic devices with therapeutic gene expression will advance next-generation personalized therapies by linking biopharmaceutical interventions to the internet of things.


Assuntos
Proteínas de Bactérias/efeitos da radiação , Diabetes Mellitus Tipo 2/terapia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Optogenética/métodos , Transativadores/efeitos da radiação , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Engenharia Celular , Diabetes Mellitus Tipo 2/genética , Feminino , Engenharia Genética , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Humanos , Luz , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Obesos , Optogenética/instrumentação , Fotopletismografia/instrumentação , Domínios Proteicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/efeitos da radiação , Thermus thermophilus/genética , Transativadores/genética , Transativadores/metabolismo , Transgenes , Dispositivos Eletrônicos Vestíveis
14.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073834

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid ß-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos/metabolismo , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Acetil-CoA Carboxilase/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Peso Corporal , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Ácido Graxo Sintases/metabolismo , Insulina/sangue , Resistência à Insulina/fisiologia , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Obesidade/metabolismo , Receptores Purinérgicos P2Y2/deficiência , Receptores Purinérgicos P2Y2/genética , Estearoil-CoA Dessaturase/metabolismo
15.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065474

RESUMO

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/-) mice were constructed. Zfp217+/- mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/- mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/- mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/- mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/- mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.


Assuntos
Metabolismo Energético/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Transativadores/metabolismo , Adipócitos Brancos/metabolismo , Adipócitos Brancos/fisiologia , Adipogenia/fisiologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Animais , Dieta Hiperlipídica , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Termogênese/fisiologia , Ganho de Peso/fisiologia
16.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063911

RESUMO

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model).


Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Transdução de Sinais/fisiologia , Animais , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos Obesos/metabolismo
17.
FASEB J ; 35(6): e21612, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33948996

RESUMO

Lipid overload is intimately connected with the change of endothelial epigenetic status which impacts cellular signaling activities and endothelial function. Activating transcription factor 4 (ATF4) is involved in the regulation of lipid metabolism and meanwhile an epigenetic modifier. However, the role of ATF4 in the angiogenesis under lipid overload is not well understood. Here, to induce lipid overload status, we employed high-fat diet (HFD)-induced obese mouse model in vivo and palmitic acid (PA) to stimulate endothelial cells in vitro. Compared with mice fed with normal chow diet (NCD), HFD-induced obese mice showed angiogenic defects evidenced by decline in (1) blood flow recovery after hind limb ischemia, (2) wound healing speed after skin injury, (3) capillary density in injured tissues and matrigel plugs, and (4) endothelial sprouts of aortic ring. ATF4 deficiency aggravated above angiogenic defects in mice while ATF4 overexpression improved the blunted angiogenic response. Mechanistically, lipid overload lowered the H3K4 methylation levels at the regulatory regions of NOS3 and ERK1 genes, leading to reduced angiogenic signaling activity. Methionine adenosyltransferase 2A (MAT2A) is identified as a target of ATF4 and formed complex with ATF4 to direct lysine methyltransferase 2A (MLL1) to the regulatory regions of both genes for the maintenance of the H3K4 methylation level and angiogenic signaling activity. Here, we uncovered a novel metabolic-epigenetic coupling orchestrated by the ATF4-MAT2A axis for angiogenesis. The ATF4-MAT2A axis links lipid overload milieu to altered epigenetic status of relevant angiogenic signaling in endothelial cells, suggesting a potential therapeutic target for angiogenesis impaired by lipid overload.


Assuntos
Fator 4 Ativador da Transcrição/fisiologia , Epigênese Genética , Isquemia/patologia , Lipídeos/efeitos adversos , Metionina Adenosiltransferase/metabolismo , Neovascularização Patológica/patologia , Obesidade/complicações , Animais , Dieta Hiperlipídica , Isquemia/etiologia , Isquemia/metabolismo , Masculino , Metionina Adenosiltransferase/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo
18.
FASEB J ; 35(6): e21608, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33977593

RESUMO

The mechanisms underpinning beta-cell compensation for obesity-associated insulin resistance and beta-cell failure in type 2 diabetes remain poorly understood. We used a large-scale strategy to determine the time-dependent transcriptomic changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice at 6 and 16 weeks of age. Differentially expressed genes were subjected to cluster, gene ontology, pathway and gene set enrichment analyses. A distinctive gene expression pattern was observed in 16 week db/db islets in comparison to the other groups with alterations in transcriptional regulators of islet cell identity, upregulation of glucose/lipid metabolism, and various stress response genes, and downregulation of specific amino acid transport and metabolism genes. In contrast, ob/ob islets displayed a coordinated downregulation of metabolic and stress response genes at 6 weeks of age, suggestive of a preemptive reconfiguration in these islets to lower the threshold of metabolic activation in response to increased insulin demand thereby preserving beta-cell function and preventing cellular stress. In addition, amino acid transport and metabolism genes were upregulated in ob/ob islets, suggesting an important role of glutamate metabolism in beta-cell compensation. Gene set enrichment analysis of differentially expressed genes identified the enrichment of binding motifs for transcription factors, FOXO4, NFATC1, and MAZ. siRNA-mediated knockdown of these genes in MIN6 cells altered cell death, insulin secretion, and stress gene expression. In conclusion, these data revealed novel gene regulatory networks involved in beta-cell compensation and failure. Preemptive metabolic reconfiguration in diabetes-resistant islets may dampen metabolic activation and cellular stress during obesity.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Células Secretoras de Insulina/patologia , Obesidade/fisiopatologia , Transcriptoma , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Obesos
19.
Bone ; 150: 116008, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33992820

RESUMO

The impact of diabetes mellitus on bone fracture healing is clinically relevant as the patients experience delayed fracture healing. Even though efforts have been made to understand the detrimental effects of type 2 diabetes mellitus (T2DM) on the fracture healing process, the exact mechanisms causing the pathophysiological outcomes remain unclear. The aim of this study was to assess alterations in bone fracture healing (tibial fracture surgery, intramedullary pinning) of diet-induced obese (DIO) mice, and to investigate the in vitro properties of osteochondroprogenitors derived from the diabetic micro-environment. High-resolution contrast-enhanced microfocus X-ray computed tomography (CE-CT) enabled a simultaneous 3D assessment of the amount and spatial distribution of the regenerated soft and hard tissues during fracture healing and revealed that osteogenesis as well as chondrogenesis are altered in DIO mice. Compared to age-matched lean controls, DIO mice presented a decreased bone volume fraction and increased callus volume and adiposity at day 14 post-fracture. Of note, bone turnover was found altered in DIO mice relative to controls, evidenced by decreased blood serum osteocalcin and increased serum CTX levels. The in vitro data revealed that not only the osteogenic and adipogenic differentiation of periosteum-derived cells (PDCs) were altered by hyperglycemic (HG) conditions, but also the chondrogenic differentiation. Elevated PPARγ expression in HG conditions confirmed the observed increase in differentiated adipocytes in vitro. Finally, chondrogenesis-related genes COL2 and COL10 were downregulated for PDCs treated with HG medium, confirming that chondrogenic differentiation is compromised in vitro and suggesting that this may affect callus formation and maturation during the fracture healing process in vivo. Altogether, these results provide novel insights into the alterations of long bone fracture repair and suggest a link between HG-induced dysfunctionality of osteochondroprogenitor differentiation and fracture healing impairment under T2DM conditions.


Assuntos
Diabetes Mellitus Tipo 2 , Consolidação da Fratura , Animais , Calo Ósseo/diagnóstico por imagem , Dieta , Humanos , Camundongos , Camundongos Obesos , Osteogênese , Tomografia , Tomografia Computadorizada por Raios X
20.
Stem Cell Res Ther ; 12(1): 277, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957965

RESUMO

Changes that occur to the stem cell microenvironment with disease are a major consideration that may affect the behavior and potential therapeutic efficacy of mesenchymal stem cells (MSCs). The purpose of this study is to evaluate the effects of adipose-derived MSCs (ADSCs) from obese mice with hyperglycemia on body weight and glucose homeostasis. After 10 weeks of high-fat diet, mice were injected with phosphate-buffered saline (PBS) and ADSCs derived from normal mice (N-ADSCs) or obese mice (O-ADSCs), respectively. Mice fed with standard rodent chow were injected with PBS and served as normal controls. Obese mice treated with O-ADSCs showed less body weight gain than those receiving PBS or N-ADSCs. The mice that received ADSCs, especially O-ADSCs, also showed improvement in obesity-related hyperglycemia. In particular, the inguinal fat was reduced in obese mice receiving O-ADSCs compared with other groups, probably caused by the increased lipolysis of inguinal fat. Moreover, ADSC infusion restored insulin receptor (INSR) expression in the muscle of obese mice. Differential expression of the CD90 surface marker was slightly increased, while monocyte chemoattractant protein 1 (MCP-1) was reduced in O-ADSCs compared to N-ADSCs. These data provide a theoretical basis that autologous ADSCs from obese individuals may be more effective for treating obesity and related hyperglycemia.


Assuntos
Hiperglicemia , Células-Tronco Mesenquimais , Tecido Adiposo , Animais , Hiperglicemia/terapia , Camundongos , Camundongos Obesos , Obesidade/terapia
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