RESUMEN
Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of ß-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of ß-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and ß-cell senescence are worth investigating in clinical trials.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiazolidinedionas , Ratones , Animales , Ratones Obesos , Ácido 3-Hidroxibutírico , Glucemia/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/metabolismo , Insulina/metabolismo , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Tiazolidinedionas/uso terapéutico , Modelos Animales de Enfermedad , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Aumento de Peso , Dieta Alta en Grasa/efectos adversos , Insuficiencia Cardíaca/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
BACKGROUND: Obesity is a worldwide epidemic and is considered a risk factor of severe manifestation of Coronavirus Disease 2019 (COVID-19). The pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host responses to infection, re-infection, and vaccination in individuals with obesity remain incompletely understood. METHODS: Using the diet-induced obese (DIO) mouse model, we studied SARS-CoV-2 Alpha- and Omicron BA.1-induced disease manifestations and host immune responses to infection, re-infection, and COVID-19 mRNA vaccination. FINDINGS: Unlike in lean mice, Omicron BA.1 and Alpha replicated to comparable levels in the lungs of DIO mice and resulted in similar degree of tissue damages. Importantly, both T cell and B cell mediated adaptive immune responses to SARS-CoV-2 infection or COVID-19 mRNA vaccination are impaired in DIO mice, leading to higher propensity of re-infection and lower vaccine efficacy. However, despite the absence of neutralizing antibody, vaccinated DIO mice are protected from lung damage upon Omicron challenge, accompanied with significantly more IFN-α and IFN-ß production in the lung tissue. Lung RNAseq and subsequent experiments indicated that COVID-19 mRNA vaccination in DIO mice boosted antiviral innate immune response, including the expression of IFN-α, when compared to the nonvaccinated controls. INTERPRETATION: Our findings suggested that COVID-19 mRNA vaccination enhances host innate antiviral responses in obesity which protect the DIO mice to a certain degree when adaptive immunity is suboptimal. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Vacunas contra la COVID-19 , COVID-19 , Animales , Humanos , Ratones , SARS-CoV-2 , Ratones Obesos , Reinfección , Dieta , Obesidad , Anticuerpos Neutralizantes , Interferón-alfa , ARN Mensajero , Antivirales , Anticuerpos Antivirales , Vacunas de ARNmRESUMEN
BACKGROUND: Retarded wound healing in patients with obesity contributes to a risk of complications associated with vascular insufficiency and oxidative stress. The high cholesterol levels of patients with obesity are associated with apoptosis of engrafted umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). Melatonin contributes to the prevention of cholesterol accumulation in patients with obesity via a mechanism that is poorly understood. We therefore investigated the regulatory mechanism of melatonin in cholesterol-induced apoptosis. METHODS: The protective effects of melatonin on cholesterol-induced apoptosis were investigated in UCB-MSCs. We used a mouse model of induced obesity to show that melatonin treatment restored the survival rate of transplanted UCB-MSCs and their wound-healing capacity. The mean values of the treatment groups were compared with those of the control group using Student's t test, and differences among three or more groups were analyzed using one-way analysis of variance with Dunnett's multiple comparison test. RESULTS: Melatonin treatment increased the expression of ATP-binding cassette subfamily A member 1 (ABCA1), which reduced cholesterol accumulation and cholesterol-induced apoptosis. The mouse skin wound healing model showed that melatonin treatment restored the survival rate of transplanted UCB-MSCs and the wound-healing capacity of obese mice. Melatonin inhibited the expression of binding immunoglobulin protein (BiP) through the regulation of MT2/Sp1-dependent microRNA-597-5p. Melatonin decreased the co-localization of BiP with nuclear factor erythroid 2-related factor 1 (NRF1), which resulted in increased ABCA1 expression. CONCLUSION: Melatonin induced the efflux of intracellular cholesterol through ABCA1 to decrease apoptosis of UCB-MSCs via an MT2-dependent BiP/NRF1 pathway.
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Hipercolesterolemia , Melatonina , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Transportador 1 de Casete de Unión a ATP/genética , Animales , Apoptosis , Proteínas Portadoras , Humanos , Inmunoglobulinas , Melatonina/farmacología , RatonesRESUMEN
Non-alcoholic fatty liver disease is the accumulation of triglycerides in liver. In its malignant form, it can proceed to steatohepatitis, fibrosis, cirrhosis, cancer and ultimately liver impairment, leading to liver transplantation. In a previous study, ultrasound-induced thermal strain imaging (US-TSI) was used to distinguish between excised fatty livers from obese mice and non-fatty livers from control mice. In this study, US-TSI was used to quantify lipid composition of fatty livers in ob/ob mice (nâ¯=â¯28) at various steatosis stages. A strong correlation coefficient was observed (R2â¯=â¯0.85) between lipid composition measured with US-TSI and hepatic triglyceride content. Hepatic triglyceride content is used to quantify adipose tissue in liver. The ob/ob mice were divided into three groups based on the degree of steatosis that is used in clinics: none, mild and moderate. A non-parametric Kruskal-Wallis test was conducted to determine if US-TSI can potentially differentiate among the steatosis grades in non-alcoholic fatty liver disease.
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Tejido Adiposo/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismo , Ultrasonografía/métodos , Animales , Ratones , Ratones Obesos , Procesamiento de Señales Asistido por ComputadorRESUMEN
BACKGROUND: Obesity and adipose tissue expansion is characterized by a chronic state of systemic inflammation that contributes to disease. The neuropeptide, oxytocin, working through its receptor has been shown to attenuate inflammation in sepsis, wound healing, and cardiovascular disease. The current study examined the effects of chronic oxytocin infusions on adipose tissue inflammation in a murine model of obesity, the leptin receptor-deficient (db/db) mouse. METHODS: The effect of obesity on oxytocin receptor protein and mRNA expression in adipose tissue was evaluated by Western blotting and real-time polymerase chain reaction. Mice were implanted with osmotic minipumps filled with oxytocin or vehicle for 8 weeks. At study endpoint adipose tissue inflammation was assessed by measurement of cytokine and adipokine mRNA tissue levels, adipocyte size and macrophage infiltration via histopathology, and plasma levels of adiponectin and serum amyloid A as markers of systemic inflammation. RESULTS: The expression of adipose tissue oxytocin receptor was increased in obese db/db mice compared to lean controls. In adipose tissue oxytocin infusion reduced adipocyte size, macrophage infiltration, IL-6 and TNFα mRNA expression, and increased the expression of the anti-inflammatory adipokine, adiponectin. In plasma, oxytocin infusion reduced the level of serum amyloid A, a marker of systemic inflammation, and increased circulating adiponectin. CONCLUSIONS: In an animal model of obesity and diabetes chronic oxytocin treatment led to a reduction in visceral adipose tissue inflammation and plasma markers of systemic inflammation, which may play a role in disease progression.
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Oxitocina/farmacología , Paniculitis/tratamiento farmacológico , Adipocitos/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Interleucina-6/genética , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismoRESUMEN
AIMS: We aimed to explore the role of SIRT6 in Insulin resistance (IR). We are the first to investigate on this crucial relationship in an obese mouse model fed on a high-fat diet (HFD) and an IR model based on the mature 3T3-L1-derived adipocytes. MAIN METHODS: Western blotting (WB) and qPCR analysis were performed to evaluate the SIRT6 protein and mRNA expressions in HFD mice as well as IR cells. Injection of adenovirus encoding SIRT6 gene in HFD mice and transfection of pcDNA3-SIRT6 in IR cells increased the glucose uptake levels and insulin sensitivity. KEY FINDINGS: The positive regulatory effects of SIRT6 on transient receptor potential vallinoid 1 (TRPV1) in IR cells were confirmed by a mechanistic investigation at both protein and mRNA levels. Further, the overexpression of SIRT6 was found to activate the TRPV1/Calcitonin gene-related peptide (CGRP) signaling and upregulate the glucose transporter (GLUT) expression at protein and mRNA levels. Additionally, administration of the TRPV1 antagonist, SB-705498 repressed the insulin sensitivity upregulated by SIRT6 overexpression accompanied with the inhibition of CGRP and decrease in GLUT proportions. The results also showed that TRPV1 agonist, Capsaicin boosted the SIRT6-induced glucose uptake, CGRP production, and GLUT4 levels. SIGNIFICANCE: Overall, SIRT6 was concluded to be involved in the TRPV1-CGRP-GLUT4 signaling axis thus leading to increased glucose uptake and decreased IR in HFD mice and 3T3-L1 adipocytes. Therefore, in terms of obesity and diabetes, SIRT6 is a novel candidate for treating IR.
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Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Sirtuinas/metabolismo , Células 3T3-L1 , Adipocitos/metabolismo , Animales , Transporte Biológico , Péptido Relacionado con Gen de Calcitonina/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Obesidad/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MIN6 beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk.
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Cilios/genética , Diabetes Mellitus Tipo 2/genética , Células Secretoras de Insulina/metabolismo , Transcriptoma , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Células Cultivadas , Cilios/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cinesinas/genética , Cinesinas/metabolismo , Masculino , RatonesRESUMEN
Angelica keiskei koidzumi (ashitaba) is consumed as a traditional folk medicine and health food in Japan. Ashitaba extract contains abundant flavonoids containing chalcones. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue plasminogen activator. Excessive amounts of PAI-1 in plasma disrupt the fibrinolytic balance and promote a prothrombotic state with which thrombosis and cardiovascular diseases are associated. In the present study, we investigated the effects of ashitaba yellow exudate (AE) on enhanced PAI-1 levels in Tsumura Suzuki obese diabetic (TSOD) mice. AE significantly decreased food efficiency and plasma PAI-1 in TSOD mice but did not affect lean control Tsumura Suzuki nonobese (TSNO) mice. AE also decreased some parameters in the plasma, such as glucose, insulin, tumor necrosis factor alpha (TNF-α) and gains in body weight, subcutaneous, mesenteric fat weight in TSOD mice but had little effect on these parameters in TSNO mice. Levels of adipose PAI-1 were significantly higher in TSOD than in TSNO mice. Major sources of plasma PAI-1 are thought to be adipose tissue and liver. AE significantly suppressed PAI-1 protein levels in the livers of both TSOD and TSNO mice. These results suggest that AE decreased plasma PAI-1 levels by suppressing both the adipose tissue retention of PAI-1 protein and liver PAI-1 production in TSOD mice. Supplementing the diet with AE might help to prevent thrombotic diseases or alleviate the risk of thrombotic diseases as well as to suppress metabolic state in obese individuals.
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Angelica , Diabetes Mellitus Experimental/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Extractos Vegetales/farmacología , Inhibidor 1 de Activador Plasminogénico/efectos de los fármacos , Adiposidad/efectos de los fármacos , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/etiología , Exudados y Transudados , Masculino , Ratones , Ratones Obesos , Obesidad/sangre , Obesidad/complicaciones , Inhibidor 1 de Activador Plasminogénico/sangreRESUMEN
OBJECTIVE: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. METHODS: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). RESULTS: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. CONCLUSIONS: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH.
Asunto(s)
Metabolismo Energético , alfa-MSH/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mutación , Unión Proteica , Proteolisis , Receptor de Melanocortina Tipo 2/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Aumento de PesoRESUMEN
BACKGROUND/OBJECTIVES: The aim of this experiments was to show anti-obesity effects of Korean solar salt from different salt fields in diet-induced obese mice. SUBJECTS/METHODS: Diet-induced obesity (DIO) was induced by a high-fat diet (HFD; 45% cal from fat) in C57BL/6J mice for eight weeks. The mice were fed with the designated diets (chow diet for Normal, HFD for Control, 0.47%-salt-mixed HFD for purified salt (PS), Guerande solar salt from France (SS-G), solar salt from Y salt field (SS-Y), solar salts from T salt field (SS-T) and S salt field (SS-S)) for another eight weeks. We checked body weight, food efficiency ratio (FER) and tissue weights (liver and epididymal adipose tissue (EAT)), and observed serum concentrations of triacylglycerol (TG), total cholesterol (TC), leptin and insulin. We also evaluated gene expressions of adipogenic / lipogenic mRNAs of C/EBPα, PPARγ and FAS and beta-oxidation-related factors (PPARα and CPT-1) in liver and EAT. The mineral composition of salt samples were analyzed using inductively coupled plasma optical emission spectrometry (ICP-OES). RESULTS: SS-T and SS-S significantly reduced body weight gain, FER, and weight of EAT compared to control and other samples (P < 0.05). SS-T and SS-S also significantly decreased serum levels of TG, TC, leptin and insulin (P < 0.05). SS-T and SS-S suppressed expressions of adipogenic / lipogenic mRNAs in liver and EAT, while promoting expression of beta-oxidation-related factors. The lowest sodium concentration was observed in SS-T (30.30 ± 0.59%), and the lowest sodium-to-potassium (Na/K) ratio was found in SS-S (17.81). CONCLUSIONS: Our study shows that well-processed Korean solar salt may have anti-obesity effects in vivo, probably owing to its differences in mineral composition and other components, presumably resulting from the manufacturing processes. Further research is needed into the mechanism and to explore optimal manufacturing processes.
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Obesity, a state of chronic low-grade inflammation, is strongly associated with the development of hypertension and diabetes. Superoxide, a free radical elevated in obese individuals, promotes hypertension through scavenging the endogenous vasodilator nitric oxide. The hypothesis was a genistein-enriched diet would promote weight loss and reduce oxidative stress and inflammation in the vasculature of intact female ob/ob mice. Aortas and mesenteric arteries were isolated from female ob/ob mice fed genistein-free (0mg genistein/kg diet; n=6), standard chow (200-300mg genistein/kg diet; n=11) or genistein-enriched (600mg genistein/kg diet; n=9) diets for 4weeks. Sections of isolated vessels were labeled with the superoxide indicator dihydroethidium and fluorescence was measured by confocal microscopy. Protein expression of the inflammatory marker inducible nitric oxide synthase (iNOS) was measured in the perivascular adipose tissue (PVAT) surrounding each vessel and plasma concentrations of superoxide dismutase (SOD) were quantified. Genistein-enriched diet promoted less weight gain compared to animals fed standard chow (P=.008). Standard chow promoted increased superoxide in the aorta (P=.030) and mesenteric arteries (P=.024) compared to a diet devoid of genistein. At all tested concentrations, genistein significantly increased iNOS expression in mesenteric artery PVAT (vs. standard chow, P<.001; vs. genistein-enriched, P=.002) and tended to increase iNOS within the aortic PVAT (standard chow, P=.075) compared to the genistein-free group. Plasma SOD activity was significantly downregulated in genistein-enriched animals as compared to those fed a genistein-free diet (P=.028). In summary, although genistein prevents weight gain, it promotes vascular oxidative stress and inflammation in obese ovarian-intact female mice.
Asunto(s)
Tejido Adiposo , Genisteína/administración & dosificación , Inflamación/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Enfermedades Vasculares/inducido químicamente , Aumento de Peso/efectos de los fármacos , Tejido Adiposo/enzimología , Animales , Aorta/química , Aorta/efectos de los fármacos , Dieta , Femenino , Genisteína/efectos adversos , Hipertensión , Arterias Mesentéricas/química , Arterias Mesentéricas/efectos de los fármacos , Ratones , Ratones Obesos , Óxido Nítrico Sintasa de Tipo II/análisis , Obesidad , Superóxido Dismutasa/sangre , Superóxidos/análisisRESUMEN
BACKGROUND/OBJECTIVES: The aim of this experiments was to show anti-obesity effects of Korean solar salt from different salt fields in diet-induced obese mice. SUBJECTS/METHODS: Diet-induced obesity (DIO) was induced by a high-fat diet (HFD; 45% cal from fat) in C57BL/6J mice for eight weeks. The mice were fed with the designated diets (chow diet for Normal, HFD for Control, 0.47%-salt-mixed HFD for purified salt (PS), Guerande solar salt from France (SS-G), solar salt from Y salt field (SS-Y), solar salts from T salt field (SS-T) and S salt field (SS-S)) for another eight weeks. We checked body weight, food efficiency ratio (FER) and tissue weights (liver and epididymal adipose tissue (EAT)), and observed serum concentrations of triacylglycerol (TG), total cholesterol (TC), leptin and insulin. We also evaluated gene expressions of adipogenic / lipogenic mRNAs of C/EBPα, PPARγ and FAS and beta-oxidation-related factors (PPARα and CPT-1) in liver and EAT. The mineral composition of salt samples were analyzed using inductively coupled plasma optical emission spectrometry (ICP-OES). RESULTS: SS-T and SS-S significantly reduced body weight gain, FER, and weight of EAT compared to control and other samples (P < 0.05). SS-T and SS-S also significantly decreased serum levels of TG, TC, leptin and insulin (P < 0.05). SS-T and SS-S suppressed expressions of adipogenic / lipogenic mRNAs in liver and EAT, while promoting expression of beta-oxidation-related factors. The lowest sodium concentration was observed in SS-T (30.30 ± 0.59%), and the lowest sodium-to-potassium (Na/K) ratio was found in SS-S (17.81). CONCLUSIONS: Our study shows that well-processed Korean solar salt may have anti-obesity effects in vivo, probably owing to its differences in mineral composition and other components, presumably resulting from the manufacturing processes. Further research is needed into the mechanism and to explore optimal manufacturing processes.
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Animales , Ratones , Tejido Adiposo , Peso Corporal , Colesterol , Dieta , Dieta Alta en Grasa , Francia , Expresión Génica , Insulina , Leptina , Hígado , Ratones Obesos , Mineros , Obesidad , Plasma , ARN Mensajero , Sales (Química) , Sodio , Análisis Espectral , Triglicéridos , Pesos y MedidasRESUMEN
The effects of 5-aminolevulinic acid (5-ALA) on obesity were investigated using a murine model (diet-induced obese mice). Diet-induced obese mice were divided into 4 groups: a control group (C group), which was fed a high-fat diet; a low-5-ALA dose (10 mg/kg/day) group (10A group); a moderate-5-ALA dose (30 mg/kg/day) group (30A group); and a high-5-ALA dose (100 mg/kg/day) group (100A group). 5-ALA was administered by mixing the high fat diet for 8 weeks. Body weight increases in the 30A and 100A groups were significantly smaller compared with those of the C group. Body fat measurements by X-ray computed tomography indicated that the 100A group showed a tendency toward low visceral fat quantities during the final week of the study. Visceral fat weights in the 30A and 100A groups were slightly low. The levels of serum alanine aminotransferase (ALT) and total cholesterol (TC) in the 10A group was slightly low, whereas the 30A and 100A groups showed significantly lower ALT and TC values. Liver lipid concentration showed a dose-dependent decrease with ALA. Thus, in this diet-induced obese murine model, administration of 5-ALA had a significantly beneficial impact on the visceral fat, serum ALT and TC, and liver lipid concentration.
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Visceral obesity is an independent risk factor for metabolic syndrome, and abnormal fat accumulation is linked to increases in the number and size of adipocytes. MiR-146b was a miRNA highly expressed in mature adipocytes while very lowly expressed in human mesenchymal stem cells (hMSCs) and human visceral preadipocytes (vHPA). In this paper, we mainly focused on the roles of miR-146b in adipogenesis. We found miR-146b could inhibit the proliferation of visceral preadipocytes and promote their differentiation. MiR-146b in human visceral adipocytes inhibited the expression of KLF7, a member of the Kruppel-like transcription factors, as demonstrated by a firefly luciferase reporter assay, indicating that KLF7 is a direct target of the endogenous miR-146b. MiR-146b expression was significantly altered in visceral and subcutaneous adipose tissues in human overweight and obese subjects, and in the epididymal fat tissues and brown fat tissues of diet-induced obese mice. Our data indicates that miR-146b may be a new therapeutic target against human visceral obesity and metabolic dysfunction.
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Adipocitos/patología , Adipogénesis/genética , Diferenciación Celular , Regulación de la Expresión Génica , MicroARNs/metabolismo , Obesidad/genética , Animales , Western Blotting , Ciclo Celular/genética , Proliferación Celular , Humanos , Ratones , Ratones Obesos , MicroARNs/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVE: This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. MATERIAL/METHODS: Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. RESULTS: MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased ß-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. CONCLUSIONS: Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.
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Ácidos Grasos/metabolismo , Hígado Graso/prevención & control , Leptina/deficiencia , Metabolismo de los Lípidos , Hígado/metabolismo , Metionina/administración & dosificación , Metionina/farmacología , Obesidad/metabolismo , Ácido 3-Hidroxibutírico/sangre , Animales , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Dieta , Progresión de la Enfermedad , Hígado Graso/sangre , Hígado Graso/metabolismo , Hígado Graso/patología , Regulación de la Expresión Génica , Homeostasis , Inflamación/etiología , Inflamación/metabolismo , Insulina/metabolismo , Lipoproteínas VLDL/sangre , Masculino , Ratones , Ratones Obesos , Obesidad/sangre , Obesidad/patología , Oxidación-Reducción , Índice de Severidad de la Enfermedad , Triglicéridos/sangreRESUMEN
A hepatic nodule was noted in a C57BL/6J mouse with diet-induced obesity at 53 weeks of age. Macroscopically, a protruding yellowish white nodule was observed on the visceral surface of the left lateral lobe. Light microscopy demonstrated clear demarcation from the compressed adjacent parenchyma, with loss of the distinct lobular pattern. The proliferating cells of the lesion varied in shape and showed cellular atypia and prominent nucleoli along with vacuoles of various sizes. Some of the cells contained various-sized eosinophilic inclusion bodies in their cytoplasm, and electron microscopy revealed the presence of lipid droplets in the rough endoplasmic reticulum. Eosinophilic inclusions were observed as electron dense granular material in the rough endoplasmic reticulum, with one or a few low density central cores. A diagnosis of hepatocellular adenoma was made based on these findings.
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OBJECTIVES: There have been many studies on the relationship between diabetes mellitus and presbycusis. Microangiopathy and neuropathy that's caused by chronic hyperglycemia may lead to damage to the inner ear. Several clinical studies on humans and animal studies have been performed to investigate the association between diabetes and hearing loss, however, this relationship is still a matter of debate. We investigated the association of diabetes and sensorineural hearing loss in an animal model of type-2 diabetes and obesity (the ob/ob mouse [OM]). METHODS: The auditory brainstem response (ABR) thresholds were obtained in the OM and the wild type mice (C57BL/6J mice) up to 25 weeks after birth. After the animals were sacrificed, their cochleae were retrieved and then subjected to histopathologic observations. RESULTS: The OM exhibited significantly elevated ABR thresholds at 21 weeks of age, yet the C57BL/6J mice exhibited no significant change until 25 weeks of age. On the histological findings, outer hair cell degeneration and loss of spiral ganglion cells were observed in the middle and basal turns of the OM. On the contrary, no degenerative change was observed until 25 weeks of age in the C57BL/6J mice. CONCLUSION: This study suggests that chronic hyperglycemia and obesity may lead to early sensorineural hearing loss.
RESUMEN
OBJECTIVES: There have been many studies on the relationship between diabetes mellitus and presbycusis. Microangiopathy and neuropathy that's caused by chronic hyperglycemia may lead to damage to the inner ear. Several clinical studies on humans and animal studies have been performed to investigate the association between diabetes and hearing loss, however, this relationship is still a matter of debate. We investigated the association of diabetes and sensorineural hearing loss in an animal model of type-2 diabetes and obesity (the ob/ob mouse [OM]). METHODS: The auditory brainstem response (ABR) thresholds were obtained in the OM and the wild type mice (C57BL/6J mice) up to 25 weeks after birth. After the animals were sacrificed, their cochleae were retrieved and then subjected to histopathologic observations. RESULTS: The OM exhibited significantly elevated ABR thresholds at 21 weeks of age, yet the C57BL/6J mice exhibited no significant change until 25 weeks of age. On the histological findings, outer hair cell degeneration and loss of spiral ganglion cells were observed in the middle and basal turns of the OM. On the contrary, no degenerative change was observed until 25 weeks of age in the C57BL/6J mice. CONCLUSION: This study suggests that chronic hyperglycemia and obesity may lead to early sensorineural hearing loss.