RESUMEN
The angiotensin II (ANG II)-ANG II type 1 receptor (AT1R) axis is a key player in the pathophysiology of obesity. Angiotensin-converting enzyme 2 (ACE2) counteracts the ANG II/AT1R axis via converting ANG II to angiotensin 1-7 (Ang 1-7), which is known to have an anti-obesity effect. In this study, we hypothesized that ACE2 exerts a strong anti-obesity effect by increasing Ang 1-7 levels. We injected intraperitoneally recombinant human ACE2 (rhACE2, 2.0 mg·kg-1·day-1) for 28 days to high-fat diet (HFD)-induced obesity mice. rhACE2 treatment decreased body weight and improved glucose metabolism. Furthermore, rhACE2 increased oxygen consumption and upregulated thermogenesis in HFD-fed mice. In the rhACE2 treatment group, brown adipose tissue (BAT) mass increased, accompanied with ameliorated insulin signaling and increased protein levels of uncoupling protein-1 (UCP-1) and PRD1-BF1-RIZ1 homologous domain containing 16. Importantly, subcutaneous white adipose tissue (sWAT) mass decreased, concomitant with browning, which was established by the increase of UCP-1 expression. The browning is the result of increased H3K27 acetylation via the downregulation of histone deacetylase 3 and increased H3K9 acetylation via upregulation of GCN5 and P300/CBP-associated factor. These results suggest that rhACE2 exerts anti-obesity effects by stimulating BAT and inducing browning in sWAT. ACE2 and the Ang 1-7 axis represent a potential therapeutic approach to prevent the development of obesity.
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Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Angiotensina I/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Obesidad/metabolismo , Fragmentos de Péptidos/efectos de los fármacos , Peptidil-Dipeptidasa A/farmacología , Termogénesis/efectos de los fármacos , Acetilación/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Angiotensina I/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Dieta Alta en Grasa , Regulación hacia Abajo , Código de Histonas/efectos de los fármacos , Histona Desacetilasas/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fragmentos de Péptidos/metabolismo , Proteínas Recombinantes , Grasa Subcutánea/efectos de los fármacos , Grasa Subcutánea/metabolismo , Proteína Desacopladora 1/efectos de los fármacos , Proteína Desacopladora 1/metabolismo , Factores de Transcripción p300-CBP/efectos de los fármacos , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Erythropoietin (EPO) has been reported to exert a beneficial effect on glucose metabolism in obesity. However, the effect of EPO on lipid metabolism and non-alcoholic fatty liver disease (NAFLD) was unclear. Furthermore, the effect of long acting erythropoiesis stimulating agents (ESA) on metabolism has not been poorly understood. The objective of this study was to investigate the effect of EPO and long acting ESA on NAFLD and lipid metabolism. We administered EPO and darbepoetin alpha (DEPO), a long acting ESA, by intraperitoneally injection for 4 weeks to mice with high-fat-diet (HFD)-induced obesity. EPO and DEPO treatment reduced body weight, ameliorated glucose tolerance and insulin resistance, and prevented lipid accumulation in liver and white adipose tissue (WAT). Administration of EPO and DEPO suppressed lipid synthesis-related protein in liver, including sterol regulatory element-binding protein 1 (SREBP-1), acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS). EPO and DEPO also increased lipolysis protein in visceral WAT, including hormone-sensitive lipase (HSL), atni-adipose triglyceride lipase (ATGL). EPO and DEPO increased phosphorylation signal transducer and activator of transcription 3 (STAT3) and STAT5, transcriptional factors with crucial roles of lipid metabolism. These data suggest that EPO and DEPO ameliorated NAFLD by improving lipid metabolism via EPO/EPOR-induced STAT3 and STAT5 activation. EPO and DEPO may be a therapeutic option for NAFLD.
Asunto(s)
Darbepoetina alfa/uso terapéutico , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Lipogénesis/efectos de los fármacos , Lipólisis/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Receptores de Eritropoyetina/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A 14-year-old girl was referred to our department because of headache and visual impairment following the resection of recurrent cardiac myxoma. Head magnetic resonance imaging (MRI) scan detected an intra- and supra-sellar tumor. Moreover, the patient showed the presence of spotty skin pigmentations on her cheeks and lower lip. Blood examination revealed hypothyrotropinemia, and ultrasonography results revealed multiple thyroid nodules. She was diagnosed with Carney complex (CNC). Her pituitary tumor was suspected as growth hormone (GH)-secreting adenoma, because overgrowth was observed in the patient. However, biochemical examinations, including oral glucose tolerance test, failed to show the characteristic findings of GH-secreting adenoma. In contrast, insulin tolerance test showed GH deficiency. Her visual impairment improved without performing decompression surgery, and the tumor size decreased, as per the MRI findings. Based on clinical course, the patient was diagnosed with pituitary apoplexy in pituitary adenoma, following which she was discharged. At 3 months after discharge, thyrotropin-releasing hormone loading test performed revealed low thyrotropin-stimulating hormone and thyroid hormone levels, and the patient was in a depressed mood. Therefore, l-T4 replacement was initiated, following which her GH secretory capacity gradually improved. Here, we report, to the best of our knowledge, the first case of a patient with pituitary apoplexy in CNC. Such condition must be identified in young patients with recurrent cardiac myxoma, and examinations, such as head MRI, must be performed.
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Procedimientos Quirúrgicos Cardíacos/efectos adversos , Complejo de Carney/complicaciones , Neoplasias Cardíacas/cirugía , Mixoma/cirugía , Apoplejia Hipofisaria/etiología , Neoplasias Hipofisarias/complicaciones , Adolescente , Complejo de Carney/diagnóstico , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Humanos , Recurrencia Local de Neoplasia/cirugía , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/cirugía , Tirotropina/deficienciaRESUMEN
The renin-angiotensin system is a key regulator of metabolism with beneficial effects of the angiotensin 1-7 (Ang 1-7) peptide. We hypothesized that the antiobesity effect of Ang 1-7 was related to the stimulation of brown adipose tissue (BAT). We administered Ang 1-7 (0.54 mg kg-1 day-1) for 28 days via implanted micro-osmotic pumps to mice with high-fat diet (HFD)-induced obesity. Ang 1-7 treatment reduced body weight, upregulated thermogenesis, and ameliorated impaired glucose homeostasis without affecting food consumption. Furthermore, Ang 1-7 treatment enlarged BAT and the increased expression of UCP1, PRDM16, and prohibitin. Alterations in PRDM16 expression correlated with increased AMPK and phosphorylation of mTOR. Ang 1-7 treatment elevated thermogenesis in subcutaneous white adipose tissue without altering UCP1 expression. These changes occurred in the context of decreased lipid accumulation in BAT from HFD-fed mice, preserved insulin signaling concomitant with phosphorylation of hormone-sensitive lipase and decreased expression of perilipin. These data suggest that Ang 1-7 induces brown adipocyte differentiation leading to upregulation of thermogenesis and improved metabolic profile in diet-induced obesity. Enhancing Ang 1-7 action represents a promising therapy to increase BAT and to reduce the metabolic complications associated with diet-induced obesity.
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Tejido Adiposo Pardo/efectos de los fármacos , Angiotensina I/farmacología , Dieta Alta en Grasa , Obesidad/prevención & control , Fragmentos de Péptidos/farmacología , Termogénesis/efectos de los fármacos , Adipocitos Marrones/efectos de los fármacos , Adipocitos Marrones/fisiología , Tejido Adiposo Pardo/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiologíaRESUMEN
BACKGROUND: Early atherosclerotic change is found even in childhood, and there is an urgent need to clarify the factors causing childhood atherosclerosis and take preventive measures. Early detection of the contributing risk factors is crucial to facilitate preventive measures. Pulse wave velocity (PWV) is a widely used technique for the assessment of atherosclerosis in children. METHODS: Lifestyle questionnaire, brachio-ankle PWV (baPWV) and anthropometric data were obtained from junior high school students in an urban area of Japan between 2006 and 2008, from seventh to ninth grades. RESULTS: Mean baPWV increased from 867.4 ± 99.5 m/s to 944.5 ± 117.5 m/s in boys, and from 864.0 ± 99.5 m/s to 923.0 ± 101.3 m/s in girls. Obese students had higher baPWV than non-obese students in both genders across each grade. On logistic regression analysis of ninth grade student data, high baPWV was dependent on systolic blood pressure (SBP), time watching television (TV) and symptoms of depression and anxiety, whereas low baPWV was dependent on time playing video games, light exercise, sleep and indoor play, as well as good friendship and motivation. CONCLUSION: Systolic blood pressure, time watching TV, and symptoms of depression and anxiety may contribute to arterial stiffness and be related to obesity in junior high school students.
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Aterosclerosis/epidemiología , Análisis de la Onda del Pulso/métodos , Conducta Sedentaria , Rigidez Vascular , Adolescente , Índice Tobillo Braquial/métodos , Antropometría , Aterosclerosis/etiología , Femenino , Humanos , Japón , Estudios Longitudinales , Masculino , Obesidad Infantil/complicaciones , Obesidad Infantil/epidemiología , Factores de Riesgo , EstudiantesAsunto(s)
Tirosinemias , Humanos , Tirosinemias/complicaciones , Tirosinemias/diagnóstico , HeptanoatosRESUMEN
Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.
Asunto(s)
Factor II del Crecimiento Similar a la Insulina/genética , Deformidades Congénitas de las Extremidades/genética , Síndrome de Silver-Russell/genética , Alelos , Femenino , Humanos , Recién Nacido , Masculino , Mutación , Secuenciación del ExomaRESUMEN
Traumatic herniation of the buccal fat pad is a rare traumatic disease. Treatment consists of either excision or replacement. We herein report the first case in which a traumatic herniation of the buccal fat pad healed naturally. It was necessary to differentiate the disease from lipoblastoma. A 17-month-old boy was admitted to a clinic with an intraoral tumor that had suddenly increased in size. The tumor was diagnosed as herniation of the buccal fat pad on pathology of a biopsy specimen. In the present case, the escaped buccal fat body returned naturally and engrafted without dysfunction or facial defects. Given that young children may easily fall down with various objects in their mouth, care is required to prevent traumatic accidents. Traumatic herniation of the buccal fat pad should be considered in the differentiation of tumors of the oral cavity in young children.
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Tejido Adiposo , Mejilla/lesiones , Traumatismos Faciales/complicaciones , Hernia/etiología , Traumatismos Faciales/diagnóstico , Hernia/diagnóstico , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Remisión EspontáneaRESUMEN
The most common form of transient neonatal diabetes mellitus (TNDM) is 6q24-related TNDM. Patients are treated with insulin during the neonatal period until spontaneous remission. However, diabetes often recurs in adolescence, and there is no standard therapy for patients with a relapse. A paternal duplication at the 6q24 critical region spanning the pleiomorphic adenoma gene-like 1 PLAGL1 gene was found in a Japanese patient with TNDM relapse. The patient was treated with a dipeptidyl peptidase-4 (DPP4) inhibitor, alogliptin, at a dose of 25 mg per day. Immediately after treatment initiation, his hemoglobin A1c (HbA1c) levels dropped from 7.0-7.5% (52-58 mmol/mol) to 6.0-6.5% (41-47 mmol/mol) and remained stable for over a year. We reported the successful treatment of relapsed 6q24-related TNDM with a DPP4 inhibitor. Although insulin has been the conventional treatment for such patients, treatments targeting the GLP1 pathway can be a useful alternative because these patients retain the ß cell mass and responsiveness through G protein-coupled pathways.
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Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Humanos , Masculino , Piperidinas/uso terapéutico , Recurrencia , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Adulto JovenRESUMEN
A six-year-old boy presented with short stature and gingival fibromatosis (GF). Dysmorphic features included slant optic fissures, a high-arched palate, thick earlobes, and an edematous face. Laboratory tests showed low levels of serum insulin-like growth factor-1 and serum free thyroxine but normal serum thyrotropin levels. Provocative tests suggested growth hormone deficiency, central hypocortisolemia, and hypothalamic hypothyroidism. At 12 years old, hypogonadotropic hypogonadism was observed. Next-generation sequencing revealed a heterozygous missense variant, KCNQ1 p. (P369L), in the proband and mother. The coexistence of multiple pituitary hormone deficiencies and GF helps diagnose KCNQ1-variant dysmorphic syndrome through genetic testing.
RESUMEN
Maternal obesity and malnutrition during gestation and lactation have been recognized to increase the risk of obesity and metabolic disorders in the offspring across their lifespan. However, the gestational period during which malnutrition exerts a decisive effect is unclear. Brown adipose tissue (BAT) plays a critical role in energy metabolism owing to its high efficiency in oxidizing glucose and fatty acids. This study aimed to determine the impact of maternal high-fat diet (HFD) consumption only during pregnancy on BAT and energy metabolism in offspring mice. Dams were fed an HFD or a normal chow diet from embryonic day 2.5. HFD consumption during pregnancy induced glucose intolerance and hypertension in dams. In the offspring of HFD-fed dams, maternal HFD lowered fetal weight without affecting placental weight, whereas HFD consumption after birth exacerbated oxygen consumption and cold-induced thermogenesis at 12 months of age, accompanied by increased lipid droplet size in BAT. These data demonstrate that HFD consumption only during pregnancy exerts a long-lasting effect on BAT. Collectively, these findings indicate the importance of nutrition during pregnancy with respect to the energy metabolism of the offspring, and pregnant women should thus ensure proper nutrition during pregnancy to ensure normal energy metabolism in the offspring.
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Tejido Adiposo Pardo , Desnutrición , Femenino , Humanos , Embarazo , Animales , Ratones , Dieta Alta en Grasa/efectos adversos , Peso Fetal , PlacentaRESUMEN
We described two Japanese siblings with arginase-1 (ARG1) deficiency. A 10-year-old girl (the proband and elder sister) was referred to our hospital complaining about her short stature. We diagnosed her with ARG1 deficiency, possibly with elevated levels of blood ammonia and plasma arginine. Her younger sister was found to have spastic paraparesis in her lower extremities and short stature at the age of 4 years. The younger sister also had high levels of plasma arginine, instead of normal levels of blood ammonia. Interestingly, they also prefer to avoid protein-rich foods such as meat, soybeans, cow milk, and dairy products. Genetic testing identified compound heterozygous mutations (c.121_122insCTT [p.Lys41Thrfs∗2] and c.298G>A [p.Asp100Asn]) in the ARG1 gene. The ARG1 mutation of p.Lys41Thrfs∗2 is a novel pathogenic mutation according to open databases and literature.
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Arginasa/genética , Mutación del Sistema de Lectura , Hiperargininemia/genética , Adolescente , Amoníaco/sangre , Arginina/sangre , Niño , Femenino , Humanos , HermanosRESUMEN
Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by congenital heart disease, hepatic cholestasis, dyslipidemia, and characteristic facies since infancy. Cholestatic hypercholesterolemia in patients diagnosed with AGS is occasionally refractory and resistant to conventional treatments. We report the case of a 4-month-old boy diagnosed with AGS and refractory dyslipidemia due to cholestatic liver disease. He had repeated episodes of cyanosis due to pulmonary artery atresia since birth and underwent a Blalock-Taussig shunt procedure at age 3 months. At age 4 months, cholestatic hyperbilirubinemia deteriorated to a serum total bilirubin level of 19.9 mg/dL. At age 12 months, a laboratory test revealed severe dyslipidemia (serum total cholesterol, 1796 mg/dL; serum triglycerides [TGs], 635 mg/dL), and the presence of xanthomas. A pathogenic variant of the JAG1 gene (c.1326Gâ >â A, p.Trp442X) was detected through genetic testing. Oral ursodeoxycholate normalized hyperbilirubinemia with a subtle improvement in dyslipidemia. Combination therapy with pravastatin and fenofibrate did not successfully improve dyslipidemia. At age 20 months, altering pravastatin to atorvastatin was effective in normalizing serum cholesterol and TGs with no adverse events. Combination therapy with atorvastatin and fenofibrate was successful in improving refractory dyslipidemia in a child with AGS. Atorvastatin is a well-known strong statin that can lower serum cholesterol, and fenofibrate can lower serum TG levels. We propose that atorvastatin be taken into consideration for the treatment of persistent hyperlipidemia in patients diagnosed with AGS, because atorvastatin upregulates bile acid synthesis and lipoprotein scavenging, and inhibits intrinsic cholesterol production.
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Genetic factors play critical roles in the onset and progression of obesity. Brown adipose tissue (BAT) activity is also critical for adiposity. The objective of this study was to evaluate the prevalence and effects of BAT gene polymorphisms in pediatric obesity. This case-control study included 270 non-obese and 86 obese children. All participants underwent genotyping for type 2 deiodinase (DIO2) Thr92Ala (rs225014). The prevalence of the homozygous Ala/Ala allele of the DIO2 gene in the obese group was 15.1% versus 6.3% in the non-obese group, resulting in an odds ratio (OR) of 3.393 (p = 0.003). The results of this study indicate that the homozygous Ala/Ala allele of the DIO2 gene is associated with an increased risk of pediatric obesity and suggest that pediatric obesity might be suitable for assessing the association with gene polymorphisms related to BAT, especially DIO2 Thr92Ala.
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Klinefelter syndrome (KS) is a sex chromosome disorder characterized by the presence of one or more extra X chromosomes. KS is well known by the common karyotype 47, XXY and presents as male infertility with hypogonadism in adults. Pediatric patients with KS commonly show neurodevelopmental disorders and cryptorchidism. We have reported a case of a 14-yr-old boy with KS and severe obesity (body mass index, 38.1 kg/m2), insulin (IRI) resistance (homeostatic model assessment 1 IRI resistance, 9.26), hyperlipidemia (serum low-density lipoprotein cholesterol level, 192 mg/dL; serum triglyceride level, 239 mg/dL), hypergonadotropic hypogonadism, and learning difficulties. The karyotype was 47, XXY, t(4;5) (q21.2;q32). Initially, he was unwilling to accept dietary restrictions and perform physical exercise against obesity. Testosterone replacement therapy was initiated at 16 years of age, which successfully improved the body composition, IRI resistance, and hyperlipidemia and increased the serum testosterone levels. Additionally, he adhered to recommendations for exercise and dietary restrictions. Patients with KS have risks of obesity and metabolic syndrome with sarcopenic conditions due to hypergonadotropic hypogonadism. Pediatricians should be aware of KS as a primary disease causing obesity. Testosterone replacement therapy could help ameliorate obesity and its comorbidities in patients with obesity and KS.
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Hypomagnesemia 1 (HOMG1) is an extremely rare disease with autosomal recessive inheritance that is caused by mutations in the transient receptor potential melastatin 6 gene (TRPM6). Here, we describe a pediatric HOMG1 case with novel compound heterozygous mutations of TRPM6 (c.1483 C > T [p.Gln495*] and c.2715del [p.Trp905*]) in a 2-month-old boy who developed refractory seizures due to hypomagnesemia with secondary hypocalcemia.
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Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp2+/- mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp2+/- mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp2+/--HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp2+/--HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp2+/- mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp2+/--HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp2+/- mice.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hiperfagia/etiología , Proteína 2 de Unión a Metil-CpG/genética , Obesidad/etiología , Síndrome de Rett/complicaciones , Animales , Apetito/fisiología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Conducta Alimentaria/fisiología , Femenino , Heterocigoto , Humanos , Hiperfagia/diagnóstico , Hiperfagia/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/diagnóstico , Obesidad/fisiopatología , Síndrome de Rett/genética , Recompensa , Índice de Severidad de la Enfermedad , Factores de Tiempo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiopatologíaRESUMEN
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, and its progression is associated with aging-associated impairment in metabolic homeostasis. Recently, energy metabolism in adipose tissue has been the subject of renewed interest, because significant energy expenditure can be induced in cells derived from white adipose tissue progenitors, in addition to brown adipose tissue (BAT). Here we evaluated whether aging-associated change in various adipose tissue depots affects the progression of NAFLD. METHODS: Six-week-old male C57BL/6NCrSlc mice were fed control chow (C) or high-fat diet (60% fat; HF) for 12 or 24 weeks (12w/C, 12w/HF, 24w/C and 24w/HF groups, respectively) or switched from C to HF diet at 18 weeks of age (24w/C/HF group) and fed for a further 24 weeks. Some 24w/HF mice received a subcutaneous transplantation of adipose progenitors (106 cells/mouse) from young donor mice. Basal energy expenditure, glucose tolerance, and liver and adipose tissue histology were then evaluated. In addition, features of senescence and the capacity of adipose progenitors to "brown" were compared in mice of various ages. RESULTS: 12w/HF mice demonstrated compensation in the forms of hypertrophy of interscapular classical BAT and the appearance of subcutaneous beige adipocytes, consistent with improved metabolic homeostasis. In contrast, 24w/HF and 24w/C/HF mice developed obesity, glucose intolerance, and severe NAFLD, with accelerated senescence and loss of adipose progenitors in subcutaneous fat tissues. Recruitment of adipose progenitors ameliorated these findings in 24w/HF mice. CONCLUSION: Impaired metabolic compensation in adipose tissue resulted in the progression of NAFLD, which was associated with aging-related deterioration in adipose progenitors. A new approach targeting adipose tissue progenitors might represent a potential strategy for the prevention of NAFLD.
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Recent studies have shown that cells from bone marrow (BM) can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved remain unknown. We performed BM transplantation in acid alpha-glucosidase (GAA) knockout mice, a model of glycogen storage disease type II, and our observations suggested that the BM cells contribute to skeletal muscle fiber formation. Furthermore, we showed that most CD45+:Sca1+ cells have a donor character in regenerating muscle of recipient mice. Based on these findings, CD45+:Sca1+ cells were sorted from regenerating muscles. The cell number was increased with granulocyte colony-stimulating factor after cardiotoxin injury, and the cells were transplanted directly into the tibialis anterior (TA) muscles of GAA knockout mice. Sections of the TA muscles stained with anti-laminin-alpha2 antibody showed that the number of CD45+:Sca1+ cells contributing to muscle fiber formation and glycogen levels were decreased in transplanted muscles. Our results indicated that hematopoietic stem cells, such as CD45+:Sca1+ cells, are involved in skeletal muscle regeneration.
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Células Madre Hematopoyéticas/fisiología , Músculo Esquelético/fisiología , Regeneración , alfa-Glucosidasas/genética , Animales , Antígenos Ly/metabolismo , Glucógeno/metabolismo , Trasplante de Células Madre Hematopoyéticas , Antígenos Comunes de Leucocito/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Fibras Nerviosas/fisiologíaRESUMEN
Primary hyperparathyroidism (PHT) causes increased bone turnover, leading to reduction in bone mineral density (BMD). Parathyroidectomy is a definitive therapy and improves BMD in adult patients with PHT. However, there are no reports regarding alterations of BMD in pediatric or adolescent patients with PHT. Here, we report a case of a 13-yr-old boy with PHT who was referred to our institution for evaluation of hypercalcemia and hyperparathyroidism. Radiological investigation revealed an ectopic parathyroid adenoma below the right thyroid lobe. A minimally invasive radio-guided parathyroidectomy was successfully performed. We followed up the patient's BMD for three years both before and after parathyroidectomy. Over the course of three years, his BMD was steadily decreased, with z-scores of +0.506 at 13 yr and 9 mo, +0.162 at 14 yr and 9 mo, and -0.411 at 15 yr and 9 mo. BMD usually increases during peak height velocity in an adolescent and improves after parathyroidectomy in adult patients with PHT. However, our patient showed decreased BMD z-scores following parathyroidectomy. Therefore, the patient had an increased risk of fracture after parathyroidectomy and was followed up closely. Both height and BMD should be carefully evaluated after parathyroidectomy in pediatric and adolescent patients with PHT.