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1.
FASEB J ; 38(1): e23391, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38145327

RESUMEN

Adipocytes play a key role in energy storage and homeostasis. Although the role of transcription factors in adipocyte differentiation is known, the effect of endogenous metabolites of low molecular weight remains unclear. Here, we analyzed time-dependent changes in the levels of these metabolites throughout adipocyte differentiation, using metabolome analysis, and demonstrated that there is a positive correlation between cyclic adenosine diphosphate ribose (cADPR) and Pparγ mRNA expression used as a marker of differentiation. We also found that the treatment of C3H10T1/2 adipocytes with cADPR increased the mRNA expression of those marker genes and the accumulation of triglycerides. Furthermore, inhibition of ryanodine receptors (RyR), which are activated by cADPR, caused a significant reduction in mRNA expression levels of the marker genes and triglyceride accumulation in adipocytes. Our findings show that cADPR accelerates adipocytic differentiation via RyR pathway.


Asunto(s)
Adipocitos , ADP-Ribosa Cíclica , Ratones , Animales , ADP-Ribosa Cíclica/metabolismo , Adipocitos/metabolismo , Factores de Transcripción/metabolismo , PPAR gamma/metabolismo , Metaboloma , ARN Mensajero/genética , Diferenciación Celular , Adenosina Difosfato Ribosa/metabolismo , Adenosina Difosfato Ribosa/farmacología , Adipogénesis/genética , Células 3T3-L1
2.
J Biol Chem ; 298(10): 102456, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36063990

RESUMEN

Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid, an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil, a prodrug of mycophenolic acid, to mice and demonstrated that mycophenolate mofetil induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.


Asunto(s)
Adipocitos , Inosina Monofosfato , Ácido Micofenólico , Animales , Ratones , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Inosina Monofosfato/metabolismo , Metabolómica , Ratones Endogámicos C57BL , Ácido Micofenólico/farmacología , Ácido Micofenólico/metabolismo , Obesidad/metabolismo , ARN Mensajero/metabolismo
3.
FASEB J ; 36(12): e22645, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36349991

RESUMEN

Melanocortin-4 receptor (MC4R) is a critical regulator of appetite and energy expenditure in rodents and humans. MC4R deficiency causes hyperphagia, reduced energy expenditure, and impaired glucose metabolism. Ligand binding to MC4R activates adenylyl cyclase, resulting in increased levels of intracellular cyclic adenosine monophosphate (cAMP), a secondary messenger that regulates several cellular processes. Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cAMP and is reportedly involved in obesity. However, the precise mechanism through which CRTC1 regulates energy metabolism remains unknown. Additionally, there are no reports linking CRTC1 and MC4R, although both CRTC1 and MC4R are known to be involved in obesity. Here, we demonstrate that mice lacking CRTC1, specifically in MC4R cells, are sensitive to high-fat diet (HFD)-induced obesity and exhibit hyperphagia and increased body weight gain. Moreover, the loss of CRTC1 in MC4R cells impairs glucose metabolism. MC4R-expressing cell-specific CRTC1 knockout mice did not show changes in body weight gain, food intake, or glucose metabolism when fed a normal-chow diet. Thus, CRTC1 expression in MC4R cells is required for metabolic adaptation to HFD with respect to appetite regulation. Our results revealed an important protective role of CRTC1 in MC4R cells against dietary adaptation.


Asunto(s)
Resistencia a la Insulina , Receptor de Melanocortina Tipo 4 , Humanos , Ratones , Animales , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Hiperfagia/genética , Hiperfagia/metabolismo , Obesidad/genética , Obesidad/metabolismo , Metabolismo Energético , Ratones Noqueados , Factores de Transcripción/metabolismo , Glucosa , Adenosina Monofosfato/metabolismo
4.
Clin Exp Nephrol ; 27(5): 435-444, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36773175

RESUMEN

BACKGROUND: The effect of low serum uric acid (sUA) levels on kidney function is unclear. This study aimed to clarify the relationship between low sUA levels and the rapid decline in kidney function. METHODS: We examined the relationship between sUA levels and kidney function decline in health check-up examinees. A total of 10,547 participants were enrolled using data from the Yuport Medical Checkup Center Study between 1998 and 2002 for baseline and data from 2002 to 2006 as the follow-up period in Japan. According to sUA level (mg/dL), we classified the participants into the following six groups: (1) 2.0-2.9 (n = 247), (2) 3.0-3.9 (n = 1457), (3) 4.0-4.9 (n = 2883), (4) 5.0-5.9 (n = 2899), (5) 6.0-6.9 (n = 2010), and (6) 7.0-7.9 (n = 1,051). The relationship between sUA level and rapid decline in estimated glomerular filtration rate (ΔeGFR ≥ 3 mL/min/1.73 m2/year) was examined using a logistic regression model. RESULTS: During study period (5.4 ± 1.6 years), the incidence of rapid eGFR decline for the respective sUA groups (2.0-2.9, 3.0-3.9, 4.0-4.9, 5.0-5.9, 6.0-6.9, 7.0-7.9) were as follows: 4.5%, 4.0%, 2.4%, 3.3%, 3.1%, 3.4%. The crude and adjusted odds ratios (OR) for rapid eGFR decline were significantly higher in the 2.0-2.9 (OR:1.93 and 1.86) and 3.0-3.9 (OR:1.72 and 1.73) groups than in the 4.0-4.9 groups (reference). Stratified analysis of age differences revealed that the detrimental effect of low sUA was not evident in older adults (age ≥ 65 years). CONCLUSION: A lower normal sUA level is related to an increased risk for a rapid decline in kidney function.


Asunto(s)
Insuficiencia Renal Crónica , Ácido Úrico , Persona de Mediana Edad , Humanos , Anciano , Factores de Riesgo , Tasa de Filtración Glomerular , Pruebas de Función Renal , Riñón
5.
Biosci Biotechnol Biochem ; 87(7): 747-757, 2023 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-37024261

RESUMEN

Soy isoflavones have been shown to have anti-inflammatory properties; however, the anti-inflammatory effects of isoflavone metabolites produced during soybean germination remain unclear. We found that the daidzein and genistein derivatives, 8-prenyl daidzein (8-PD) and 8-prenyl genistein (8-PG), demonstrated a more potent effect than daidzein and genistein on repressing inflammatory responses in macrophages. Although IkB protein levels were unaltered, 8-PD and 8-PG repressed nuclear factor kappa B (NF-κB) activation, which was associated with reduced ERK1/2, JNK, and p38 MAPK activation and suppressed mitogen- and stress-activated kinase 1 phosphorylation. Inflammatory responses induced by the medium containing hypertrophic adipocyte secretions were successfully suppressed by 8-PD and 8-PG treatment. In the ex vivo study, 8-PD and 8-PG significantly inhibited proinflammatory C-C motif chemokine ligand 2 (CCL2) secretion from the adipose tissues of mice fed a long-term high-fat diet. The data suggest that 8-PD and 8-PG could regulate macrophage activation under obesity conditions.


Asunto(s)
Genisteína , Isoflavonas , Ratones , Animales , Genisteína/farmacología , Genisteína/metabolismo , Glycine max/metabolismo , Isoflavonas/farmacología , Isoflavonas/metabolismo , Macrófagos/metabolismo , Antiinflamatorios/farmacología
6.
Biochem J ; 479(21): 2279-2296, 2022 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-36256829

RESUMEN

Certain metabolic intermediates produced during metabolism are known to regulate a wide range of cellular processes. Methylglyoxal (MG), a natural metabolite derived from glycolysis, has been shown to negatively influence systemic metabolism by inducing glucose intolerance, insulin resistance, and diabetic complications. MG plays a functional role as a signaling molecule that initiates signal transduction. However, the specific relationship between MG-induced activation of signal transduction and its negative effects on metabolism remains unclear. Here, we found that MG activated mammalian target of rapamycin complex 1 (mTORC1) signaling via p38 mitogen-activated protein kinase in adipocytes, and that the transforming growth factor-ß-activated kinase 1 (TAK1) is needed to activate p38-mTORC1 signaling following treatment with MG. We also found that MG increased the phosphorylation levels of serine residues in insulin receptor substrate (IRS)-1, which is involved in its negative regulation, thereby attenuating insulin-stimulated tyrosine phosphorylation in IRS-1. The negative effect of MG on insulin-stimulated IRS-1 tyrosine phosphorylation was exerted due to the MG-induced activation of the TAK1-p38-mTORC1 signaling axis. The involvement of the TAK1-p38-mTORC1 signaling axis in the induction of IRS-1 multiple serine phosphorylation was not unique to MG, as the proinflammatory cytokine, tumor necrosis factor-α, also activated the same signaling axis. Therefore, our findings suggest that MG-induced activation of the TAK1-p38-mTORC1 signaling axis caused multiple serine phosphorylation on IRS-1, potentially contributing to insulin resistance.


Asunto(s)
Resistencia a la Insulina , Piruvaldehído , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Piruvaldehído/farmacología , Piruvaldehído/metabolismo , Resistencia a la Insulina/fisiología , Serina/metabolismo , Transducción de Señal/fisiología , Adipocitos/metabolismo , Insulina/farmacología , Insulina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Tirosina/metabolismo , Fosfoproteínas/metabolismo
7.
BMC Health Serv Res ; 23(1): 1404, 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38093353

RESUMEN

BACKGROUND: Japan's medical education system produces 9,000 graduates annually. Despite the government's implementation of several strategies, including increasing the number of doctors trained, the country still struggles with a shortage of physicians in rural areas. This study examined this issue, focusing on gender and considering years of physician experience, demographic and geographic factors. METHODS: We analyzed the Physician Census from 1994, 2004, and 2014, examining data on physicians' gender and the number of years since licensure. To correct the impact of municipal mergers, the analysis was aligned with the number of municipalities in 2014 (1741). We examined data from each physician (gender and years of medical experience) and analyzed the demographic and geographic distribution trend using Spearman correlation coefficients. We then used the Gini coefficient to evaluate the distribution change of physicians based on gender and years of experience. RESULTS: The number of physicians increased 1.29-fold over the 20-year observation period (1.23-fold for male physicians and 2.17-fold for female physicians), and the percentage of female physicians increased from 13.4% to 20.4%. We found that 87.7% of physicians were concentrated in the top 1/3 municipalities in terms of population. The number of female physicians was higher at 91.8% compared to 86.8% for male physicians. The Gini coefficients were lower for veteran physicians of both sexes than for younger physicians. The Gini coefficient for all physicians was 0.315-0.298-0.298 (male physicians: 0.311-0.289-0.283, female physicians: 0.394-0.385-0.395) The Gini coefficients for female compared to male physicians were higher in all age groups, showing that The distribution of female physicians is skewed toward urban areas. CONCLUSION: Female physicians are less distributed in rural areas than male physicians. In addition, despite the fact that the number of female physicians has increased more than male physicians over the past 20 years, the geographic ubiquity of female physicians has not improved. Since the trend of increasing the number of female physicians is expected to continue in the future, it is necessary to take some measures, such as providing a work-life balance suitable for female physicians.


Asunto(s)
Educación Médica , Médicos Mujeres , Médicos , Humanos , Masculino , Femenino , Japón/epidemiología , Factores Sexuales
8.
Am J Physiol Endocrinol Metab ; 322(5): E436-E445, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35344393

RESUMEN

The melanocortin 4 receptor (MC4R) plays an important role in the regulation of appetite and energy expenditure in humans and rodents. Impairment of MC4R signaling causes severe obesity. MC4R mainly couples to the G-protein Gs. Ligand binding to MC4R activates adenylyl cyclase resulting in increased intracellular cAMP levels. cAMP acts as a secondary messenger, regulating various cellular processes. MC4R can also couple with Gq and other signaling pathways. Therefore, the contribution of MC4R/Gs signaling to energy metabolism and appetite remains unclear. To study the effect of Gs signaling activation in MC4R cells on whole body energy metabolism and appetite, we generated a novel mouse strain that expresses a Gs-coupled designer receptors exclusively activated by designer drugs [Gs-DREADD (GsD)] selectively in MC4R-expressing cells (GsD-MC4R mice). Chemogenetic activation of the GsD by a designer drug [deschloroclozapine (DCZ); 0.01∼0.1 mg/kg body wt] in MC4R-expressing cells significantly increased oxygen consumption and locomotor activity. In addition, GsD activation significantly reduced the respiratory exchange ratio, promoting fatty acid oxidation, but did not affect core (rectal) temperature. A low dose of DCZ (0.01 mg/kg body wt) did not suppress food intake, but a high dose of DCZ (0.1 mg/kg body wt) suppressed food intake in MC4R-GsD mice, although either DCZ dose (0.01 or 0.1 mg/kg body wt) did not affect food intake in the control mice. In conclusion, the current study demonstrated that the stimulation of Gs signaling in MC4R-expressing cells increases energy expenditure and locomotor activity and suppresses appetite.NEW & NOTEWORTHY We report that Gs signaling in melanocortin 4 receptor (MC4R)-expressing cells regulates energy expenditure, appetite, and locomotor activity. These findings shed light on the mechanism underlying the regulation of energy metabolism and locomotor activity by MC4R/cAMP signaling.


Asunto(s)
Proteínas de Unión al GTP , Obesidad , Receptor de Melanocortina Tipo 4 , Animales , Ingestión de Alimentos , Metabolismo Energético , Proteínas de Unión al GTP/metabolismo , Locomoción , Ratones , Obesidad/metabolismo , Receptor de Melanocortina Tipo 4/genética
9.
Biosci Biotechnol Biochem ; 86(4): 509-518, 2022 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-35102395

RESUMEN

The cluster of differentiation 36 (CD36) is a transmembrane receptor expressed in various cells and has diverse lipid ligands. The expression of CD36 in the murine olfactory epithelium and its ability to recognize certain species of fatty aldehydes, a class of odor-active volatile compounds, have suggested a role for this receptor in the capture of specific odorants in the nasal cavity of mammals. However, the spectrum of CD36-recognizable volatile compounds is poorly understood. In this study, we employed our recently devised assay with fluorescently labeled peptides as probes (fluorescence intensity assay) and identified distinct fatty acetates as volatile compounds that bind specifically to amino acid region 149-168 of CD36 (eg dodecyl and tetradecyl acetates). The present findings demonstrate the utility of our assay for the discovery of novel CD36 ligands and support the notion that the receptor functions as a captor of volatile compounds in the mammalian olfactory system.


Asunto(s)
Antígenos CD36 , Odorantes , Acetatos , Aminoácidos , Animales , Antígenos CD36/metabolismo , Fluorescencia , Mamíferos/metabolismo , Ratones
10.
Biosci Biotechnol Biochem ; 86(3): 380-389, 2022 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-34935880

RESUMEN

Uncoupling protein 1 (UCP1) in brown or beige adipocytes is a mitochondrial protein that is expected to enhance whole-body energy expenditure. For the high-throughput screening of UCP1 transcriptional activity regulator, we established a murine inguinal white adipose tissue-derived Ucp1-luciferase reporter preadipocyte line. Using this reporter preadipocyte line, 654 flavor compounds were screened, and a novel Ucp1 expression-inducing compound, 5-methylquinoxaline, was identified. Adipocytes treated with 5-methylquinoxaline showed increased Ucp1 mRNA expression levels and enhanced oxygen consumption. 5-Methylquinoxaline induced Ucp1 expression through peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and 5-methylquinoxaline-induced PGC1α activation seemed to be partially regulated by its phosphorylation or deacetylation. Thus, our Ucp1-luciferase reporter preadipocyte line is a useful tool for screening of Ucp1 inductive compounds.


Asunto(s)
Proteína Desacopladora 1
11.
J Biol Chem ; 295(20): 7033-7045, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32273338

RESUMEN

Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced Ucp1 up-regulation in inguinal white adipose tissue (iWAT) was partially abolished by Gyk knockdown (KD) in vivo Consistently, the Gyk KD inhibited Ucp1 expression induced by treatment with the ß-adrenergic receptors (ßAR) agonist isoproterenol (Iso) in vitro and resulted in impaired uncoupled respiration. Gyk KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element-binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore Gyk KD related to Iso-induced cAMP products. In Iso-treated Gyk KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 down-regulation and POA treatment down-regulated Iso-activated Ucp1 Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the ßAR-cAMP-CREB pathway and Gyk-mediated regulation of fatty acid metabolism.


Asunto(s)
Adipocitos Beige/metabolismo , Frío , Ácidos Grasos/metabolismo , Glicerol Quinasa/metabolismo , Sistemas de Mensajero Secundario , Termogénesis , Activación Transcripcional , Proteína Desacopladora 1/biosíntesis , Adipocitos Beige/citología , Animales , AMP Cíclico/genética , AMP Cíclico/metabolismo , Ácidos Grasos/genética , Glicerol Quinasa/genética , Isoproterenol/farmacología , Masculino , Ratones , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Proteína Desacopladora 1/genética
12.
FASEB J ; 33(12): 14095-14102, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31652095

RESUMEN

The functions of the brain, which is thought of as an organ highly independent from the periphery, are often affected by the peripheral environment. Indeed, epidemiologic studies demonstrated that diabetes was a risk factor for dementia. It was also reported that the intake of dairy products, such as milk, reduces the risk of developing dementia. We found that mice on a short-term high-fat diet (HFD) for 1 wk had reduced cognitive function. Thus, using this acute model, we investigated the effects of milk-derived peptide on cognitive decline induced by HFD. Tyr-Leu-Gly (YLG), a tripeptide derived from αS1-casein, a major bovine milk protein, is released by gastrointestinal proteases. We found that orally administered YLG improved cognitive decline induced by 1-wk HFD intake in the object recognition test. YLG also improved cognitive decline in the object location test. Thus, we found that YLG improved cognitive decline induced by HFD. Next, we examined the effects of YLG on the hippocampus, a brain area essential for cognitive function. HFD intake decreased the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells, and this decrease was improved by YLG administration. HFD intake decreased nerve growth factor (NGF) and glial cell line-derived neurotrophic factor, whereas YLG increased NGF and ciliary neurotrophic factor, suggesting that these neurotropic factors play a role in hippocampal neurogenesis after YLG administration. In conclusion, we demonstrated that 1-wk HFD reduced cognitive function. Furthermore, we found that YLG, a milk-derived tripeptide, improved cognitive decline in mice on HFD. The HFD reduced neural stem cell proliferation, and YLG improved this reduction. YLG is the first reported milk peptide to improve cognitive decline induced by HFD intake.-Nagai, A., Mizushige, T., Matsumura, S., Inoue, K., Ohinata, K. Orally administered milk-derived tripeptide improved cognitive decline in mice fed a high-fat diet.


Asunto(s)
Cognición/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Leche/química , Péptidos/farmacología , Administración Oral , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Péptidos/administración & dosificación , Péptidos/química
13.
Biosci Biotechnol Biochem ; 84(2): 305-313, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31601163

RESUMEN

Specific conditions, such as exposure to cold, can induce the production of brown-like adipocytes in white adipose tissue. These adipocytes express high levels of uncoupling protein 1 (UCP1) and energy expended by generating heat. Thus, these are a potential target for the prevention or treatment of obesity. The present study involved a comprehensive analysis of the adipose tissue to understand the relationship between long non-coding RNA (lncRNA) 2310069B03Rik and UCP1. Cold exposure increased both lncRNA 2310069B03Rik and Ucp1 expression in inguinal white adipose tissue (iWAT). However, overexpression of lncRNA 2310069B03Rik suppressed the Ucp1 mRNA expression and the promoter activity of UCP1 in the iWAT primary adipocytes. In addition, compared to the early induction of Ucp1 expression by cold stimulation, the induction of lncRNA 2310069B03Rik expression was later. These results suggest that lncRNA 2310069B03Rik functions as a suppression factor of Ucp1 expression.


Asunto(s)
Frío , ARN Largo no Codificante/metabolismo , Proteína Desacopladora 1/genética , Adipocitos Beige , Agonistas Adrenérgicos beta/farmacología , Animales , Células Cultivadas , Regulación hacia Abajo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Termogénesis/genética , Proteína Desacopladora 1/metabolismo
14.
Tohoku J Exp Med ; 251(3): 183-191, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32669486

RESUMEN

Prior studies have shown an association between the incidence of diabetes with liver enzymes, such as alanine transaminase (ALT). Liver fibrosis scores, such as the Fibrosis-4 index which indicates chronic liver damage, were also associated with diabetes development. However, no literature compared predictive accuracy between ALT and Fibrosis-4 index. Thus, we aimed to determine it, and to assess its association using inverse probability of treatment weighting. This was a non-concurrent prospective cohort study of 9,748 subjects without diabetes receiving Yuport Health Checkup in Japan between 1998 and 2006. ALT was categorized into three groups: the highest ALT group (men ≥ 30 U/L and women ≥ 20 U/L), the middle (men ≥ 20 and < 30 U/L, and women ≥ 14 and < 20 U/L), and the lowest (men < 20 U/L and women < 14 U/L). The primary outcome was the new onset of diabetes. The area under the receiver operating characteristic curves (AUC) of ALT for predicting the diabetes development was higher than that of any other markers of liver damage. The AUC for ALT was 0.71, while that for the Fibrosis-4 index was 0.51 (p < 0.001 for the difference between the AUCs). The highest and middle ALT groups had a significantly higher incidence of diabetes than the lowest group: adjusted relative risk 1.79 [95% confidence interval (CI): 1.29, 2.58], and 1.64 [95% CI: 1.17, 2.38] respectively. Of the various indicators of liver function, ALT is likely to be the most accurate and associated predictor of diabetes development.


Asunto(s)
Alanina Transaminasa/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Adulto , Anciano , Algoritmos , Área Bajo la Curva , Biomarcadores , Estudios de Cohortes , Femenino , Hepatitis/sangre , Hepatitis/complicaciones , Humanos , Incidencia , Japón/epidemiología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Curva ROC , Medición de Riesgo
15.
Endocr Res ; 44(4): 127-137, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30895902

RESUMEN

Aim: White blood cell (WBC) count or C-reactive protein (CRP) level alone may not fully indicate the chronic inflammation causing type 2 diabetes. We examined both WBC count and CRP level, independently and in combination, as predictive markers for type 2 diabetes and also considered the influence of obesity and other individual characteristics on the relationship. Materials and Methods: In total, 9,706 participants were enrolled with WBC < 10*109/L and CRP < 10 mg/L using data from the Yuport Medical Checkup Center Study. The cumulative incidence of type 2 diabetes [defined either as known diabetes, fasting plasma glucose ≥ 7.0 mmol/L, or HbA1c ≥ 6.5% (47.5 mmol/mol)] was measured. Hazard ratios (HRs) were estimated using a Cox proportional hazards model. Results: During study period, 272 men (5.5%) and 113 women (2.4%) progressed to diabetes. The progression to diabetes was predicted by both increased baseline levels of WBC count [adjusted HR = 1.29 (95% CI: 1.04-1.60)] and CRP level [1.39 (1.10-1.74)], even after adjusting for possible confounders. The combined presence was more predictive of diabetes than either alone in a four-groups analysis [1.75 (1.28-2.40)]. In addition, the elevated HRs of either or both higher WBC and CRP levels were observed across four subgroups of body mass index (BMI), including low BMI, and people who had at least one occurrence of dyslipidemia. Conclusion: Increased WBC counts and CRP levels were predictive for type 2 diabetes and the combination augmented the risk of diabetes, regardless of whether the BMI was high or low.


Asunto(s)
Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Leucocitos/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Conjuntos de Datos como Asunto , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Incidencia , Recuento de Leucocitos , Leucocitos/citología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tokio , Adulto Joven
16.
J Surg Res ; 227: 44-51, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29804861

RESUMEN

BACKGROUND: Nutritional management is crucial during the acute phase of severe illnesses. However, the appropriate nutritional requirements for patients with sepsis are poorly understood. We investigated alterations in carbohydrate, fat, and protein metabolism in mice with different degrees of sepsis. MATERIALS AND METHODS: C57BL/6 mice were divided into three groups: control mice group, administered with saline, and low- and high-dose lipopolysaccharide (LPS) groups, intraperitoneally administered with 1 and 5 mg of LPS/kg, respectively. Rectal temperature, food intake, body weight, and spontaneous motor activity were measured. Indirect calorimetry was performed using a respiratory gas analysis for 120 h, after which carbohydrate oxidation and fatty acid oxidation were calculated. Urinary nitrogen excretion was measured to evaluate protein metabolism. The substrate utilization ratio was recalculated. Plasma and liver carbohydrate and lipid levels were evaluated at 24, 72, and 120 h after LPS administration. RESULTS: Biological reactions decreased significantly in the low- and high-LPS groups. Fatty acid oxidation and protein oxidation increased significantly 24 h after LPS administration, whereas carbohydrate oxidation decreased significantly. Energy substrate metabolism changed from glucose to predominantly lipid metabolism depending on the degree of sepsis, and protein metabolism was low. Plasma lipid levels decreased, whereas liver lipid levels increased at 24 h, suggesting that lipids were transported to the liver as the energy source. CONCLUSIONS: Our findings revealed that energy substrate metabolism changed depending on the degree of sepsis. Therefore, in nutritional management, such metabolic alterations must be considered, and further studies on the optimum nutritional intervention during severe sepsis are necessary.


Asunto(s)
Metabolismo Energético , Glucosa/metabolismo , Metabolismo de los Lípidos , Sepsis/metabolismo , Animales , Peso Corporal , Calorimetría Indirecta , Modelos Animales de Enfermedad , Ingestión de Alimentos , Escherichia coli/inmunología , Humanos , Inyecciones Intraperitoneales , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , Sepsis/diagnóstico , Sepsis/dietoterapia , Sepsis/inmunología , Índice de Severidad de la Enfermedad
17.
Biosci Biotechnol Biochem ; 82(4): 698-708, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29207921

RESUMEN

The transient receptor potential (TRP) V1 is a cation channel belonging to the TRP channel family and it has been reported to be involved in energy metabolism, especially glucose metabolism. While, we have previously shown that intragastric administration of allyl isothiocyanate (AITC) enhanced glucose metabolism via TRPV1, the underlying mechanism has not been elucidated. In this study, we examined the relationship between insulin secretion and the increase in carbohydrate oxidation due to AITC. Intragastric administration of AITC elevated blood insulin levels in mice and AITC directly enhanced insulin secretion from isolated islets. These observations were not reproduced in TRPV1 knockout mice. Furthermore, AITC did not increase carbohydrate oxidation in streptozotocin-treated mice. These results suggest that intragastric administration of AITC could induce insulin secretion from islets via TRPV1 and that enhancement of insulin secretion was related to the increased carbohydrate oxidation due to AITC.


Asunto(s)
Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Insulina/metabolismo , Isotiocianatos/farmacología , Canales Catiónicos TRPV/fisiología , Acetilcisteína/química , Animales , Dióxido de Carbono/metabolismo , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Gliburida/farmacología , Hipoglucemiantes/farmacología , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Isotiocianatos/administración & dosificación , Isotiocianatos/química , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidación-Reducción , Consumo de Oxígeno , Estómago , Estreptozocina/administración & dosificación , Canales Catiónicos TRPV/genética
18.
FASEB J ; 30(2): 849-62, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26514166

RESUMEN

ß-Klotho (ß-Kl), a transmembrane protein expressed in the liver, pancreas, adipose tissues, and brain, is essential for feedback suppression of hepatic bile acid synthesis. Because bile acid is a key regulator of lipid and energy metabolism, we hypothesized potential and tissue-specific roles of ß-Kl in regulating plasma lipid levels and body weight. By crossing ß-kl(-/-) mice with newly developed hepatocyte-specific ß-kl transgenic (Tg) mice, we generated mice expressing ß-kl solely in hepatocytes (ß-kl(-/-)/Tg). Gene expression, metabolomic, and in vivo flux analyses consistently revealed that plasma level of cholesterol, which is over-excreted into feces as bile acids in ß-kl(-/-), is maintained in ß-kl(-/-) mice by enhanced de novo cholesterogenesis. No compensatory increase in lipogenesis was observed, despite markedly decreased plasma triglyceride. Along with enhanced bile acid synthesis, these lipid dysregulations in ß-kl(-/-) were completely reversed in ß-kl(-/-)/Tg mice. In contrast, reduced body weight and resistance to diet-induced obesity in ß-kl(-/-) mice were not reversed by hepatocyte-specific restoration of ß-Kl expression. We conclude that ß-Kl in hepatocytes is necessary and sufficient for lipid homeostasis, whereas nonhepatic ß-Kl regulates energy metabolism. We further demonstrate that in a condition with excessive cholesterol disposal, a robust compensatory mechanism maintains cholesterol levels but not triglyceride levels in mice.


Asunto(s)
Peso Corporal/fisiología , Hepatocitos/metabolismo , Metabolismo de los Lípidos/fisiología , Proteínas de la Membrana/metabolismo , Animales , Colesterol/genética , Colesterol/metabolismo , Metabolismo Energético/fisiología , Hepatocitos/citología , Proteínas Klotho , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo
19.
Biosci Biotechnol Biochem ; 81(8): 1561-1568, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28585464

RESUMEN

Katsuodashi, a dried bonito broth, is very basic and indispensable in Japanese cuisine and contains taste-exhibiting components and unique aroma. We previously reported that its unique aroma contributes to the preference and reinforcement effect associated with dried bonito. This study aims to elucidate the contribution of aromatic components in Katsuobushi to preference formation and reinforcement effect. Volatile components obtained from dried bonito were fractionated and the fractions were subjected to two-bottle choice test. The fractionation test suggested that the component responsible for the preference is not one but comprises multiple components. In the GC-MS analysis/reconstruction test, solution with aromatic flavor narrowed down to 125 compounds had preference, and also had reinforcement effect. Moreover, GC-MS-olfactometry analysis narrowed down the candidate components to 28 out of 125. Mice showed preference for the test solution with aromatic flavor reconstructed with 28 components but did not show reinforcement behavior.


Asunto(s)
Conducta de Elección/efectos de los fármacos , Aromatizantes/aislamiento & purificación , Odorantes/análisis , Perciformes/metabolismo , Percepción del Gusto/fisiología , Gusto/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Fraccionamiento Químico , Conducta de Elección/fisiología , Desecación , Aromatizantes/química , Aromatizantes/farmacología , Cromatografía de Gases y Espectrometría de Masas , Masculino , Ratones , Ratones Endogámicos BALB C , Refuerzo en Psicología , Olfato/fisiología
20.
Tohoku J Exp Med ; 242(3): 247-249, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28740037

RESUMEN

On March 11, 2011, a magnitude 9.0 earthquake and huge tsunami occurred near the Pacific coast of northeast Japan, in which more than 18,000 people died or went missing and more than 120,000 buildings were destroyed. In Taro district, one of the areas struck hardest by the tsunami, a middle-aged woman was found deceased in the rubble. Generally, a family physician can recognize victims based on their appearance; the place where they were found; their home or work address; their belongings; the identifying marks on their clothes; their dental charts; and their living biological parents, children, or multiple siblings through DNA analysis. However, in this case, the middle-aged woman remained the area's sole unidentified person for months, because her appearance was different, her body was slightly swollen, and she was missing some teeth. The district's medical and dental facilities were destroyed and almost all medical records and dental charts lost. Fortunately, a family physician who had worked in the district for many years survived the disaster, and was available to provide background information about the victim, her family, and their relationship. He recalled the existence of tissue samples of her mother who had died several years earlier. Subsequently, the individual was identified through the DNA analysis of her blood and mother's tissue samples. As demonstrated in the case, appropriately managed medical information and samples from previously deceased relatives can aid disaster victim identification. The destruction caused by the Great East Japan Earthquake forms our investigation's background.


Asunto(s)
Víctimas de Desastres , Madres , Preservación Biológica , Muerte , Terremotos , Femenino , Humanos , Masculino , Linaje , Tsunamis
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