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Papers - ITOH Hiroshi

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Pancreas Fat and beta Cell Mass in Humans With and Without Diabetes: An Analysis in the Japanese Population

Murakami, R., Saisho, Y., Watanabe, Y., Inaishi, J., Tsuchiya, T., Kou, K., Sato, S., Kitago, M., Kitagawa, Y., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 102 ( 9 ) 3251 - 3260 2017.09

ISSN 0021-972

Context: The mechanisms by which beta cell mass is reduced in patients with type 2 diabetes remain unclear. It has been postulated that ectopic fat deposits in the pancreas induce beta cell apoptosis, leading to the development of diabetes. Objective: The aim of this study was to clarify the effects of intrapancreatic fat on beta and alpha cell mass in humans with and without diabetes. Design and Subjects: Using our tissue database, pancreas sections of 72 Japanese nondiabetic (NDM) autopsy cases and 50 diabetic and 49 age- and body mass index (BMI)-matched NDM patients who underwent pancreatic surgery were analyzed. In addition to histological grading, intrapancreatic fat area (IPFA) was quantified as fractional intralobular, but not interlobular, fat area to the whole pancreas area. Results: Although IPFA was positively correlated with age and BMI, there was no significant difference in IPFA between cases with and without diabetes. Moreover, no association was found between IPFA and either beta or alpha cell area, or glycated hemoglobin. Conclusion: These findings suggest that pancreatic fat deposits have little effect on beta cell mass and the development of diabetes in humans.

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GLP-1 receptor agonist, liraglutide, ameliorates hepatosteatosis induced by anti-CD3 antibody in female mice

Itoh, A., Irie, J., Tagawa, H., Kusumoto, Y., Kato, M., Kobayashi, N., Tanaka, K., Kikuchi, R., Fujita, M., Nakajima, Y., Wu, Y., Yamada, S., Kawai, T., Ridgway, W. M. and Itoh, H.

J Diabetes Complications 31 ( 9 ) 1370 - 1375 2017.09

ISSN 1056-8727

AIMS: Hepatosteatosis is mainly induced by obesity and metabolic disorders, but various medications also induce hepatosteatosis. The administration of anti-CD3 antibody was shown to induce hepatosteatosis, but changes in lipid and glucose metabolism remain unclear. We investigated the mechanism of hepatosteatosis induced by anti-CD3 antibody and the effects of glucagon-like peptide-1 (GLP-1) receptor agonist that was recently shown to affect immune function in metabolic disorders. METHODS: Anti-CD3 antibody was administered to female BALB/c and C.B-17-scid mice with or without reconstitution by naive CD4-positive splenocytes. Hepatic lipid content, serum lipid profile and glucose tolerance were evaluated. Splenic CD4-positive T lymphocytes were stimulated with the GLP-1R agonist, liraglutide, and cytokine production was measured. The effect of liraglutide on metabolic parameters in vivo was investigated in a T-cell activation-induced hepatosteatosis model. RESULTS: The administration of anti-CD3 antibody induced hepatosteatosis, hyperlipidemia, and glucose intolerance. C.B-17-scid mice reconstituted with CD4-positive T lymphocytes developed hepatosteatosis induced by anti-CD3 antibody. Liraglutide suppressed CD4-positive T lymphocyte cytokine expression in vitro and in vivo, and improved hepatosteatosis, glucose tolerance, and insulin sensitivity. CONCLUSIONS: Liraglutide suppressed the activation of CD4-positive T lymphocytes, and improved hepatosteatosis and metabolic disorders induced by T-cell activation in female mice.

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Nanogel-based nasal ghrelin vaccine prevents obesity.

Azegami T, Yuki Y, Sawada S, Mejima M, Ishige K, Akiyoshi K, Itoh H, Kiyono H

Mucosal immunology 10 ( 5 ) 1351 - 1360 2017.09

ISSN 1933-0219

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Intranasal vaccination against angiotensin II type 1 receptor and pneumococcal surface protein A attenuates hypertension and pneumococcal infection in rodents

Azegami, T., Yuki, Y., Hayashi, K., Hishikawa, A., Sawada, S. I., Ishige, K., Akiyoshi, K., Kiyono, H. and Itoh, H.

J Hypertens (Journal of Hypertension) 36 ( 2 ) 387 - 394 2017.08

ISSN 0263-6352

OBJECTIVES: To combat global increases in the prevalence of lifestyle-related diseases and concomitant infectious diseases, we aimed to develop an innovative intranasal vaccine that simultaneously targets both hypertension and pneumonia, is not given by invasive injection, and offers prolonged therapeutic effect and reduced frequency of administration. METHODS: Angiotensin II type 1 receptor-pneumococcal surface protein A (AT1R-PspA) vaccine, consisting of a cationic nanometer-sized hydrogel incorporating AT1R partial peptide conjugated with PspA and cyclic diguanylate monophosphate adjuvant, was created and given intranasally to spontaneously hypertensive rats (SHRs). Antigen-specific antibodies and blood pressure were examined to evaluate immune responses and the antihypertensive effect of the vaccine. To examine the protective effect of antibodies induced by vaccination on pneumococcal infection, sera obtained from immunized SHRs were incubated with a lethal dose of Streptococcus pneumoniae and then administered to mice. RESULTS: Five doses of AT1R-PspA nasal-vaccine-induced AT1R-specific serum IgG antibody production and attenuated the development of hypertension in SHRs in the long term. Both in-vitro and in-vivo studies revealed that responses to angiotensin II were suppressed in vaccinated rats. Mice passively immunized with sera obtained from AT1R-PspA-vaccinated SHRs were protected from lethal pneumococcal infection. CONCLUSION: Intranasal immunization with AT1R-PspA vaccine has the potential to simultaneously attenuate the development of hypertension and protect from lethal pneumococcal infection.

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Investigation of Metabolic Factors Associated with eGFR Decline Over 1 Year in a Japanese Population without CKD

Hayashi, K., Takayama, M., Abe, T., Kanda, T., Hirose, H., Shimizu-Hirota, R., Shiomi, E., Iwao, Y. and Itoh, H.

J Atheroscler Thromb 24 ( 8 ) 863 - 875 2017.08

ISSN 1340-3478

AIM: Early intervention before the progression of chronic kidney disease (CKD) is essential to prevent end-stage renal disease (ESRD) and cardiovascular complications. This study evaluated the correlation between metabolic and lifestyle-related factors and the decline of estimated glomerular filtration rate (eGFR) over 1 year in a Japanese population without CKD. METHODS: Subjects who received two consecutive annual health checkups from 2013 to 2015 were involved. Factors associated with eGFR decline were identified using multiple regression models. RESULTS: A total of 2531 subjects aged 58.9+/-11.7 years old were included in this study. Baseline levels of HDL-C and ApoA1 correlated with the eGFR decline over 1 year defined as eGFR reduction rate of 15% or more and/or eGFR at the next year 60 ml/min/m2 (odds ratio (OR) 0.87 (per 10 mg/dl); 95% CI, 0.80-0.94; p=0.0012, 0.90 (per 10 mg/dl); 0.86-0.96; p=0.0004, respectively). A U-shaped relationship between the eGFR decline and HDL-C or ApoA1 levels was not observed in non-CKD population of this study. Metabolic syndrome was significantly associated with eGFR decline (OR 1.32; 1.04-1.67; p=0.0205), although obesity-related factors did not show a significant correlation with eGFR decline over 1 year. CONCLUSION: Low HDL-C and ApoA1 levels significantly correlated with eGFR decline in a short period of 1 year. Metabolic syndrome also showed a significant association with eGFR decline. This study suggests the importance of hypertension and low HDL-C in the metabolic syndrome effect on eGFR decline rather than obesity in non-CKD population.

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Association of Kidney Dysfunction With Asymptomatic Cerebrovascular Abnormalities in a Japanese Population With Health Checkups

Hayashi, K., Takayama, M., Kanda, T., Kashiwagi, K., Hishikawa, A., Iwao, Y. and Itoh, H.

Circ J 81 ( 8 ) 1191 - 1197 2017.07

ISSN 1346-9843

BACKGROUND: Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.Methods and Results:In total, 1,716 subjects aged 40-80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima-media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m2was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs. CONCLUSIONS: Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.

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Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid

Fujii, C., Miyashita, K., Mitsuishi, M., Sato, M., Fujii, K., Inoue, H., Hagiwara, A., Endo, S., Uto, A., Ryuzaki, M., Nakajima, M., Tanaka, T., Tamaki, M., Muraki, A., Kawai, T. and Itoh, H.

Sci Rep 7 ( 1 ) 4013 2017.06

ISSN 2045-2322

Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.

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Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials

Itoh, H., Kurihara, I., Miyashita, K. and Tanaka, M.

Hypertens Res 40 ( 6 ) 526 - 534 2017.06

ISSN 0916-9636

'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory.

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Bile acid binding resin prevents fat accumulation through intestinal microbiota in high-fat diet-induced obesity in mice

Kusumoto, Y., Irie, J., Iwabu, K., Tagawa, H., Itoh, A., Kato, M., Kobayashi, N., Tanaka, K., Kikuchi, R., Fujita, M., Nakajima, Y., Morimoto, K., Sugizaki, T., Yamada, S., Kawai, T., Watanabe, M., Oike, Y. and Itoh, H.

Metabolism 71 1 - 6 2017.06

ISSN 0026-0495

BACKGROUND: Bile acid binding resin (BAR) absorbs intestinal bile acids, and improves obesity and metabolic disorders, but the precise mechanism remains to be clarified. Recent findings reveal that obesity is associated with skewed intestinal microbiota. Thus, we investigated the effect of BAR on intestinal microbiota and the role of microbiota in the prevention of obesity in high-fat diet-induced obesity in mice. PROCEDURES: Male Balb/c mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD with BAR (HFD+BAR), and then metabolic parameters, caecal microbiota, and metabolites were investigated. The same interventions were conducted in germ-free and antibiotic-treated mice. MAIN FINDINGS: The frequency of Clostridium leptum subgroup was higher in both HFD-fed and HFD+BAR-fed mice than in LFD-fed mice. The frequency of Bacteroides-Prevotella group was lower in HFD-fed mice than in LFD-fed mice, but the frequency was higher in HFD+BAR-fed mice than in HFD-fed mice. Caecal propionate was lower in HFD-fed mice than in LFD-fed mice, and higher in HFD+BAR-fed mice than in HFD-fed mice. HFD+BAR-fed mice showed lower adiposity than HFD-fed mice, and the reduction was not observed in germ-free or antibiotic-treated mice. Colonized germ-free mice showed a reduction in adiposity by BAR administration. Energy expenditure was lower in HFD-fed mice and higher in HFD+BAR-fed mice, but the increments induced by administration of BAR were not observed in antibiotic-treated mice. CONCLUSIONS: Modulation of intestinal microbiota by BAR could be a novel therapeutic approach for obesity.

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Eggshell membrane powder ameliorates intestinal inflammation by facilitating the restitution of epithelial injury and alleviating microbial dysbiosis.

Jia H, Hanate M, Aw W, Itoh H, Saito K, Kobayashi S, Hachimura S, Fukuda S, Tomita M, Hasebe Y, Kato H

Scientific reports 7 43993 2017.03

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A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH)

Kobayashi, S., Yoshimura Noh, J., Shimizu, T., Sato, T., Kurihara, I., Sugino, K., Itoh, H. and Ito, K.

Endocr J 64 ( 2 ) 207 - 212 2017.02

ISSN 0918-8959

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition and is the most commonly inherited euthyroid hyperthyroxinemia in Caucasians. However, it is extremely rare in Asian populations. A 30-year-old Japanese woman, who was incidentally found to have apparent thyroid dysfunction, was admitted to our hospital in 2004. She had extremely elevated serum free thyroxine (FT4), moderately elevated free triiodothyronine (FT3), and normal thyroid-stimulating hormone (TSH). Clinical thyroid examination revealed no abnormalities other than small goiter. Anti-thyroglobulin antibody titer was positive, but titers of other anti-thyroid antibodies, including antithyroid peroxidase antibody, TSH receptor antibodies, and thyroid-stimulating antibody, were negative. Levels of FT3, FT4, and TSH were similar when measured by three different laboratory kits, and FT4 was still high when measured by equilibrium dialysis. By affinity chromatography, FT4, TT4, and albumin were extracted to the same fraction, and the levels of FT4 and TT4 were extremely high. By combination of reversed phase liquid chromatography and mass spectrometry techniques, the amino acid sequence of human serum albumin was determined. The patient was found to be a heterozygote for p.R218P mutation in the gene for human serum albumin and was diagnosed as FDH. This patient, who harbored the p.R218P mutation in the albumin gene, is the fifth case report of FDH in Japan. This condition is characterized by extremely high serum FT4 and moderately high serum FT3 levels. Although rare, FDH should be considered in the differential diagnosis for syndrome of inappropriate secretion of TSH (SITSH) in Japan.

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Temporal trends in renal function and birthweight in Japanese adolescent males (1998-2015)

Kanda, T., Takeda, A., Hirose, H., Abe, T., Urai, H., Inokuchi, M., Wakino, S., Tokumura, M., Itoh, H. and Kawabe, H.

Nephrol Dial Transplant (Nephrology Dialysis Transplantation) 33 ( 2 ) 304 - 310 2017.01

ISSN 0931-0509

Background: Low birthweight (LBW) is a worldwide public health problem, demonstrating an increasing incidence in developed countries, including Japan. LBW is also a risk factor for later development of chronic kidney disease (CKD). To date, studies have not evaluated the population impacts of increasing LBW rates on renal function. Methods: Estimated glomerular filtration rate (eGFR) was evaluated in 3737 Japanese adolescent males (15-16 years old) using annual cross-sectional data over an 18-year period (1998-2015). Results: Between the initial (1998-2003) and final (2010-15) periods of the study, the mean birthweight decreased from 3213.4 +/- 383.8 to 3116.2 +/- 382.3 g and the LBW rate increased from 2.5 to 5.5% (both P </= 0.01). Additionally, the mean eGFR decreased from 105.1 +/- 15.9 to 97.4 +/- 13.8 mL/min/1.73 m 2 and the prevalence of mildly reduced renal function (eGFR </= 60- <90 mL/min/1.73 m 2 ) increased from 16.4 to 30.0% (both P </= 0.01), most evident in the LBW group (from 10.3 to 41.7%, P </=0.01). The prevalence of proteinuria also increased significantly. Mildly reduced renal function was significantly associated with LBW [odds ratio (LBW 3000-3999 g) 1.51; 95% confidence interval 1.00-2.55; P = 0.047]. Conclusions: . In this population of Japanese adolescents, the frequency of mildly reduced renal function increased as the LBW frequency increased. Our findings may have implications for the broader Japanese population as well as for other populations in which the prevalence of LBW is increasing.

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A case of autoimmune polyendocrine syndrome type I with strong positive GAD antibody titer, followed up with glucose tolerance measured by oral glucose tolerance test

Murakami, R., Kawai, T., Meguro, S., Hayashi, M. and Itoh, H.

Neuro Endocrinol Lett 37 ( 8 ) 540 - 542 2017.01

ISSN 0172-780X

A 26-year-old Japanese woman presented with adrenal insufficiency, and treatment was started with cortisone and fludrocortisone in 1975. A few years later, she presented with hypoparathyroidism and was diagnosed with autoimmune polyendocrine syndrome type I (APS I), and treatment with calcium and alfacalcidol was started. She was found to have subacute thyroiditis and relative adrenal failure in 2006. Her condition remained stable under treatment with cortisone, fludrocortisone, levothyroxine, calcium lactate, precipitated calcium carbonate and alfacalcidol. While antibodies against pancreatic glutamic acid decarboxylase (GAD) were strongly positive (7,690 U/ml), fasting glucose level was 4.9 mmol/L and HbA1c was 6.3% on admission. As GAD antibody showed a high-titer of >10,000 U/ml and fasting plasma glucose level showed a rising trend, we performed 75-g oral glucose tolerance test (OGTT) 6 years after discharge. Whereas OGTT in 2012 showed impaired glucose tolerance, glucose tolerance had reverted to normal in 2014. A patient with a high-titer GAD antibody does not always have progressive glucose intolerance. GAD antibody positivity is common in not only type 1 diabetes, but also APS I and stiff-person syndrome (SPS). There are differences in recognized epitopes among the three disorders. Epitopes for GAD65 antibody associated with type 1 diabetes are located in the middle region and the COOH-terminal of the GAD65 protein, whereas epitopes associated with SPS reside in the NH2-terminal in addition to the middle region and COOH-terminal. The present case suggests that these differences in epitopes may be related to various pathogenic mechanisms including glucose intolerance.

Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation

Tamaki, M., Miyashita, K., Hagiwara, A., Wakino, S., Inoue, H., Fujii, K., Fujii, C., Endo, S., Uto, A., Mitsuishi, M., Sato, M., Doi, T. and Itoh, H.

Endocr J 64 ( Suppl. ) S47 - s51 2017

ISSN 0918-8959

Chronic kidney disease (CKD) impairs physical performance in humans, which leads to a risk of all-cause mortality. In our previous study, we demonstrated that a reduction in muscle mitochondria rather than muscle mass was a major cause of physical decline in 5/6 nephrectomized CKD model mice. Because ghrelin administration has been reported to enhance oxygen utilization in skeletal muscle, we examined the usefulness of ghrelin for a recovery of physical decline in 5/6 nephrectomized C57Bl/6 mice, focusing on the epigenetic modification of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha), a master regulator of mitochondrial biogenesis. The mice were intraperitoneally administered acylated ghrelin (0.1 nmol/gBW; three times per week) for a month. Muscle strength and exercise endurance were measured by using a dynamometer and treadmill, respectively. Mitochondrial DNA copy number was determined by quantitative PCR. The methylation levels of the cytosine residue at 260 base pairs upstream of the translation initiation point (C-260) of PGC-1alpha, which has been demonstrated to decrease the expression, was evaluated by methylation-specific PCR and bisulfite genomic sequencing methods after the ghrelin administration. Ghrelin administration improved both muscle strength and exercise endurance in the mice and was associated with an increase in muscle mass and muscle mitochondrial content. Ghrelin administration decreased the methylation ratio of C-260 of PGC-1alpha in the skeletal muscle and increased the expression. Therefore, ghrelin administration effectively reduced the physical decline in 5/6 nephrectomized mice and was accompanied with an increased mitochondrial content through de-methylation of the promoter region of PGC-1alpha in the muscle.

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Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

Sugizaki, T., Zhu, S., Guo, G., Matsumoto, A., Zhao, J., Endo, M., Horiguchi, H., Morinaga, J., Tian, Z., Kadomatsu, T., Miyata, K., Itoh, H. and Oike, Y.

NPJ Aging Mech Dis 3 12 2017

ISSN 2056-3973

A favorable effect of an inhibitor of the sodium-glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA-1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance.

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The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2-type macrophages

Nakajima, A., Nakatani, A., Hasegawa, S., Irie, J., Ozawa, K., Tsujimoto, G., Suganami, T., Itoh, H. and Kimura, I.

PLoS One 12 ( 7 ) e0179696 2017

ISSN 1932-6203

The regulation of inflammatory responses within adipose tissue by various types of immune cells is closely related to tissue homeostasis and progression of metabolic disorders such as obesity and type 2 diabetes. G-protein-coupled receptor 43 (GPR43), which is activated by short-chain fatty acids (SCFAs), is known to be most abundantly expressed in white adipose tissue and to modulate metabolic processes. Although GPR43 is also expressed in a wide variety of immune cells, whether and how GPR43 in adipose tissue immune cells regulates the inflammatory responses and metabolic homeostasis remains unknown. In this study, we investigated the role of GPR43 in adipose tissue macrophages by using Gpr43-deficient mice and transgenic mice with adipose-tissue-specific overexpression of GPR43. We found that GPR43 activation by SCFA resulted in induction of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in anti-inflammatory M2-type macrophages within adipose tissue. By contrast, this effect was not noted in inflammatory M1-type macrophages, suggesting that GPR43 plays distinct functions depending on macrophage types. Local TNF-alpha signaling derived from steady-state adipose tissue is associated with proper tissue remodeling as well as suppression of fat accumulation. Thus, GPR43-involving mechanism that we have identified supports maintenance of adipose tissue homeostasis and increase in metabolic activity. This newly identified facet of GPR43 in macrophages may have clinical implications for immune-metabolism related episodes.

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L-Carnitine improves gastrointestinal disorders and altered the intestinal microbiota in hemodialysis patients

Irie, J., Kanno, Y., Kikuchi, R., Yoshida, T., Murai, S., Watanabe, M., Itoh, H. and Hayashi, M.

Biosci Microbiota Food Health 36 ( 1 ) 11 - 16 2017

ISSN 2186-6953

Patients receiving hemodialysis also manifest gastrointestinal symptoms, such as constipation, caused by restriction of water intake and the loss of body water balance. Because dietary carnitine deficiency is considered to cause smooth muscle dysmotility of the gastrointestinal tract similarly to that in skeletal muscles, carnitine deficiency in hemodialysis patients may be one cause of gastrointestinal discomfort and dysfunctions. We performed a multicenter nonrandomized single-arm prospective clinical trial. Fifteen Japanese patients receiving hemodialysis were administered L-carnitine tablets (900 mg) for 3 months, and clinical and biochemical analyses were performed before and after treatment. The serum total carnitine level was increased significantly by supplementation with L-carnitine for 3 months (from 40.9 +/- 2.6 mumol/l to 172.3 +/- 19.0 mumol/l, p<0.05). The myasthenia score was decreased significantly by the supplementation (from 1.3 +/- 0.3 to 0.8 +/- 0.2, p<0.05). The frequency of passing stool tended to increase with the treatment for 3 months (from 4.2 +/- 0.5 times/week to 4.8 +/- 0.5 times/week). A phyla-level analysis of the microbiota showed that the composition of the individual microbiota was not different between before and after supplementation. A genus-level analysis, however, revealed that the relative abundance of genus Clostridium subcluster 4 was significantly decreased by the supplementation (from 7.7 +/- 1.9% to 4.7 +/- 1.3%, p<0.05). Oral supplementation of L-carnitine to the patients receiving hemodialysis improved not only their muscle discomfort but also their gastrointestinal disorders and microbiota, although its effect on the prognosis of hemodialysis patients should be further investigated.

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[Aging and homeostasis. Age-associated diseases and clinical application of NMN(Nicotinamide Mononucleotide).]

Irie, J. and Itoh, H.

Clin Calcium 27 ( 7 ) 983 - 990 2017

ISSN 0917-5857

Sirtuins are NAD+-dependent deacetylase and have drawn much attention as important regulators of aging and longevity. Because NAD+ decline during the aging process, the approach to regulating aging using NAD+ precursor such as nicotinamide mononucleotide (NMN) to replenish cellular NAD+ through the activation of sirtuins have been investigated. In various animal models, NMN has been shown to mitigate age-associated physiological changes in liver, adipose tissue, muscle, pancreas, kidney, retina, and central nerve system. In animal models of metabolic diseases, NMN has been demonstrated to improve obesity, insulin resistance, and muscle mitochondrial dysfunction. In this review, recent findings in the NMN research will be summarized, and the potential of NMN on the regulation of age-associated diseases in humans will be discussed.

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Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese

Fujii, C., Kawai, T., Azuma, K., Oguma, Y., Katsukawa, F., Hirose, H., Tanaka, K., Meguro, S., Matsumoto, H. and Itoh, H.

J Diabetes Res 2017 1567467 2017

Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r = -0.411, p < 0.0001), fasting glucose (r = -0.330, p < 0.0001), HbA1c (r = -0.231, p = 0.0146), and systolic blood pressure (r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.

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One-year eGFR decline rate is a good predictor of prognosis of renal failure in patients with type 2 diabetes.

Nojima J, Meguro S, Ohkawa N, Furukoshi M, Kawai T, Itoh H

Proceedings of the Japan Academy. Series B, Physical and biological sciences 93 ( 9 ) 746 - 754 2017

ISSN 0386-2208

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