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Koro Gotoh,
Takayuki Masaki,
Seiichi Chiba,
Hisae Ando,
Kansuke Fujiwara,
Takanobu Shimasaki,
Kimihiko Mitsutomi,
Isao Katsuragi,
Tetsuya Kakuma,
Toshiie Sakata, Hironobu Yoshimatsu
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ABSTRACT: Brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild-type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1-R) in BDNF neurons. BDNF-induced feeding suppression was partially attenuated in rats pre-treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1-Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12213.
Journal of Neurochemistry 02/2013; · 4.06 Impact Factor
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ABSTRACT: We have previously shown that an acute osmotic stimulation induces the expression of a c-fos and monomeric red fluorescent protein 1 (mRFP1) fusion transgene in osmosensitive rat brain areas, including the supraoptic (SON) and paraventricular nuclei (PVN). However, the effects of chronic stimuli, such as dehydration, have not been investigated. In the present study, the expression patterns of the c-fos-mRFP1 fusion gene in the forebrain and the brainstem of male and female transgenic rats were studied in seven experimental groups - ad libitum water (euhydration), water deprivation for 12 h, 24 h or 48 h (dehydration) and water deprivation for 46 h plus ad libitum water for 2 h, 6 h or 12 h (rehydration). The number of cells that express nuclear mRFP1 fluorescence was quantified in the hypothalamus, the circumventricular organs and the brainstem. Compared to the euhydrated state, the number of transgene expressing cells significantly increased in all forebrain areas and in the rostral ventrolateral medulla after dehydration and 2 h rehydration. In the nucleus of the solitary tract and area postrema, the number of mRFP1 fluorescent cells was markedly increased after 2 h rehydration. Although the number of mRFP1 fluorescent cells in the organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ remained significantly increased after 6 h rehydration, reaching control levels after 12 h of rehydration, the number of mRFP1 fluorescent cells in the SON and the PVN reached control levels after 6 h rehydration. There were no significant differences between male and female rats. These results show that the expression of the c-fos-mRFP1 fusion gene changes in the forebrain and the brainstem not only after acute osmotic stimulation, but also chronic osmotic stimulation. Interestingly, these studies reveal differential activation of different neuronal groups over the time course of dehydration and rehydration. © 2013 British Society for Neuroendocrinology.
Journal of Neuroendocrinology 01/2013; · 3.14 Impact Factor
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Koro Gotoh,
Megumi Inoue,
Takayuki Masaki,
Seiichi Chiba,
Kentaro Shiraishi,
Takanobu Shimasaki,
Kazue Matsuoka,
Hisae Ando,
Kansuke Fujiwara,
Naoya Fukunaga,
Kohei Aoki,
Tomoko Nawata,
Isao Katsuragi,
Tetsuya Kakuma,
Masataka Seike, Hironobu Yoshimatsu
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ABSTRACT: Background
Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen.Methods
We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated.ResultsObesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice.Conclusions
We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.
Nephrology Dialysis Transplantation 12/2012; · 3.40 Impact Factor
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Koro Gotoh,
Takayuki Masaki,
Seiichi Chiba,
Hisae Ando,
Kansuke Fujiwara,
Takanobu Shimasaki,
Kimihiko Mitsutomi,
Isao Katsuragi,
Tetsuya Kakuma,
Toshiie Sakata, Hironobu Yoshimatsu
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ABSTRACT: Understanding the molecular mechanism of the regulation of glucagon secretion is critical for treating the α cells dysfunction observed in diabetes. GLP-1 analogues reduce plasma glucagon and are thought to contribute to their action to lower blood glucose. It has been previously demonstrated that central administration of brain-derived neurotrophic factor (BDNF) improves glucose metabolism by a mechanism independent of feeding behavior in obese subjects. Using male rats, we examined whether BDNF influences glucagon secretion from α cells through the central nervous system. We investigate whether 1) the central infusion of BDNF stimulates glucagon and/or insulin secretion through pancreatic efferent nerve from the hypothalamus, 2) the intraportal infusion of GLP-1 regulates glucose metabolism through the central and peripheral nervous system, 3) BDNF receptor and/or BDNF-positive fibers are localized nearby α cells of islets. Portal glucagon level decreased with the central administration of BDNF (n=6, in each, p < 0.05), in contrast, there was no significant change in portal insulin, peripheral glucagon and insulin levels with same treatment. This reduction of glucagon secretion was abolished by pancreatic efferent denervation (n=6, in each, p < 0.05). In immunohistochemical study, pancreatic α cells were stained specifically with BDNF and TrkB, a specific receptor for BDNF and α cells were also co-localized with BDNF. Moreover, intraportal administration of GLP-1 decreased glucagon secretion as well as blood glucose whereas it increased the BDNF content in the pancreas; these effects were inhibited with the central infusion of BDNF antibody (n=6, in each, p < 0.05). BDNF and GLP-1 affect glucose metabolism with modulated glucagon secretion from pancreatic α cells through central and peripheral nervous system. © 2012 British Society for Neuroendocrinology.
Journal of Neuroendocrinology 11/2012; · 3.14 Impact Factor
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Koro Gotoh,
Takayuki Masaki,
Seiichi Chiba,
Hisae Ando,
Takanobu Shimasaki,
Kimihiko Mitsutomi,
Kansuke Fujiwara,
Isao Katsuragi,
Tetsuya Kakuma,
Toshiie Sakata, Hironobu Yoshimatsu
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ABSTRACT: Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH) and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affect the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12066.
Journal of Neurochemistry 10/2012; · 4.06 Impact Factor
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ABSTRACT: The aim of the present study is to examine the effects of the antihypertensive drug cilnidipine on glucose metabolism and adipocytokines, including adiponectin, in diet-induced obese (DIO) mice. The effects of cilnidipine on insulin sensitivity and the levels of adiponectin in DIO mice were examined after the mice had been treated with cilnidipine dissolved in water at a dose of 0.2 g l(-1) for 14 days. As expected, treatment with cilnidipine decreased the systolic and diastolic blood pressures in DIO mice, compared with control mice (P<0.05 for each parameter). Cilnidipine treatment improved glucose and insulin sensitivity in DIO mice. In addition, cilnidipine treatment dramatically increased the level of adiponectin in white adipose tissue (P<0.05) and the circulating levels of total and high-molecular weight (HMW) adiponectin in DIO mice (P<0.01 for each parameter). Furthermore, the secretion of HMW adiponectin and the ratio of HMW adiponectin/total adiponectin were both increased after cilnidipine treatment. Finally, the secretion of adiponectin from adipocytes was increased after cilnidipine treatment. Taken together, these results indicate that cilnidipine improves insulin tolerance and adiponectin levels, especially high-molecular type adiponectin, in DIO mice.Hypertension Research advance online publication, 11 October 2012; doi:10.1038/hr.2012.141.
Hypertension Research 10/2012; · 2.58 Impact Factor
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ABSTRACT: INTRODUCTION: Laparoscopic bariatric surgery has gradually spread in Japan since it was introduced in 2000. In 2005, we introduced laparoscopic adjustable gastric banding (LAGB) with the LAP-BAND system into Japan. Here, we evaluate our intermediate-term results with the LAP-BAND system. METHODS: Between August 2005 and June 2010, 27 Japanese patients with morbid obesity (BMI ≥ 35 kg/m(2) ) underwent LAGB with the LAP-BAND system in our institution. Our patients' average weight was 111 kg and BMI was 41 kg/m(2) . All LAGB procedures were performed through the pars flaccida pathway with band fixation using gastric-to-gastric sutures. The average follow-up period was 48 months. RESULTS: All procedures were completed laparoscopically. One early complication (sudden cardiac arrest due to postoperative bleeding) and three late complications (port trouble, megaesophagus, and band slippage) were experienced, and reoperations were performed in three of the patients. Weight loss and percentage of excess weight loss on average were 26 kg and 53% after 3 years and 22 kg and 53% after 6 years, respectively. In line with this good weight loss, comorbidities, especially those of type 2 diabetes and metabolic syndrome were frequently resolved or improved. CONCLUSION: LAGB with the LAP-BAND system appears to be beneficial in obese Japanese patients.
Asian Journal of Endoscopic Surgery 09/2012;
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Koro Gotoh,
Megumi Inoue,
Takayuki Masaki,
Seiichi Chiba,
Takanobu Shimasaki,
Hisae Ando,
Kansuke Fujiwara,
Isao Katsuragi,
Tetsuya Kakuma,
Masataka Seike,
Toshiie Sakata, Hironobu Yoshimatsu
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ABSTRACT: Obesity is associated with systemic low-grade inflammation and obesity-related metabolic disorders. Considering that obesity decreases the expression of proinflammatory cytokines in the spleen, we assessed the role of interleukin (IL)-10, an anti-inflammatory cytokine produced by the spleen, in the pathogenesis of obesity. Changes in obesity-related pathogenesis, including inflammatory responses in multiple organs, were assessed after systemic administration of exogenous IL-10 to splenectomy (SPX)-treated obese wild-type and IL-10 knockout (IL-10KO) mice. Obesity resulted in the inability of the spleen to synthesize cytokines, including IL-10, and proinflammatory cytokines in obesity are then likely to emerge from tissues other than the spleen because serum levels of IL-10, but not proinflammatory cytokines, decreased despite the expression of these cytokines in the spleen being reduced in high fat-induced obese mice. SPX aggravated the inflammatory response in white adipose tissue (WAT) and the liver and suppressed adiposity in WAT. However, it accentuated adiposity in the liver. These SPX-induced changes were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on the inflammatory responses in WAT and the liver of IL-10KO mice. These data show the role of spleen-derived IL-10 in diet-induced changes as a result of inflammatory responses in WAT and the liver.
Diabetes 05/2012; 61(8):1994-2003. · 8.29 Impact Factor
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ABSTRACT: Obesity is considered a systemic low-grade inflammatory state. Although the spleen is the main immune organ with a close anatomical relationship with the liver, its role in the progression of fatty liver disease remains uncertain. Therefore, we sought to clarify the functional role of the spleen in the development of steatohepatitis in high-fat (HF)-diet-induced obese rats. Male Sprague-Dawley rats were fed HF food and divided into two groups, a splenectomy (SPX) group and a sham-operation (Sham) group. The liver and abdominal white adipose tissue (WAT) were removed one and six months after surgery, and we evaluated the effects of SPX on WAT and HF-induced fatty liver. SPX rats exhibited worse dyslipidemia and inflammatory changes in WAT one month after surgery. Hepatic steatosis and inflammation were accelerated by SPX, based on the time after surgery. At one month after surgery, the tissue triglyceride content increased in SPX rats, compared with Sham controls (P < 0.05). The liver histology also showed a worsening of steatosis in those rats. At six months after SPX, dramatic inflammatory and fibrotic changes were observed in liver tissue sections. Hepatic carnitine palmitoyltransferase-1 was suppressed at one and six months after SPX (P < 0.05 for each). WAT and liver tissue levels of inflammatory markers such as tumor necrosis factor-α, and the expression of Kupffer cells were all increased at six months in SPX rats, compared with Sham controls (P < 0.05 for each). Our results indicate that the preservation of the spleen contributes to the prevention of the progression of hepatic steatosis to steatohepatitis in obese rats.
Experimental Biology and Medicine 04/2012; 237(4):461-70. · 2.64 Impact Factor
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ABSTRACT: To clarify the functional roles of urotensin II in regulating energy balance, we investigated the effects of a central infusion of urotensin II on food intake, uncoupling protein (UCP) 1 mRNA expression, temperature, and sympathetic nervous system activity in brown adipose tissue (BAT), a site that regulates energy expenditure in rodents. A bolus central infusion of urotensin II at a dose of 1 nmol/rat into the third cerebral ventricle decreased food intake (p<0.05). Additionally, urotensin II induced c-Fos-like-immunoreactivity (c-FLI) in the paraventricular nucleus (PVN) as compared with that in the control (phosphate buffered saline [PBS]-treated) group. Furthermore, urotensin II increased BAT UCP 1 mRNA expression (p<0.05). Finally, central infusion of urotensin II significantly increased BAT sympathetic nerve activity, which was accompanied by a significant elevation in BAT temperature (p<0.05) in rats. Taken together, central infusion of urotensin II regulates food intake and BAT sympathetic nerve activity in rats.
Peptides 03/2012; 35(1):131-5. · 2.43 Impact Factor
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ABSTRACT: Type 2 diabetes mellitus (DM) is associated with cognitive dysfunction and hippocampus volume. The aim of the present study was to test the hypothesis that the level of the adipocytokine adiponectin correlates with hippocampus volume and insulin resistance in patients with type 2 DM. A total of 45 patients with type 2 DM were divided into two groups: a low adiponectin group and a normal adiponectin group. Hippocampus volume was measured by computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease as the end point for assessment of hippocampus volume. Mean hippocampus volume was lower in the low adiponectin group than in the normal adiponectin group (P<.0001). Fasting serum concentrations of glucose (P<.05) and insulin (P<.0001), and homeostasis model assessment index (P<.0001), were all higher in the low adiponectin group than in the normal adiponectin group. Multiple regression analysis showed that hippocampus volume independently predicted serum adiponectin level. These results suggest that circulating levels of adiponectin are related to hippocampus volume in patients with type 2 DM.
Metabolism: clinical and experimental 03/2012; 61(8):1197-200. · 2.59 Impact Factor
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Kikuko Hotta,
Aya Kitamoto,
Takuya Kitamoto,
Seiho Mizusawa,
Hajime Teranishi,
Rina So,
Tomoaki Matsuo,
Yoshio Nakata,
Hideyuki Hyogo,
Hidenori Ochi, [......],
Kazuyuki Hamaguchi,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa, Hironobu Yoshimatsu,
Toshiie Sakata,
Kiyoji Tanaka,
Yuji Matsuzawa,
Kazuwa Nakao,
Akihiro Sekine
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ABSTRACT: Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.
Journal of Human Genetics 03/2012; 57(5):305-10. · 2.57 Impact Factor
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ABSTRACT: The aim of present study is to clarify the role of apelin in regulating energy homeostasis in brown adipose tissue (BAT). We examined the central effects of apelin-13 on the brain c-fos like immunoreactivity (c-FLI), BAT temperature and the activity of the sympathetic nerve activity innervating BAT in rats. In the hypothalamus, central infusion into the third cerebral ventricle (i3vt) of apelin-13 caused induction of c-FLI in the paraventricular nucleus (PVN) compared with the controls (PBS-treated) group. In addition, microinjection of apelin-13 into the PVN produced significant increases in BAT temperature. Furthermore, microinjection of apelin-13 treatment increased BAT sympathetic nerve activity compared with controls. We conclude that apelin-13 microinjection into PVN increases sympathetic nerve activity innervating BAT.
Brain research bulletin 02/2012; 87(6):540-3. · 2.18 Impact Factor
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Koro Gotoh,
Megumi Inoue,
Kentaro Shiraishi,
Takayuki Masaki,
Seiichi Chiba,
Kimihiko Mitsutomi,
Takanobu Shimasaki,
Hisae Ando,
Kansuke Fujiwara,
Isao Katsuragi,
Tetsuya Kakuma,
Masataka Seike,
Toshiie Sakata, Hironobu Yoshimatsu
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ABSTRACT: Obesity is associated with systemic low-grade inflammation and is a risk factor for non-alcoholic fatty pancreas disease (NAFPD), but the molecular mechanisms of these associations are not clear. Interleukin (IL)-10, a potent anti-inflammatory cytokine, is released during acute pancreatitis and is known to limit inflammatory responses by downregulating the release of proinflammatory mediators. The origin of IL-10 that suppresses pancreatitis has not been investigated. Since obesity is known to reduce expression of proinflammatory cytokines in the spleen, we examined whether spleen-derived IL-10 regulates NAFPD caused by high-fat (HF) diet-induced obesity. The following investigations were performed: 1) IL-10 induction from spleen was examined in male mice fed a HF diet; 2) triglyceride content, expression of pro- and anti-inflammatory cytokines and infiltration of M1 and M2 macrophages were determined to evaluate ectopic fat accumulation and inflammatory responses in the pancreas of splenectomy (SPX)-treated mice fed HF diet; 3) exogenous IL-10 was systemically administered to SPX-treated obese mice and the resulting pathogenesis caused by SPX was assessed; and 4) IL-10 knockout (IL-10KO) mice were treated with SPX and ectopic fat deposition and inflammatory conditions in the pancreas were investigated. Obesity impaired the ability of the spleen to synthesize cytokines, including IL-10. SPX aggravated fat accumulation and inflammatory responses in the pancreas of HF diet-induced obese mice and these effects were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on fat deposition and inflammatory responses in the pancreas of IL-10KO mice. Our findings indicate that obesity reduces IL-10 production by the spleen and that spleen-derived IL-10 may protect against the development of NAFPD.
PLoS ONE 01/2012; 7(12):e53154. · 4.09 Impact Factor
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Koro Gotoh,
Megumi Inoue,
Takayuki Masaki,
Seiichi Chiba,
Takanobu Shimasaki,
Hisae Ando,
Kansuke Fujiwara,
Isao Katsuragi,
Tetsuya Kakuma,
Masataka Seike,
Toshiie Sakata, Hironobu Yoshimatsu
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ABSTRACT: Obesity can be associated with systemic low-grade inflammation that contributes to obesity-related metabolic disorders. Recent studies raise the possibility that hypothalamic inflammation contributes to the pathogenesis of diet-induced obesity (DIO), while another study reported that obesity decreases the expression of pro-inflammatory cytokines in spleen. The following study examines the hypothesis that obesity suppresses the splenic synthesis of the anti-inflammatory cytokine, interleukin (IL)-10, thereby resulting in chronic hypothalamic inflammation. The results showed that due to oxidative stress or apoptosis, the synthesis of splenic IL-10 was decreased in DIO when compared with non-obesity rats. Splenectomy (SPX) accelerated DIO-induced inflammatory responses in the hypothalamus. Interestingly, SPX suppressed the DIO-induced increases in food intake and body weight and led to a hypothalamic pro-inflammatory state that was similar to that produced by DIO, indicating that hypothalamic inflammation exerts a dual effect on energy metabolism. These SPX-induced changes were inhibited by the systemic administration of IL-10. Moreover, SPX had no effect on hypothalamic inflammatory responses in IL-10-deficient mice. These data suggest that spleen-derived IL-10 plays an important role in the prevention of hypothalamic inflammation and may be a therapeutic target for the treatment of obesity and hypothalamic inflammation.
Journal of Neurochemistry 12/2011; 120(5):752-64. · 4.06 Impact Factor
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Keisuke Maeshima,
Kunihiro Yamaoka,
Satoshi Kubo,
Kazuhisa Nakano,
Shigeru Iwata,
Kazuyoshi Saito,
Masanobu Ohishi,
Hisaaki Miyahara,
Shinya Tanaka,
Koji Ishii, Hironobu Yoshimatsu,
Yoshiya Tanaka
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ABSTRACT: Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). The aim of this study was to examine the effects of tofacitinib in vitro and in vivo in RA, in order to elucidate the role of JAK in the disease process.
CD4+ T cells, CD14+ monocytes, and synovial fibroblasts (SFs) were purified from the synovium and peripheral blood of patients with RA and were evaluated for the effect of tofacitinib on cytokine production and cell proliferation. For in vivo analysis, synovium and cartilage samples obtained from patients with RA were implanted in immunodeficient mice (SCID-HuRAg mice), and tofacitinib was administered via an osmotic minipump.
Tofacitinib treatment of CD4+ T cells originating from synovium and peripheral blood inhibited the production of interleukin-17 (IL-17) and interferon-γ (IFNγ) in a dose-dependent manner, affecting both proliferation and transcription, but had no effect on IL-6 and IL-8 production. Tofacitinib did not affect IL-6 and IL-8 production by RASFs and CD14+ monocytes. However, conditioned medium from CD4+ T cells cultured with tofacitinib inhibited IL-6 production by RASFs and IL-8 production by CD14+ monocytes. Treatment of SCID-HuRAg mice with tofacitinib decreased serum levels of human IL-6 and IL-8 and markedly suppressed invasion of synovial tissue into cartilage.
Tofacitinib directly suppressed the production of IL-17 and IFNγ and the proliferation of CD4+ T cells, resulting in inhibition of IL-6 production by RASFs and IL-8 production by CD14+ cells and decreased cartilage destruction. In CD4+ T cells, presumably Th1 and Th17 cells, JAK plays a crucial role in RA synovitis.
Arthritis & Rheumatism 12/2011; 64(6):1790-8. · 7.87 Impact Factor
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ABSTRACT: Aim: This study investigated the correlation between remnant spleen volume after splenectomy (SPX) and the degree of hepatic steatosis and/or inflammation. Methods: Male Sprague-Dawley rats were fed HF food and divided into three groups: sham-operation (Sham) group, a hemisplenectomy (H-SPX) group, and a total-splenectomy (T-SPX) group. Serum was collected and livers removed 12 weeks after surgery. We measured serum lipid markers and evaluated liver changes by comparing the three groups. Additionally, we examined liver changes 24 weeks after SPX. Results: Serum triglyceride and free fatty acid levels after SPX were higher than those of sham controls, and a significant difference was found between T-SPX and the other groups (P < 0.05 for each). Increased intrahepatic fat accumulation was shown in SPX rats along with lower residual spleen volume; this fat accumulation after SPX was accelerated in rats at 24 weeks. Additionally, liver inflammatory changes, including an increase in the Kupffer cell population and pro-inflammatory cytokine production, as well as a high level of oxidative stress, were observed in the liver sections from SPX rats, which correlated significantly with less volume of the residual spleen. Also, an increase in pro-inflammatory cytokine content and a decrease in anti-inflammatory cytokine content were shown in the residual spleen from H-SPX rats, as compared to those of sham controls (P < 0.05 for each). Conclusion: These results indicate the importance of preserving splenic tissue. This residual spleen may play an important role in preventing the progression from diet-induced hepatic steatosis to steatohepatitis.
Hepatology Research 12/2011; 42(2):203-12. · 2.20 Impact Factor
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ABSTRACT: Cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphy is an established method of assessment of cardiovascular sympathetic function. The aim of the present study was to investigate the long-term cardiovascular predictive value of cardiac (123)I-MIBG scintigraphy parameters in Japanese type 2 diabetic patients without structural heart disease.
Cardiac (123)I-MIBG scintigraphy in 108 patients with type 2 diabetes who did not have structural heart disease, was evaluated. The washout rate (WR) was considered enhanced if it was ≥40%. Accurate follow-up information for 4.6 years was obtained in 54 enhanced WR patients (27 male; mean age, 61 ± 11 years) and in 54 sex- and age-matched preserved WR patients (27 male; mean age, 61 ± 10 years). Major adverse cardiac and cerebrovascular events (MACCE) were investigated. During follow-up, 10 enhanced WR patients developed MACCE including cardiac death, coronary revascularization, stroke, and congestive heart failure, while MACCE occurred in only 3 male patients. The Kaplan-Meier curves indicated that enhanced WR patients had higher incidence of MACCE than those with preserved WR (P<0.05). Cox proportional hazards regression analysis showed that age and enhanced WR were independently associated with the incidence of MACCE (hazard ratio, 4.06; 95% confidence interval: 1.194-18.76, P = 0.0237).
Abnormal WR of cardiac (123)I-MIBG scintigraphy at baseline has long-term cardiovascular predictive value in Japanese patients with type 2 diabetes without structural heart disease.
Circulation Journal 11/2011; 76(2):399-404. · 3.77 Impact Factor
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Kikuko Hotta,
Aya Kitamoto,
Takuya Kitamoto,
Seiho Mizusawa,
Hajime Teranishi,
Tomoaki Matsuo,
Yoshio Nakata,
Hideyuki Hyogo,
Hidenori Ochi,
Takahiro Nakamura, [......],
Kazuyuki Hamaguchi,
Kentaro Yamada,
Toshiaki Hanafusa,
Shinichi Oikawa, Hironobu Yoshimatsu,
Toshiie Sakata,
Kiyoji Tanaka,
Yuji Matsuzawa,
Kazuwa Nakao,
Akihiro Sekine
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ABSTRACT: Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.
Journal of Human Genetics 11/2011; 57(1):46-51. · 2.57 Impact Factor
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ABSTRACT: Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppresses food intake. Recent studies indicate that the hepatic vagal afferent nerve is involved in this response. Dipeptidyl peptidase-IV (DPP-IV) inhibitor extends the half-life of endogenous GLP-1 by preventing its degradation. This study aimed to determine whether DPP-IV inhibitor-induced elevation of portal GLP-1 levels affect insulin secretion and feeding behavior via the vagal afferent nerve and hypothalamus. The effect of DPP-IV inhibitor infusion into the portal vein or peritoneum on portal and peripheral GLP-1 levels, food intake, and plasma insulin and glucose was examined in sham-operated and vagotomized male Sprague-Dawley rats. Analyses of neuronal histamine turnover and immunohistochemistry were used to identify the CNS pathway that mediated the response. Intraportal administration of the DPP-IV inhibitor significantly increased portal (but not peripheral) GLP-1 levels, increased insulin levels, and decreased glucose levels. The DPP-IV inhibitor suppressed 1- and 12- but not 24-h cumulative food intake. Intraportal infusion of the DPP-IV inhibitor increased hypothalamic neuronal histamine turnover and increased c-fos expression in several areas of the brain. These responses were blocked by vagotomy. Our results indicate that DPP-IV inhibitor-induced changes in portal but not systemic GLP-1 levels affect insulin secretion and food intake. Furthermore, our findings suggest that a neuronal pathway that includes the hepatic vagal afferent nerve and hypothalamic neuronal histamine plays an important role in the pharmacological actions of DPP-IV inhibitor.
Journal of Neurochemistry 10/2011; 121(1):66-76. · 4.06 Impact Factor
