Saori Hokari, Sachiko Chikahisa, Tetsuya Shiuchi, Yoshiaki Nakayama, Morichika Konishi, Seiji Nishino, Nobuyuki itoh and Hiroyoshi Sei : Social stress alters sleep in FGF21-deficient mice, Brain Research Bulletin, Vol.191, 40-47, 2022.
(要約)
Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress.
P Chavan, Sachiko Chikahisa, Tetsuya Shiuchi, Noriyuki Shimizu, Junhel Dalanon, Kazuo Okura, Hiroyoshi Sei and Yoshizo Matsuka : Dual orexin receptor antagonist drug suvorexant can help in amelioration of predictable chronic mild stress-induced hyperalgesia, Brain Research Bulletin, Vol.188, 39-46, 2022.
(要約)
This study aimed to evaluate the involvement of the orexin system in predictable chronic mild stress (PCMS) and the effects of suvorexant, a dual orexin receptor antagonist, on nociceptive behavior in PCMS. Male C57BL/6 J mice were separated into various PCMS groups: a control group with sawdust on the floor of the rearing cage (C), a group with mesh wire on the floor (M), and a group with water just below the mesh wire (W). Activation of lateral hypothalamic orexin neurons was assessed using immunofluorescence. In another experiment, half of the mice in each group were administered an intraperitoneal injection of suvorexant (10 mg/kg), and the remaining mice were injected with the same amount of vehicle (normal saline). Thermal hyperalgesia was examined using tail immersion and hot plate tests, while mechanical hyperalgesia was investigated using the tail pinch test after 21 days of PCMS. Animals subjected to PCMS showed an increased percentage of activated orexin neurons in the lateral hypothalamic region after 21 days. Mice raised in the PCMS environment showed increased pain sensitivity in several pain tests; however, the symptoms were significantly reduced by suvorexant administration. The findings revealed that PCMS activates hypothalamic orexin neuronal activity, and the use of suvorexant can help attenuate PCMS-induced thermal and mechanical hyperalgesia.
Saori Kakehi, Yoshifumi Tamura, Shin-Ichi Ikeda, Naoko Kaga, Hikari Taka, Noriko Ueno, Tetsuya Shiuchi, Atsushi Kubota, Keishoku Sakuraba, Ryuzo Kawamori and Hirotaka Watada : Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation., American Journal of Physiology, Endocrinology and Metabolism, Vol.321, No.6, E766-E781, 2021.
(要約)
Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization to mice with normal or high-fat diet and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. We found that even short-term immobilization increases intramyocellular diacylglycerol and impairs insulin sensitivity in muscle via enhanced lipin1 activity.
Tetsuya Shiuchi, Airi Otsuka, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle., International Journal of Molecular Sciences, Vol.22, No.19, 2021.
(要約)
Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance.
Daisuke Tanioka, Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi, Noriaki Sakai, Seiji Nishino and Hiroyoshi Sei : Intracranial mast cells contribute to the control of social behavior in male mice., Behavioural Brain Research, Vol.403, 113143, 2021.
(要約)
Mast cells (MCs) exist intracranially and have been reported to affect higher brain functions in rodents. However, the role of MCs in the regulation of emotionality and social behavior is unclear. In the present study, using male mice, we examined the relationship between MCs and social behavior and investigated the underlying mechanisms. Wild-type male mice intraventricularly injected with a degranulator of MCs exhibited a marked increase in a three-chamber sociability test. In addition, removal of MCs in Mast cell-specific Toxin Receptor-mediated Conditional cell Knock out (Mas-TRECK) male mice showed reduced social preference levels in a three-chamber sociability test without other behavioral changes, such as anxiety-like and depression-like behavior. Mas-TRECK male mice also had reduced serotonin content and serotonin receptor expression and increased oxytocin receptor expression in the brain. These results suggested that MCs may contribute to the regulation of social behavior in male mice. This effect may be partially mediated by serotonin derived from MCs in the brain.
Yasumasa Ikeda, Hiroaki Watanabe, Tetsuya Shiuchi, Hirofumi Hamano, Yuya Horinouchi, Masaki Imanishi, Mitsuhiro Goda, Yoshito Zamami, Kenshi Takechi, Yuki Izawa-Ishizawa, Licht Miyamoto, Keisuke Ishizawa, Ken-ichi Aihara, Koichiro Tsuchiya and Toshiaki Tamaki : Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice, Diabetologia, Vol.63, No.8, 1588-1602, 2020.
(要約)
Iron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron-storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes. Conditional macrophage-specific H-ferritin (Fth, also known as Fth1) knockout (LysM-Cre Fth KO) mice were used and divided into four groups: wild-type (WT) and LysM-Cre Fth KO mice with normal diet (ND), and WT and LysM-Cre Fth KO mice with high-fat diet (HFD). These mice were analysed for characteristics of obesity and diabetes, tissue iron content, inflammation, oxidative stress, insulin sensitivity and metabolic measurements. RAW264.7 macrophage cells were used for in vitro experiments. Iron concentration reduced, and mRNA expression of ferroportin increased, in macrophages from LysM-Cre Fth KO mice. HFD-induced obesity was lower in LysM-Cre Fth KO mice than in WT mice at 12 weeks (body weight: KO 34.6 ± 5.6 g vs WT 40.1 ± 5.2 g). mRNA expression of inflammatory cytokines and infiltrated macrophages and oxidative stress increased in the adipose tissue of HFD-fed WT mice, but was not elevated in HFD-fed LysM-Cre Fth KO mice. However, WT mice fed an HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre Fth KO mice fed an HFD (adipose tissue [μmol Fe/g protein]: KO 1496 ± 479 vs WT 2316 ± 866; spleen [μmol Fe/g protein]: KO 218 ± 54 vs WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre Fth KO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and lipopolysaccharide-induced Tnf-α (also known as Tnf) mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA. Deletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes.
Yoshitsugu Kondoh, Sachiko Chikahisa, Tetsuya Shiuchi, Noriyuki Shimizu, Daisuke Tanioka, Haruo Uguisu and Hiroyoshi Sei : Sleep profile during fasting in PPAR-alpha knockout mice., Physiology & Behavior, Vol.214, 112760, 2020.
(要約)
Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that belongs to the nuclear receptor family and plays an important role in regulating gene expression associated with lipid metabolism. PPARα promotes hepatic fatty acid oxidation and ketogenesis in response to fasting. Because energy metabolism is known to affect sleep regulation, manipulations that change PPARα are likely to affect sleep and other physiological phenotypes. In this study, we examined the role of PPARα in sleep/wake regulation using PPARα knockout (KO) mice. Sleep, body temperature (BT), locomotor activity, arterial pressure (AP) and heart rate (HR) were recorded in KO mice and wild-type (WT) controls under ad libitum-fed conditions and 24-hour food deprivation (FD). KO and WT mice were identical in basal sleep amount, BT, mean AP and HR, although KO mice showed enhanced sleepiness (enhanced EEG slow-wave activity). In response to FD, KO mice showed a large drop in wakefulness and locomotor activity at the end of the dark phase, whereas WT mice did not. Similarly, AP and HR, which were suppressed by FD, decreased more in KO than in WT mice. Compared to WT mice, KO mice showed a reduced concentration of plasma ketone bodies and decreased mRNA expression of the ketogenic enzyme gene Hmgcs2 in the liver and brain under FD conditions. These results suggest that PPARα and/or lipid metabolism is involved in the maintenance of wakefulness and locomotor activity during fasting in mice.
Tetsuya Shiuchi, Takuya Masuda, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Dopamine stimulation of the septum enhances exercise efficiency during complicated treadmill running in mice., The Journal of Physiological Sciences, Vol.69, No.6, 1019-1028, 2019.
(要約)
We aimed to identify the neurotransmitters and brain regions involved in exercise efficiency in mice during continuous complicated exercises. Male C57BL/6J mice practiced treadmill running with intermittent obstacles on a treadmill for 8 days. Oxygen uptake (VO
Tetsuya Shiuchi, Yumiko Miyatake, Airi Otsuka, Sachiko Chikahisa, Hiroshi Sakaue and Hiroyoshi Sei : Role of orexin in exercise-induced leptin sensitivity in the mediobasal hypothalamus of mice., Biochemical and Biophysical Research Communications, Vol.514, No.1, 166-172, 2019.
(要約)
Orexin is known as an important neuropeptide in the regulation of energy metabolism. However, the role of orexin in exercise-induced leptin sensitivity in the hypothalamus has been unclear. In this study, we determined the effect of transient treadmill exercise on leptin sensitivity in the mediobasal hypothalamus (MBH) of mice and examined the role of orexin in post-exercise leptin sensitivity. Treadmill running for 45min increased the orexin neuron activity in mice. Intraperitoneal injection of a submaximal dose of leptin after exercise stimulated the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in MBH of mice post-exercise compared with that in non-exercised mice, although intracerebroventricular (icv) injection of leptin did not enhance STAT3 phosphorylation, even after exercise. Icv injection of an orexin receptor antagonist, SB334867 reduced STAT3 phosphorylation, which was enhanced by icv injection of orexin but not by direct injection of orexin into MBH. Exercise increased the phosphorylation of extracellular signal-regulated kinases (ERKs) in the MBH of mice, while ERK phosphorylation was reduced by SB334867. Leptin injection after exercise increased the leptin level in MBH, whereas icv injection of SB334867 suppressed the increase in the leptin level in MBH of mice. These results indicate that the activation of orexin neurons by exercise may contribute to the enhancement of leptin sensitivity in MBH. This effect may be mediated by increased transportation of circulating leptin into MBH, with the involvement of ERK phosphorylation.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa, Noriyuki Shimizu and Hiroyoshi Sei : Sufficient intake of high-fat food attenuates stress-induced social avoidance behavior., Life Sciences, Vol.219, 219-230, 2019.
(要約)
Mice subjected to SDS ate either a high-fat or normal chow diet for 10 days. Behavioral tests were conducted following the completion of the SDS paradigm. The hypothalamus, liver, and blood were examined post-mortem.
Sachiko Chikahisa, Daiki Chida, Tetsuya Shiuchi, Saki Harada, Noriyuki Shimizu, Airi Otsuka, Daisuke Tanioka and Hiroyoshi Sei : Enhancement of fear learning in PPAR knockout mice., Behavioural Brain Research, Vol.359, 664--670, 2019.
(要約)
Peroxisome proliferator-activated receptor alpha (PPAR) is a member of the nuclear receptor superfamily and regulates fatty acid oxidation. Although PPAR is expressed not only in the peripheral tissues but also in the brain, its role in higher brain function is unclear. In this study, we investigated the role of PPAR in the control of behavior, including memory/learning and mood change, using PPAR knockout (KO) mice. A significant difference between wild-type (WT) and KO mice was seen in the passive avoidance test, demonstrating that KO mice showed enhanced fear leaning. In the amygdala of KO mice, the levels of dopamine and its metabolites were increased, and the mRNA expression of dopamine degrading enzyme was decreased. When dopamine D1 receptor antagonist was administered, the enhanced fear learning observed in KO mice was attenuated. These results suggest that PPAR is involved in the regulation of emotional memory via the dopamine pathway in the amygdala.
Tetsuya Shiuchi, Chitoku Toda, Shiki Okamoto, A Eulalia Coutinho, Kumiko Saito, Shinji Miura, Osamu Ezaki and Yasuhiko Minokoshi : Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle 2-adrenergic receptor but not by AMPK., Scientific Reports, Vol.7, No.1, 2017.
Sachiko Chikahisa, Saki Harada, Noriyuki Shimizu, Tetsuya Shiuchi, Airi Otsuka, Seiji Nishino and Hiroyoshi Sei : Mast cell involvement in glucose tolerance impairment caused by chronic mild stress with sleep disturbance., Scientific Reports, Vol.7, No.1, 2017.
(要約)
We have developed a chronic mild stress (MS) mouse model by simply rearing mice on a wire net for 3 weeks and investigated the effects of MS on glucose homeostasis and sleep. MS mice showed impaired glucose tolerance and disturbed sleep. One-week treatment with a histamine H1 receptor antagonist (H1RA) ameliorated the glucose intolerance and improved sleep quality in MS mice. MS mice showed an increased number of mast cells in both adipose tissue and the brain. Inhibition of mast cell function ameliorated the impairment in both glucose tolerance and sleep. Together, these findings indicate that mast cells may represent an important pathophysiological mediator in sleep and energy homeostasis.
There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.
Kanna Oura, Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa, Noriyuki Shimizu and Hiroyoshi Sei : Late feeding in the active period decreases slow-wave activity., Life Sciences, Vol.160, 18-26, 2016.
(要約)
Sleep and feeding behaviors closely interact to maintain energy homeostasis. While it is known that sleep disorders can lead to various metabolic issues such as insulin resistance, the mechanism for this effect is poorly understood. We thus investigated whether different feeding rhythms during the active period affect sleep-wake regulation. For 2weeks, mice were randomly assigned to 1 of 3 feeding schedules as follows: free access to lab chow during the active period (ZT12-24, Ad-lib group), free access to lab chow during the first half of the active period (ZT12-18; Morning group), or free access to lab chow during the second half of the active period (ZT18-24, Evening group). Food intake, body weight, body temperature, locomotor activity, and sleep were evaluated. The hypothalamus and cerebral cortex were examined post-mortem. No alterations in food intake or body weight were observed among the 3 groups. The Evening group showed lower slow-wave activity (SWA) than the other 2 groups, in addition to higher expression of orexin mRNA in the hypothalamus and higher concentrations of dopamine and its metabolites in the cerebral cortex. AMPK phosphorylation was increased in the hypothalamus of mice in the Evening group; however, AMPK inhibition had no effect on SWA. We concluded that late feeding reduces SWA in NREM sleep via a mechanism that involves orexin-mediated arousal in the hypothalamus and elevated monoamines in the cerebral cortex. These data have important implications for the relationship between sleep-wake disturbances and metabolic disorders.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa, Noriyuki Shimizu and Hiroyoshi Sei : Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice., Physiology & Behavior, Vol.151, 264-271, 2015.
(要約)
It is well-established that exercise can influence psychological conditions, cognitive function, and energy metabolism in peripheral tissues including the skeletal muscle. However, it is not clear whether exercise can influence social interaction with others and alleviate defeat stress. This study investigated the effect of voluntary wheel running on impaired social interaction induced by chronic social defeat stress (SDS) using the resident-intruder social defeat model. Mice were divided into three groups: control, stress alone, and stress+exercise. SDS was performed by exposing C57BL/6 mice to retired ICR mice for 2.5 min. The C57BL/6 mice were continuously defeated by these resident (aggressor) mice and, following 5 days of SDS, experienced 2 days of rest with no SDS. Mice in the stress+exercise group were allowed to voluntarily run on a wheel for 2h after every SDS exposure. Two weeks later, compared to the control group, the stress group showed a higher ratio of time spent in the corner zone of a social interaction paradigm even though SDS did not elicit depressive- and anxiety-like behaviors. We also observed that voluntary exercise, which did not affect muscle weight and gene expression, decreased social avoidance behavior of stressed mice without clear changes in brain monoamine levels. Interestingly, food intake in the stress+exercise group was the greatest among the three groups. To test the effect of the exercise-induced increase in food intake on social behavior, we set up a pair-fed group where food intake was restricted. We then compared these mice to mice in the stress alone group. We found that the ratio of time spent in the corner zone of the social interaction test was not different between ad libitum- and pair-fed groups, although pair-fed mice spent more time in the corner zone when an aggressor mouse was present than when it was absent. In addition, pair-feeding did not show exercise-induced reductions of adrenal gland weight and enhanced the loss of body fat. Our findings indicate that voluntary exercise reduces social avoidance behavior induced by SDS. Further, we determined that SDS and exercise-induced increases in food intake partially influence energy metabolism and social avoidance behavior.
Lijun Tang, Shiki Okamoto, Tetsuya Shiuchi, Chitoku Toda, Kazuyo Takagi, Tatsuya Sato, Kumiko Saito, Shigefumi Yokota and Yasuhiko Minokoshi : Sympathetic Nerve Activity Maintains an Anti-inflammatory State in Adipose Tissue in Male Mice by Inhibiting TNF- Gene Expression in Macrophages., Endocrinology, Vol.156, No.10, 3680-3694, 2015.
(要約)
Adipose tissue macrophages (ATMs) play an important role in the inflammatory response in obese animals. How ATMs are regulated in lean animals has remained elusive, however. We now show that the sympathetic nervous system (SNS) is necessary to maintain the abundance of the mRNA for the proinflammatory cytokine tumor necrosis factor- (TNF-) at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti related neuropeptide (AgRP) increased the amount of TNF- mRNA in epididymal (epi) white adipose tissue (WAT), but not in interscapular brown adipose tissue (BAT), through inhibition of sympathetic nerve activity in epiWAT. The surgical denervation and -adrenergic antagonist propranolol up-regulated TNF- mRNA in both epiWAT and BAT in vivo. Signaling by the 2-adrenergic receptor (2-AR) and protein kinase A (PKA) down-regulated TNF- mRNA in epiWAT explants, and suppressed lipopolysaccharide-induced up-regulation of TNF- mRNA in the stromal vascular fraction (SVF) of this tissue. -AR-deficient (-less) mice manifested an increased plasma TNF- concentration and increased TNF- mRNA abundance in epiWAT and BAT. TNF- mRNA abundance was greater in ATMs (CD11b(+) cells of the SVF) from epiWAT or BAT of wild-type mice than in corresponding CD11b(-) cells, and 2-AR mRNA abundance was greater in ATMs than in CD11b(-) cells of epiWAT. Our results show that the SNS and 2-AR-PKA pathway maintain an anti-inflammatory state in ATMs of lean mice in vivo, and that the brain melanocortin pathway plays a role in maintaining this state in WAT of lean mice via the SNS.
Yumiko Miyatake, Tetsuya Shiuchi, Tomoyo Ueta, Yasuko Taniguchi, Akari Futami, Fukiko Sato, Tadahiro Kitamura, Rie Tsutsumi, Nagakatsu Harada, Yutaka Nakaya and Hiroshi Sakaue : Intracerebroventricular injection of adiponectin regulates locomotor activity in rats, The Journal of Medical Investigation : JMI, Vol.62, No.3-4, 199-203, 2015.
(要約)
Enhancing exercise motivation is the best way to prevent obesity and diabetes. In this study, we examined whether adiponectin affects locomotion activity in Wister and Spontaneously-Running Tokushima-Shikoku (SPORTS) rats using two types of behavioral assays: home cage and wheel running activity. SPORTS rats were established from an original line from Wister strain that had shown high level of wheel running activity in our laboratory. Injection of adiponectin into the lateral ventricle of Wister rats and SPORTS rats decreased home cage activity, but no change was observed in the food intake and oxygen consumption. This result indicates the possibility that adiponectin can reduce non-exercise activity thermogenesis (NEAT) and physical activity via the central nervous system. In contrast, injection of adiponectin did not change wheel running activity in SPORTS rats. We produced hypothalamus-destructed model rat using monosodium glutamate (MSG) to elucidate the regulation site of adiponectin. Injection of adiponectin into MSG-treated SPORTS rats did not change amount of home cage activity and food intake, suggesting that adiponectin action on home cage activity was in the hypothalamic area. These results suggest that adiponectin regulates locomotion activity through mediobasal hypothalamus.
Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi and Hiroyoshi Sei : Ketone body metabolism and sleep homeostasis in mice., Neuropharmacology, Vol.79, 399-404, 2014.
(要約)
A link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and -hydroxybutyrate, generated from the breakdown of fatty acids, are major metabolic fuels for the brain under conditions of low glucose availability. Ketogenesis is modulated by the activity of peroxisome proliferator-activated receptor alpha (PPAR), and treatment with a PPAR activator has been shown to induce a marked increase in plasma acetoacetate and decreased -hydroxybutyrate in mice, accompanied by increased slow-wave activity during non-rapid eye movement (NREM) sleep. The present study investigated the role of ketone bodies in sleep regulation. Six-hour sleep deprivation increased plasma ketone bodies and their ratio (acetoacetate/-hydroxybutyrate) in 10-week-old male mice. Moreover, sleep deprivation increased mRNA expression of ketogenic genes such as PPAR and 3-hydroxy-3-methylglutarate-CoA synthase 2 in the brain and decreased ketolytic enzymes such as succinyl-CoA: 3-oxoacid CoA transferase. In addition, central injection of acetoacetate, but not -hydroxybutyrate, markedly increased slow-wave activity during NREM sleep and suppressed glutamate release. Central metabolism of ketone bodies, especially acetoacetate, appears to play a role in the regulation of sleep homeostasis.
Chitoku Toda, Tetsuya Shiuchi, Hiroaki Kageyama, Shiki Okamoto, Eulalia A. Coutinho, Tatsuya Sato, Yuko Okamatsu-Ogura, Shigefumi Yokota, Kazuyo Takagi, Lijun Tang, Kumiko Saito, Seiji Shioda and Yasuhiko Minokoshi : Extracellular SignalRegulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle, Diabetes, Vol.62, No.7, 2295-2307, 2013.
(要約)
Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal-regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle.
Nutritional state in the gestation period influences fetal growth and development. We hypothesized that undernutrition during gestation would affect offspring sleep architecture and/or homeostasis. Pregnant female mice were assigned to either control (fed ad libitum; AD) or 50% dietary restriction (DR) groups from gestation day 12 to parturition. After parturition, dams were fed AD chow. After weaning, the pups were also fed AD into adulthood. At adulthood (aged 8-9 weeks), we carried out sleep recordings. Although offspring mice displayed a significantly reduced body weight at birth, their weights recovered three days after birth. Enhancement of electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (NREM) sleep was observed in the DR mice over a 24-hour period without changing the diurnal pattern or amounts of wake, NREM, or rapid eye movement (REM) sleep. In addition, DR mice also displayed an enhancement of EEG-SWA rebound after a 6-hour sleep deprivation and a higher threshold for waking in the face of external stimuli. DR adult offspring mice exhibited small but significant increases in the expression of hypothalamic peroxisome proliferator-activated receptor (Ppar) and brain-specific carnitine palmitoyltransferase 1 (Cpt1c) mRNA, two genes involved in lipid metabolism. Undernutrition during pregnancy may influence sleep homeostasis, with offspring exhibiting greater sleep pressure.
Nobuya Ogawa, Makoto Ito, Hideki Yamaguchi, Tetsuya Shiuchi, Shiki Okamoto, Korekiyo Wakitani, Yasuhiko Minokoshi and Masamitsu Nakazato : Intestinal fatty acid infusion modulates food preference as well as calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways in rats., Metabolism: Clinical and Experimental, 2012.
(要約)
The intestine plays important roles in the regulation of feeding behavior by sensing macronutrients. Intestinal fatty acids strongly suppress food intake, but little is known about whether intestinal fatty acids affect food preference. We investigated the effects of jejunal fatty acids infusion on food preference by conducting two-diet choice experiments in rats fed a high-fat diet (HFD) and a high-carbohydrate diet (HCD). Jejunal linoleic acid (18:2) infusion reduced HFD intake dose-dependently, while HCD intake increased with the middle dose of the infusion we examined (100 L/h) and reduced to the control level with the higher doses (150 and 200 L/h). -Linolenic acid (18:3), but not caprylic acid (8:0), altered the food preference and total calorie intake in the same manner as linoleic acid. Linoleic acid infusion dose-dependently increased plasma glucagon-like peptide-1, peptide YY and cholecystokinin levels, but not ghrelin levels. Subdiaphragmatic vagotomy or midbrain transection prevented the change in food preference and total calorie intake by linoleic acid infusion. Jejunal linoleic acid infusion increased norepinephrine turnover in the paraventricular hypothalamic nucleus, while intracerebroventricular injection of idazoxan, an 2-adrenergic receptor (AR) antagonist, suppressed the increased HCD intake, but did not affect the decreased HFD intake. These findings indicated that intestinal long-chain fatty acids modulated food preference as well as total calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways. The effects of the 2-AR antagonist in the brain suggested that the brain distinctly controlled HCD and HFD intake in response to jejunal linoleic acid infusion.
Orexins are synthesized by lateral hypothalamic neurons and are suggested to be implicated in feeding behavior. Recent studies have shown that intracerebroventricular administration of orexin-A increases intake of sweet-tasting solution. Effects of suppressing the orexin system on consumption of sweet-tasting solution and sensory processing with sweet taste inputs, however, have yet to be examined. We examined the effects of orexin deficiency on sucrose solution intake, locomotor activity, and preference for sweet solution using male orexin knockout (OxKO) and littermate wild-type (WT) mice. In the dark and over 24-h periods, OxKO mice showed significantly less sucrose intake and lower locomotor activity than WT mice without alteration in food intake whereas preferences for 100 mM sucrose were not different between the genotypes. Moreover, sucrose intake of OxKO mice was significantly less than sucrose intake of a subgroup of WT mice with similar locomotor activity compared to that of OxKO mice. These results suggest that factors other than the lower energy expenditure due to lower locomotor activity are likely responsible for the decreased sucrose intake of OxKO mice. Orexin deficiency may lower the satiety threshold resulting in reduced sucrose intake, without altering food intake.
Kumiko Saito, Suni Lee, Tetsuya Shiuchi, Chitoku Toda, Masahiro Kamijo, Kyoko Inagaki-Ohara, Shiki Okamoto and Yasuhiko Minokoshi : An enzymatic photometric assay for 2-deoxyglucose uptake in insulin-responsive tissues and 3T3-L1 adipocytes., Analytical Biochemistry: Methods in the Biological Sciences, Vol.412, No.1, 9-17, 2011.
(要約)
An enzymatic assay adapted to photometric analysis with 96-well microplates was evaluated for the measurement of 2-deoxyglucose (2DG) uptake in insulin-responsive tissues and differentiated 3T3-L1 adipocytes. For in vivo measurements, a small amount of nonradiolabeled 2DG was injected into mice without affecting glucose metabolism. For photometric quantification of the small amount of 2-deoxyglucose 6-phosphate (2DG6P) that accumulates in cells, we introduced glucose-6-phosphate dehydrogenase, glutathione reductase, and 5,5'-dithiobis(2-nitrobenzoic acid) to the recycling amplification reaction of NADPH. We optimized the enzyme reaction for complete oxidation of endogenous glucose 6-phosphate (G6P) and glucose in mouse tissues in vivo and serum as well as in 3T3-L1 adipocytes in vitro. All reactions are performed in one 96-well microplate by consecutive addition of reagents, and the assay is able to quantify 2DG and 2DG6P in the range of 5-80 pmol. The results obtained with the assay for 2DG uptake in vitro and in vivo in the absence or presence of insulin stimulation was similar to those obtained with the standard radioisotopic method. Thus, the enzymatic assay should prove to be useful for measurement of 2DG uptake in insulin-responsive tissues in vivo as well as in cultured cells.
Kunitoshi Uchida, Katsuya Dezaki, Boldbaatar Damdindorj, Hitoshi Inada, Tetsuya Shiuchi, Yasuo Mori, Toshihiko Yada, Yasuhiko Minokoshi and Makoto Tominaga : Lack of TRPM2 Impaired Insulin Secretion and Glucose Metabolisms in Mice., Diabetes, Vol.60, No.1, 119-126, 2011.
(要約)
OBJECTIVE TRPM2 is a Ca(2+)-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by coapplication of heat and intracellular cyclic adenosine 5'-diphosphoribose, which has been suggested to be involved in intracellular Ca(2+) increase in immunocytes and pancreatic β-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice. RESEARCH DESIGN AND METHODS Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type mice. We also measured cytosolic free Ca(2+) in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets. RESULTS Basal blood glucose levels were higher in TRPM2-KO mice than in wild-type mice without any difference in plasma insulin levels. The OGTT and IPGTT demonstrated that blood glucose levels in TRPM2-KO mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated β-cells, smaller intracellular Ca(2+) increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in wild-type cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an ATP-sensitive potassium channel inhibitor, was not different between the two groups. CONCLUSIONS These results indicate that TRPM2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, TRPM2 may be a new target for diabetes therapy.
Tsutomu Sasaki, Hye-Jin Kim, Masaki Kobayashi, Yukari-Ido Kitamura, Hiromi Yokota-Hashimoto, Tetsuya Shiuchi, Yasuhiko Minokoshi and Tadahiro Kitamura : Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide., Endocrinology, Vol.151, No.6, 2556-2566, 2010.
(要約)
Silent information regulator (SIR)2 is an nicotinamide adenine dinucleotide dependent deacetylase implicated in the regulation of life span in species as diverse as yeast, worms, and flies. Mammalian Sirt1 is the most closely related homolog of the SIR2 gene. Pharmacological activators of Sirt1 have been reported to increase the life span and improve the health of mice fed a high-fat diet and to reverse diabetes in rodents. Sirt1 links the energy availability status with cellular metabolism in peripheral organs including liver, pancreas, muscle, and white adipose tissue. Insulin and leptin signaling regulate food intake by controlling the expression of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of the hypothalamus via Forkhead box O (Foxo)-1 and signal transducer and activator of transcription-3. Sirt1 has been reported to improve insulin sensitivity in vitro, but the role of hypothalamic Sirt1 in regulating feeding has not been addressed. We found that hypothalamic Sirt1 protein levels increase on feeding, and this induction is abrogated in diet-induced obese mice and db/db mice. We also demonstrate for the first time that Sirt1 protein turnover is regulated by the proteasome and ubiquitination in a hypothalamic cell line and in vivo by feeding, and this regulation is not seen in a pituitary cell line AtT20. Forced expression of wild-type Sirt1 in the mediobasal hypothalamus by adenovirus microinjection suppressed Foxo1-induced hyperphagia, a model for central insulin resistance. Moreover, Sirt1 suppressed Foxo1-dependent expression of the orexigenic neuropeptide Agouti-related peptide in vitro. We propose that on feeding, Sirt1 protein is stabilized in the hypothalamus, leading to decreased Foxo1-dependent expression of orexigenic neuropeptide Agouti-related peptide and cessation of feeding.
Kunitoshi Uchida, Tetsuya Shiuchi, Hitoshi Inada, Yasuhiko Minokoshi and Makoto Tominaga : Metabolic adaptation of mice in a cool environment., Pflügers Archiv : European Journal of Physiology, Vol.459, No.5, 765-774, 2010.
(要約)
Homeothermic animals, including humans, live by adapting to changes in ambient temperature. Numerous studies have demonstrated cold exposure (at approximately 5 degrees C) improves glucose tolerance despite reducing insulin secretion and increasing energy expenditure. To determine the effects of a small reduction in ambient temperature on energy metabolism, we compared two groups of mice; one exposed to a cool environment (20 degrees C) and the other maintained in a near-thermoneutral environment (25 degrees C) for 10 days. Both glucose-induced insulin secretion and glucose response were significantly impaired in mice exposed to a cool environment. In the cool temperature-exposed mice, skin temperatures were reduced, and plasma norepinephrine levels were increased, suggesting that impairment of insulin secretion was facilitated by induction of sympathetic nervous activity due to skin cooling. In addition, expression of GLUT4 mRNA was increased significantly in inguinal subcutaneous adipose tissue (IWAT) but not in epididymal or brown adipose tissue or skeletal muscle in these mice. Moreover, expression of Dok1, a molecule linked to activation of insulin receptors in adipocyte hypertrophy, and Cd36, a molecule related to NEFA uptake, were also increased at mRNA and/or protein levels only in IWAT of the cool temperature-exposed mice. Fatty acid synthesis was also facilitated, and fat weights were increased only in IWAT from mice kept at 20 degrees C. These results suggest that a small reduction in ambient temperature can affect glucose homeostasis through regulation of insulin secretion and preferentially enhances fat storage in IWAT. These adaptations can be interpreted as preparation for a further reduction in ambient temperature.
(キーワード)
Adipose Tissue / Animals / Blood Glucose / Body Temperature / Drinking / Eating / Energy Metabolism / Fatty Acids, Nonesterified / Glucose / Insulin / Male / Mice / Mice, Inbred C57BL / Skin Physiological Phenomena / Temperature / Time Factors
Tetsuya Shiuchi, Shahidul Mohammad Haque, Shiki Okamoto, Tsuyoshi Inoue, Haruaki Kageyama, Suni Lee, Chitoku Toda, Atsushi Suzuki, S Eric Bachman, Young-Bum Kim, Takashi Sakurai, Masashi Yanagisawa, Seiji Shioda, Keiji Imoto and Yasuhiko Minokoshi : Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system., Cell Metabolism, Vol.10, No.6, 466-480, 2009.
(要約)
Hypothalamic neurons containing orexin (hypocretin) are activated during motivated behaviors and active waking. We show that injection of orexin-A into the ventromedial hypothalamus (VMH) of mice or rats increased glucose uptake and promoted insulin-induced glucose uptake and glycogen synthesis in skeletal muscle, but not in white adipose tissue, by activating the sympathetic nervous system. These effects of orexin were blunted in mice lacking beta-adrenergic receptors but were restored by forced expression of the beta(2)-adrenergic receptor in both myocytes and nonmyocyte cells of skeletal muscle. Orexin neurons are activated by conditioned sweet tasting and directly excite VMH neurons, thereby increasing muscle glucose metabolism and its insulin sensitivity. Orexin and its receptor in VMH thus play a key role in the regulation of muscle glucose metabolism associated with highly motivated behavior by activating muscle sympathetic nerves and beta(2)-adrenergic signaling.
Chitoku Toda, Tetsuya Shiuchi, Suni Lee, Maya Yamato-Esaki, Yusuke Fujino, Atsushi Suzuki, Shiki Okamoto and Yasuhiko Minokoshi : Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues., Diabetes, Vol.58, No.12, 2757-2765, 2009.
(要約)
The VMH mediates leptin- and MT-II-induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II-induced glucose uptake in peripheral tissues.
Wakako Fujimoto, Tetsuya Shiuchi, Takashi Miki, Yasuhiko Minokoshi, Yoshihisa Takahashi, Ayako Takeuchi, Kazuhiro Kimura, Masayuki Saito, Toshihiko Iwanaga and Susumu Seino : Dmbx1 is essential in agouti-related protein action., Proceedings of the National Academy of Sciences of the United States of America, Vol.104, No.39, 15514-15519, 2007.
(要約)
Dmbx1 is a paired-class homeodomain transcription factor. We show here that mice deficient in Dmbx1 exhibit severe leanness associated with hypophagia and hyperactivity and that isolation of a Dmbx1(-/-) mouse from its cohabitants induces self-starvation, sometimes leading to death, features similar to those of anorexia nervosa in humans. Interestingly, overexpression of agouti in Dmbx1(-/-) mice failed to induce aspects of the A(y)/a phenotype, including hyperphagia, obesity, and diabetes mellitus. In Dmbx1(-/-) mice, administration of agouti-related protein increased cumulative food intake for the initial 6 h but significantly decreased it over 24- and 48-h periods. In addition, Dmbx1 was shown to be expressed at embryonic day 15.5 in the lateral parabrachial nucleus, the rostral nucleus of the tractus solitarius, the dorsal motor nucleus of the vagus, and the reticular nucleus in the brainstem, all of which receive melanocortin signaling, indicating involvement of Dmbx1 in the development of the neural network for the signaling. Thus, Dmbx1 is essential for various actions of agouti-related protein and plays a role in normal regulation of energy homeostasis and behavior.
Adiponectin has been shown to stimulate fatty acid oxidation and enhance insulin sensitivity through the activation of AMP-activated protein kinase (AMPK) in the peripheral tissues. The effects of adiponectin in the central nervous system, however, are still poorly understood. Here, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARH. Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of adiponectin and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system.
Shinji Miura, Kentaro Kawanaka, Yuko Kai, Mayumi Tamura, Masahide Goto, Tetsuya Shiuchi, Yasuhiko Minokoshi and Osamu Ezaki : An increase in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to exercise is mediated by beta-adrenergic receptor activation., Endocrinology, Vol.148, No.7, 3441-3448, 2007.
(要約)
A single bout of exercise increases expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1alpha expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1alpha mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol, but not alpha-, beta1-, or beta3-AR agonists, increased PGC-1alpha mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1alpha mRNA expression in mice was inhibited by pretreatment with the beta-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to beta2-AR agonist, but not alpha-, beta1-, and beta3-AR agonist, led to an increase in levels of PGC-1alpha mRNA. Injection of beta2-AR agonist did not increase PGC-1alpha mRNA expression in beta1-, beta2-, and beta3-AR knockout mice (beta-less mice). PGC-1alpha mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1alpha mRNA was inhibited by approximately 70% by propranolol or the beta2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1alpha mRNA in beta-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1alpha expression in skeletal muscle by exercise is mediated, at least in part, by beta-ARs activation. Among ARs, beta2-AR may mediate an increase in PGC-1alpha by exercise.
Atsushi Suzuki, Shiki Okamoto, Suni Lee, Kumiko Saito, Tetsuya Shiuchi and Yasuhiko Minokoshi : Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase., Molecular and Cellular Biology, Vol.27, No.12, 4317-4327, 2007.
(要約)
Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor alpha (PPARalpha). We now show that leptin stimulates fatty acid oxidation and PPARalpha gene expression in the C2C12 muscle cell line through the activation of AMPK containing the alpha2 subunit (alpha2AMPK) and through changes in the subcellular localization of this enzyme. Activated alpha2AMPK containing the beta1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, alpha2AMPK containing the beta2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPARalpha gene transcription. A nuclear localization signal and Thr(172) phosphorylation of alpha2 were found to be essential for nuclear translocation of alpha2AMPK, whereas the myristoylation of beta1 anchors alpha2AMPK in the cytoplasm. The prevention of alpha2AMPK activation and the change in its subcellular localization inhibited the metabolic effects of leptin. Our data thus suggest that the activation of and changes in the subcellular localization of alpha2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPARalpha gene expression in muscle cells.
Tomohiro Tanaka, Hiroaki Masuzaki, Shintaro Yasue, Ken Ebihara, Tetsuya Shiuchi, Takako Ishii, Naoki Arai, Masakazu Hirata, Hiroshi Yamamoto, Tatsuya Hayashi, Kiminori Hosoda, Yasuhiko Minokoshi and Kazuwa Nakao : Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet., Cell Metabolism, Vol.5, No.5, 395-402, 2007.
(要約)
Little is known about the role of the central melanocortin system in the control of fuel metabolism in peripheral tissues. Skeletal muscle AMP-activated protein kinase (AMPK) is activated by leptin and serves as a master regulator of fatty acid beta-oxidation. To elucidate an unidentified role of the central melanocortin system in muscle AMPK regulation, we treated conscious, unrestrained mice intracerebroventricularly with the melanocortin agonist MT-II or the antagonist SHU9119. MT-II augmented phosphorylation of AMPK and its target acetyl-CoA carboxylase (ACC) independent of caloric intake. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the coadministration of SHU9119 or in KKA(y) mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat-diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin but was markedly restored by MT-II. Our data provide evidence for the critical role of the central melanocortin system in the leptin-skeletal muscle AMPK axis and highlight the system as a therapeutic target in leptin resistance.
(キーワード)
Animals / Blotting, Western / Dietary Fats / Leptin / Melanocortins / Melanocyte-Stimulating Hormones / Metallothionein / Mice / Muscle, Skeletal / Phosphorylation / Protein Kinases / Signal Transduction
Masarsu Iwai, Huan-Sheng Li, Rui Chen, Tetsuya Shiuchi, Lan Wu, Li-Juan Min, Jian-Mei Li, Masahiro Tsuda, Jun Suzuki, Yumiko Tomono, Hirokazu Tomochika, Masaki Mogi and Masatsugu Horiuchi : Calcium channel blocker azelnidipine reduces glucose intolerance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan., The Journal of Pharmacology and Experimental Therapeutics, Vol.319, No.3, 1081-1087, 2006.
(要約)
The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their antioxidative action. Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in the fed state, attenuated the increase in plasma glucose in the oral glucose tolerance test (OGTT), and increased 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake into skeletal muscle with the increase in translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Both blockers also decreased the in situ superoxide production in skeletal muscle. The decrease in plasma concentrations of glucose and insulin in the fed state and superoxide production in skeletal muscle, as well as GLUT4 translocation to the plasma membrane, after azelnidipine administration was not significantly affected by coadministration of an antioxidant, 2,2,6,6-tetramethyl-1-piperidinyloxy (tempol). However, those changes caused by olmesartan were further improved by tempol. Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it. Coadministration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[(3)H]DG uptake in skeletal muscle. These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, as well as the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance.
Masaru Iwai, Rui Chen, Zhen Li, Tetsuya Shiuchi, Jun Suzuki, Ayumi Ide, Masahiro Tsuda, Midori Okumura, Li-Juan Min, Masaki Mogi and Masatsugu Horiuchi : Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice., Circulation, Vol.112, No.11, 1636-1643, 2005.
(要約)
These results suggest that AT2 receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT2 receptor stimulation by unbound Ang II.
Masaru Iwai, Hong-Wei Liu, Rui Chen, Ayumi Ide, Shoko Okamoto, Ryuji Hata, Masahiro Sakanaka, Tetsuya Shiuchi and Masatsugu Horiuchi : Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation., Circulation, Vol.110, No.7, 843-848, 2004.
(要約)
These results suggest that AT2 receptor stimulation has a protective effect on ischemic brain lesions, at least partly through the modulation of cerebral blood flow and superoxide production.
Tetsuya Shiuchi, Masaru Iwai, Huan-Sheng Li, Lan Wu, Li-Juan Min, Jian-Mei Li, Midori Okumura, Tai-Xing Cui and Masatsugu Horiuchi : Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice., Hypertension, Vol.43, No.5, 1003-1010, 2004.
(要約)
Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT1) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling in type 2 diabetic KK-Ay mice. Treatment of KK-Ay mice with valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, significantly increased insulin-mediated 2-[3H]deoxy-d-glucose (2-[3H]DG) uptake into skeletal muscle and attenuated the increase in plasma glucose concentration after a glucose load and plasma concentrations of glucose and insulin. In contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-alpha (TNF-alpha) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane.
Yuko Takeda-Matsubara, Masaru Iwai, Tai-Xing Cui, Tetsuya Shiuchi, Hong-Wei Liu, Midori Okumura, Masaharu Ito and Masatsugu Horiuchi : Roles of angiotensin type 1 and 2 receptors in pregnancy-associated blood pressure change., American Journal of Hypertension, Vol.17, No.8, 684-689, 2004.
(要約)
Our results suggested that disturbance of the balance of the AT1 and AT2 receptors could trigger pregnancy induced hypertension.
Lan Wu, Masaru Iwai, Zhen Li, Tetsuya Shiuchi, Li-Juan Min, Tai-Xing Cui, Jian-Mei Li, Midori Okumura, Clara Nahmias and Masatsugu Horiuchi : Regulation of inhibitory protein-κB and monocyte chemoattractant protein-1 by angiotensin II type 2 receptor-activated Src homology protein tyrosine phosphatase-1 in fetal vascular smooth muscle cells., Molecular Endocrinology, Vol.18, No.3, 666-678, 2003.
(要約)
In the present study we examined the effects of angiotensin II (Ang II) type 2 (AT(2)) receptor stimulation on AT(1) receptor-mediated monocyte chemoattractant protein-1 (MCP-1) expression and the possible mechanisms of AT(2) receptor-mediated signaling in cultured rat fetal vascular smooth muscle cells, which express both AT(1) and AT(2) receptors. Ang II stimulation induced MCP-1 mRNA expression as well as an increase in nuclear factor-kappaB (NF-kappaB) binding to the corresponding cis DNA element of the MCP-1 promoter region and a decrease in the cytosolic inhibitory protein-kappaB (IkappaB) protein level via AT(1) receptor stimulation, whereas stimulation of the AT(2) receptor decreased Ang II-induced MCP-1 expression, NF-kappaB DNA binding, and IkappaB degradation, suggesting that activation of the AT(2) receptor attenuated AT(1) receptor-mediated MCP-1 expression via a decrease in NF-kappaB DNA binding and an increase in IkappaB stability. Moreover, we demonstrated that AT(2) receptor stimulation attenuated TNFalpha-mediated NF-kappaB activation and MCP-1 expression. A tyrosine phosphatase inhibitor, orthovanadate, attenuated the AT(2) receptor-mediated increase in IkappaB protein. Moreover, we observed that two IkappaB subunits (IkappaBalpha and IkappaBbeta) were tyrosine-phosphorylated after Ang II stimulation. Transfection of a dominant-negative Src homology protein tyrosine phosphatase-1 mutant into vascular smooth muscle cells inhibited the AT(2) receptor-mediated increase in IkappaB, leading to a significant increase in AT(1) receptor-induced NF-kappaB activation and MCP-1 expression. Taken together, our results demonstrated that AT(2) receptor stimulation attenuated MCP-1 expression via IkappaB stabilization, and Src homology protein tyrosine phosphatase-1 might play a critical role in the transcriptional regulation of MCP-1 expression through the control of IkappaB protein stability.
(キーワード)
Animals / Cells, Cultured / Chemokine CCL2 / Cytosol / Gene Expression Regulation / I-kappa B Proteins / Imidazoles / Intracellular Signaling Peptides and Proteins / Muscle, Smooth, Vascular / Mutation / NF-kappa B / Oligopeptides / Protein Phosphatase 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Protein Tyrosine Phosphatases / Pyridines / Rats / Rats, Sprague-Dawley / Receptor, Angiotensin, Type 1 / Receptor, Angiotensin, Type 2
Jian-Mei Li, Tai-Xing Cui, Tetsuya Shiuchi, Hong-Wei Liu, Li-Juan Min, Midori Okumura, Toyohisa Jinno, Lan Wu, Masaru Iwai and Masatsugu Horiuchi : Nicotine enhances angiotensin II-induced mitogenic response in vascular smooth muscle cells and fibroblasts., Arteriosclerosis, Thrombosis, and Vascular Biology, Vol.24, No.1, 80-84, 2003.
(要約)
These results suggest that nicotine exerts a growth-promoting effect on vascular cells and enhances the Ang II-induced vasotrophic effect, which is at least partly mediated by the activation of ERK, STAT, and p38MAPK.
Rui Chen, Masaru Iwai, Lan Wu, Jun Suzuki, Li-Juan Min, Tetsuya Shiuchi, Takashi Sugaya, Hong-Wei Liu, Tai-Xing Cui and Masatsugu Horiuchi : Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury., Hypertension, Vol.42, No.4, 542-547, 2003.
(要約)
To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
Zhen Li, Masaru Iwai, Lan Wu, Tetsuya Shiuchi, Toyohisa Jinno, Tai-Xing Cui and Masatsugu Horiuchi : Role of AT2 receptor in the brain in regulation of blood pressure and water intake., American Journal of Physiology, Heart and Circulatory Physiology, Vol.284, No.1, H116-21, 2002.
(要約)
The effects of intracerebroventricular (ICV) injection of angiotensin II (ANG II) on blood pressure and water intake were examined with the use of ANG II receptor-deficient mice. ICV injection of ANG II increased systolic blood pressure in a dose-dependent manner in wild-type (WT) mice and ANG type 2 AT(2) receptor null (knockout) (AT(2)KO) mice; however, this increase was significantly greater in AT(2)KO mice than in WT mice. The pressor response to a central injection of ANG II in WT mice was inhibited by ICV preinjection of the selective AT(1) receptor blocker valsartan but exaggerated by the AT(2) receptor blocker PD-123319. ICV injection of ANG II also increased water intake. It was partly but significantly suppressed both in AT(2)KO and AT(1)aKO mice. Water intake in AT(2)/AT(1)aKO mice did not respond to ICV injection of ANG II. Both valsartan and PD-123319 partly inhibited water intake in WT mice. These results indicate an antagonistic action between central AT(1)a and AT(2) receptors in the regulation of blood pressure, but they act synergistically in the regulation of water intake induced by ANG II.
Takashi Miki, Kohtaro Minami, Li Zhang, Mizuo Morita, Tohru Gonoi, Tetsuya Shiuchi, Yasuhiko Minokoshi, Jean-Marc Renaud and Susumu Seino : ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue., American Journal of Physiology, Endocrinology and Metabolism, Vol.283, No.6, E1178-84, 2002.
(要約)
ATP-sensitive potassium (K(ATP)) channels are known to be critical in the control of both insulin and glucagon secretion, the major hormones in the maintenance of glucose homeostasis. The involvement of K(ATP) channels in glucose uptake in the target tissues of insulin, however, is not known. We show here that Kir6.2(-/-) mice lacking Kir6.2, the pore-forming subunit of these channels, have no K(ATP) channel activity in their skeletal muscles. A 2-deoxy-[(3)H]glucose uptake experiment in vivo showed that the basal and insulin-stimulated glucose uptake in skeletal muscles and adipose tissues of Kir6.2(-/-) mice is enhanced compared with that in wild-type (WT) mice. In addition, in vitro measurement of glucose uptake indicates that disruption of the channel increases the basal glucose uptake in Kir6.2(-/-) extensor digitorum longus and the insulin-stimulated glucose uptake in Kir6.2(-/-) soleus muscle. In contrast, glucose uptake in adipose tissue, measured in vitro, was similar in Kir6.2(-/-) and WT mice, suggesting that the increase in glucose uptake in Kir6.2(-/-) adipocytes is mediated by altered extracellular hormonal or neuronal signals altered by disruption of the K(ATP) channels.
Yuko Takeda-Matsubara, Hironori Nakagami, Masaru Iwai, Tai-Xing Cui, Tetsuya Shiuchi, Masahiro Akishita, Clara Nahmias, Masaharu Ito and Masatsugu Horiuchi : Estrogen activates phosphatases and antagonizes growth-promoting effect of angiotensin II., Hypertension, Vol.39, No.1, 41-45, 2002.
(要約)
Accumulating evidence suggests that estrogen exerts cardioprotective effects and protects against neointima formation in response to vascular injury in vivo, whereas angiotensin (Ang) II stimulation via the Ang II type 1 (AT(1)) receptor exaggerates vascular injury. We postulate that estrogen treatment antagonizes the AT(1) receptor-mediated growth-promoting effects in vascular smooth muscle cells (VSMCs). The present in vitro study was designed to explore this possibility and to establish the cellular mechanism whereby estrogen attenuates the growth of VSMCs. Primary cultures of VSMCs derived from male adult Sprague-Dawley rats express exclusively AT(1) receptors. Treatment with Ang II enhanced proliferation of VSMC and c-fos expression, whereas 17beta-estradiol (E2) attenuated these vasotrophic effects of Ang II. We also demonstrated that E2 attenuated AT(1) receptor-mediated extracellular signal-regulated kinase activation and that this effect of E2 was restored by pretreatment with vanadate or okadaic acid. Moreover, we demonstrated that E2 enhanced SHP-1 activity, rapidly reaching a peak after 3 minutes of E2 stimulation, whereas E2 transactivated mitogen-activated protein kinase phosphatase-1 expression, showing a peak after 60 minutes of E2 treatment. SHP-1 activation was not influenced by actinomycin D treatment, whereas E2-mediated mitogen-activated protein kinase phosphatase-1 expression was attenuated. Taken together, our results suggest a novel mechanism of vasoprotection by which estrogen antagonizes the effect of the AT(1) receptor via the activation and induction of phosphatases through nongenomic as well as genomic signaling.
(キーワード)
Angiotensin Receptor Antagonists / Animals / Cell Cycle Proteins / Cell Division / Cells, Cultured / Drug Interactions / Dual Specificity Phosphatase 1 / Enzyme Activation / Estradiol / Immediate-Early Proteins / Intracellular Signaling Peptides and Proteins / MAP Kinase Signaling System / Male / Mitogen-Activated Protein Kinase Kinases / Muscle, Smooth, Vascular / Phosphoprotein Phosphatases / Protein Phosphatase 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Protein Tyrosine Phosphatases / Rats / Rats, Sprague-Dawley / Receptor Cross-Talk / Receptor, Angiotensin, Type 1 / Receptors, Angiotensin / Receptors, Estrogen
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11799076
Hironori Nakagami, Tai-Xing Cui, Masaru Iwai, Tetsuya Shiuchi, Yuko Takeda-Matsubara, Lan Wu and Masatsugu Horiuchi : Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells., Arteriosclerosis, Thrombosis, and Vascular Biology, Vol.22, No.2, 238-242, 2002.
(要約)
Src homology 2-containing protein-tyrosine phosphatase 1 (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor-alpha (TNF-alpha) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-fos promoter activity, whereas TNF-alpha (5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNF-alpha activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-alpha on thymidine incorporation and c-fos promoter activity. In addition, TNF-alpha attenuated vascular endothelial growth factor- and epidermal growth factor-induced extracellular signal-regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF-alpha. Taken together, our results suggested that TNF-alpha inhibited growth factor-mediated cell proliferation through SHP-1 activation.
(キーワード)
Cattle / Cell Division / DNA / Endothelial Growth Factors / Endothelium, Vascular / Epidermal Growth Factor / Humans / Lymphokines / Mitogen-Activated Protein Kinases / Phosphorylation / Protein Phosphatase 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Protein Tyrosine Phosphatases / Tumor Necrosis Factor-alpha / Vascular Endothelial Growth Factor A / Vascular Endothelial Growth Factors
Tai-Xing Cui, Hironori Nakagami, Clara Nahmias, Tetsuya Shiuchi, Yuko Takeda-Matsubara, Jian-Mei Li, Lan Wu, Masaru Iwai and Masatsugu Horiuchi : Angiotensin II subtype 2 receptor activation inhibits insulin-induced phosphoinositide 3-kinase and Akt and induces apoptosis in PC12W cells., Molecular Endocrinology, Vol.16, No.9, 2113-2123, 2002.
(要約)
In the present study, we identified novel negative cross-talk between the angiotensin II subtype 2 (AT2) receptor and insulin receptor signaling in the regulation of phosphoinositide 3-kinase (PI3K), Akt, and apoptosis in rat pheochromocytoma cell line, PC12W cells, which exclusively express AT2 receptor. We demonstrated that insulin-mediated insulin receptor substrate (IRS)-2-associated PI3K activity was inhibited by AT2 receptor stimulation, whereas IRS-1-associated PI3K activity was not significantly influenced. AT2 receptor stimulation did not change insulin-induced tyrosine phosphorylation of IRS-2 or its association with the p85alpha subunit of PI3K, but led to a significant reduction of insulin-induced p85alpha phosphorylation. AT2 receptor stimulation increased the association of a protein tyrosine phosphatase, SHP-1, with IRS-2. Moreover, we demonstrated that AT2 receptor stimulation inhibited insulin-induced Akt phosphorylation and that insulin-mediated antiapoptotic effect was also blocked by AT2 receptor activation. Overexpression of a catalytically inactive dominant negative SHP-1 markedly attenuated the AT2 receptor- mediated inhibition of IRS-2-associated PI3K activity, Akt phosphorylation, and antiapoptotic effect induced by insulin. Taken together, these results indicate that AT2 receptor-mediated activation of SHP-1 and the consequent inhibition IRS-2-associated PI3K activity contributed at least partly to the inhibition of Akt phosphorylation, thereby inducing apoptosis.
Tetsuya Shiuchi, Tai-Xing Cui, Lan Wu, Hironori Nakagami, Yuko Takeda-Matsubara, Masaru Iwai and Masatsugu Horiuchi : ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO., Hypertension, Vol.40, No.3, 329-334, 2002.
(要約)
Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[3H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.
(キーワード)
Animals / Biological Transport / Blood Glucose / Bradykinin / Cell Line / Deoxyglucose / Diabetes Mellitus, Type 2 / Glucose Transporter Type 4 / Insulin Receptor Substrate Proteins / Insulin Resistance / Kinetics / Male / Mice / Mice, Inbred C57BL / Monosaccharide Transport Proteins / Muscle Proteins / Muscle, Skeletal / Nitric Oxide / Phosphoproteins / Phosphorylation / Protein Transport / Thiazepines
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12215475
T Miki, B Liss, K Minami, Tetsuya Shiuchi, A Saraya, Y Kashima, M Horiuchi, F Ashcroft, Y Minokoshi, J Roeper and S Seino : ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis., Nature Neuroscience, Vol.4, No.5, 507-512, 2001.
(要約)
Glucose-responsive (GR) neurons in the hypothalamus are thought to be critical in glucose homeostasis, but it is not known how they function in this context. Kir6.2 is the pore-forming subunit of K(ATP) channels in many cell types, including pancreatic beta-cells and heart. Here we show the complete absence of both functional ATP-sensitive K+ (K(ATP)) channels and glucose responsiveness in the neurons of the ventromedial hypothalamus (VMH) in Kir6.2-/- mice. Although pancreatic alpha-cells were functional in Kir6.2-/-, the mice exhibited a severe defect in glucagon secretion in response to systemic hypoglycemia. In addition, they showed a complete loss of glucagon secretion, together with reduced food intake in response to neuroglycopenia. Thus, our results demonstrate that KATP channels are important in glucose sensing in VMH GR neurons, and are essential for the maintenance of glucose homeostasis.
Tetsuya Shiuchi, H Nakagami, M Iwai, Y Takeda, T Cui, R Chen, Y Minokoshi and M Horiuchi : Involvement of bradykinin and nitric oxide in leptin-mediated glucose uptake in skeletal muscle., Endocrinology, Vol.142, No.2, 608-612, 2001.
(要約)
Regulation of glucose metabolism in peripheral tissues by leptin has been highlighted recently, although its mechanism is unclear. In this study, we postulated that bradykinin and nitric oxide (NO) are involved in the effect of leptin-mediated glucose uptake in peripheral tissues and examined these possibilities. Injection of leptin (200 pg/mouse) into the ventromedial hypothalamus-enhanced glucose uptake in skeletal muscle and brown adipose tissue, but not in white adipose tissue. Treatment with Hoe140 (0.1 mg/kg), bradykinin B2 receptor antagonist, or L-NAME (N:(G)-nitro-L-arginine methyl ester) (30 mg/kg), nitric oxide synthase inhibitor, did not influence the basal level of glucose uptake in skeletal muscle and the adipose tissue, whereas Hoe140 and L-NAME inhibited leptin-mediated glucose uptake in skeletal muscles, but had no effect in adipose tissue. However, Hoe140 and L-NAME did not inhibit insulin (1.0 U/kg)-mediated glucose uptake in all tissues examined. Taken together, these results suggest that leptin enhances bradykinin and/or the NO system, which contributes at least partially to the enhanced glucose uptake in skeletal muscles.
T Cui, H Nakagami, M Iwai, Y Takeda, Tetsuya Shiuchi, L Daviet, C Nahmias and M Horiuchi : Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell., Cardiovascular Research, Vol.49, No.4, 863-871, 2001.
(要約)
These results indicate that a crosstalk between AT1 and AT2 receptors regulates the survival of fetal VSMCs and substantiate SHP-1 as a key molecule in AT2 receptor signaling.
(キーワード)
Angiotensin II / Animals / Apoptosis / Cells, Cultured / Enzyme Activation / Immunoblotting / Intracellular Signaling Peptides and Proteins / Mitogen-Activated Protein Kinases / Muscle, Smooth, Vascular / Phosphorylation / Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Protein Tyrosine Phosphatases / Rats / Rats, Sprague-Dawley / Receptor Cross-Talk / Receptor, Angiotensin, Type 1 / Receptor, Angiotensin, Type 2 / Receptors, Angiotensin
T Cui, H Nakagami, M Iwai, Y Takeda, Tetsuya Shiuchi, K Tamura, L Daviet and M Horiuchi : ATRAP, novel AT1 receptor associated protein, enhances internalization of AT1 receptor and inhibits vascular smooth muscle cell growth., Biochemical and Biophysical Research Communications, Vol.279, No.3, 938-941, 2000.
(要約)
We have identified a novel, membrane-located protein that interacts specifically with the carboxyl-terminal cytoplasmic domain of the AT1a receptor, which we named ATRAP (for AT1 receptor-associated protein). To further investigate the role of ATRAP in AT1 receptor function, we examined the effect of overexpression of ATRAP on angiotensin II (Ang II)-induced AT1 receptor desensitization and/or internalization, and cell proliferation in adult vascular smooth muscle cells (VSMCs). Transfection of ATRAP potentiated AT1 receptor internalization upon Ang II stimulation in these VSMCs. Moreover, we observed that AT1 receptor-induced DNA synthesis was markedly inhibited in ATRAP transfected VSMCs associated with the inhibition of the phosphorylation of signal transducers and activators of transcription (STAT) 3 and Akt. Our results suggest that ATRAP functions as a negative regulator in AT1 receptor-mediated cell proliferation in VSMCs.
<p> A molecular clock exists within almost all organizations in a living body, and these clocks influence the periodicity of many physiological phenomena such as eating behaviors, the sleep-wake cycle, and hormone secretion. Especially, a living body's energy metabolism is involved with the molecular clocks genetically driven in peripheral tissues, which act in strong relation to eating rhythms. However, the possibility that rhythms may also have an inverse influence has recently been pointed out. In this manuscript, we review the outline of circadian rhythms, then refer to the possibility that a clock gene in the peripheral tissues, capable of being changed by eating rhythms, may influence sleep-wake regulation and energy metabolism.</p>
Yasuhiko Minokoshi, Tetsuya Shiuchi, Suni Lee, Atsushi Suzuki and Shiki Okamoto : Role of hypothalamic AMP-kinase in food intake regulation., Nutrition, Vol.24, No.9, 786-790, 2008.
(要約)
Adenosine monophosphate-activated protein kinase (AMPK) functions as a cellular fuel gauge that regulates metabolic pathways in nutrient metabolism. Recent studies have strongly implicated that AMPK in the hypothalamus regulates energy metabolism by integrating inputs from multiple hormones, peptides, neurotransmitters, and nutrients. Leptin is an adipocyte hormone that regulates food intake and energy expenditure in peripheral tissues. Leptin inhibits AMPK activity in the arcuate and paraventricular hypothalamus, and its inhibition is necessary for the anorexic effect of leptin. Alteration of hypothalamic AMPK activity is sufficient to change food intake and body weight. Furthermore, fasting/refeeding, glucose, and melanocortin receptor alter AMPK activity in the hypothalamus. Adiponectin has also been shown to increase food intake by activating AMPK in the arcuate hypothalamus. Recent data have shown that acetyl-coenzyme A carboxylase/malonyl-coenzyme A/carnitine palmitoyltransferase-1/fatty acid oxidation and mammalian target of rapamycin signalings are putative downstream pathways for food intake regulation in response to hypothalamic AMPK. Thus, these results suggest that food intake and nutrient metabolism are coordinately regulated by the common signaling pathway of AMPK in the hypothalamus.
(キーワード)
Animals / Body Weight / Eating / Energy Metabolism / Feeding Behavior / Hormones / Hypothalamus / Leptin / Mice / Signal Transduction
Tetsuya Shiuchi, Takuya Masuda, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Role of dopaminergic function in septum on exercise efficiency, FAOSP2019, Mar. 2019.
2.
Sachiko Chikahisa, Tetsuya Shiuchi, Tanioka Daisuke, Noriyuki Shimizu, Otsuka Airi and Hiroyoshi Sei : Chronic mild stress increases aggressive behavior in mice, FAOPS 2019, Kobe, Mar. 2018.
3.
Airi Otsuka, Tetsuya Shiuchi and Hiroyoshi Sei : Intake timing and amounts of high fat diet affect the benefit which improves social avoidance induced by social defeat stress, The 26th Annual Meeting of the IBNS, Jun. 2017.
4.
Sachiko Chikahisa, Harada Saki, Noriyuki Shimizu, Tetsuya Shiuchi, Nishino Seiji and Hiroyoshi Sei : Sleep loss induces diabetes in mice model, Neuroscience 2016, San Diego, USA, Nov. 2016.
5.
Noriyuki Shimizu, Yu Yoshioka, Sachiko Chikahisa, Yuki Kito, Tetsuya Shiuchi and Hiroyoshi Sei : Short time running exercise enhances sleep pressure in mice., Neuroscience 2016, San Diego, USA, Nov. 2016.
6.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa and Hiroyoshi Sei : Restricted high fat diet can improve social avoidance induced by social-defeat stress as same as ad libitum high fat feeding, Neuroscience 2016, Nov. 2016.
7.
Tetsuya Shiuchi : Motivation for wheel running is enhanced by peripheral PPAR-alpha stimulation in mice, Intergrative Biology of Exercise VII, Vol.Phoenix, Nov. 2016.
8.
Tetsuya Shiuchi : Hypothalamic control of insulin sensitivity in skeletal muscle is modulated by feeding rhythm, Keystone Symposia "Diabetes: New Insights into Molecular Mechanisms and Therapeutic Strategies ", Kyoto, Oct. 2015.
9.
Tetsuya Shiuchi : Hypothalamic regulation of insulin sensitivity in skeletal muscle is influenced by feeding rhythm during active phase, 8th Asia-Oceania Conference on Obesity, Nagoya, Oct. 2015.
10.
Yumiko Miyatake, Tetsuya Shiuchi, C. Azuma, R Tsutsumi, N Harada, H Sei, Y Minokoshi, K Goto, Y Nakaya and H Sakaue : Intracerebroventricular injection of ghrelin decreases wheel running activity in rats., Cell Symposia "Exercise Metabolism", Amsterdam, Jul. 2015.
11.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa, Junji Terao and Hiroyoshi Sei : Ingestion of restrickted comfortable food improves social avoidance induced by social defeat stress, 12th Asian Congress of Nutrition, Yokohama, May 2015.
12.
Tetsuya Shiuchi, Airi Otuska, Sachiko Chikahisa, Noriyuki Shimizu and Hiroyoshi Sei : Feeding rhythm during active phase influences hypothalamic regulation of insulin sensitivity in skeletal muscle, 12th Asian Congress of Nutrition, Yokohama, May 2015.
13.
Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi and Hiroyoshi Sei : Contribution of PPARa and Ketone Body to Sleep Homeostasis in Mice, The FASEB journal, Boston, Apr. 2015.
14.
Tetsuya Shiuchi, Airi Otuska, Sachiko Chikahisa, Noriyuki Shimizu and Hiroyoshi Sei : Hypothalamic AgRP-mediated energy metabolism in skeletal muscle is a critical regulatory system in feeding rhythm-induced insulin resistance, Experimental Biology 2015, Boston, Mar. 2015.
15.
Sachiko Chikahisa, Saki Harada, Noriyuki Shimizu, Tetsuya Shiuchi and Hiroyoshi Sei : Sleep quality affects glucose homeostasis in a mouse model, Homeodynamics in Clocks, Sleep and Metabolism, Tokyo Translational Therapeutics Meeting, Sep. 2014.
16.
Tetsuya Shiuchi : Feeding rhythm during active phase influences hypothalamic regulation of energy metabolism in skeletal muscle, Tokyo Translational Therapeutics Meeting "Homeodynamics in Clocks, Sleep and Metabolism", Sep. 2014.
17.
Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi and Hiroyoshi Sei : Ketone bodies in the brain regulate sleep homeostasis in mice, Gordon Research Conference on Sleep Regulation and Function, Galveston, USA, Mar. 2014.
18.
Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi and Hiroyoshi Sei : Ketone bodies regulate sleep homeostasis, Neuroscience 2013, Nov. 2013.
(要約)
Ketone bodies regulate sleep homeostasis 2013, Nov 9-13, Neuroscience 2013 (San Diego, USA)
19.
Kanna Oura, Tetsuya Shiuchi, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Effect of feeding rhythm on sleep/wake regulation, EASD, Sep. 2013.
20.
Tetsuya Shiuchi, Sachiko Chikahisa, Kanna Oura, Noriyuki Shimizu and Hiroyoshi Sei : Different feeding rhythm influences hypothalamic regulation of energy metabolism in skeletal muscle, EASD, Sep. 2013.
21.
Saki Harada, Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi and Hiroyoshi Sei : Does sleep loss induce diabetes?, 49th EASD, Sep. 2013.
22.
Sachiko Chikahisa, Noriyuki Shimizu, Hiroaki Fujihara, Tetsuya Shiuchi and Hiroyoshi Sei : Sleep homeostatic regulations in PPAR-knockout mice, Frontiers in Behavioral Brain Science-Solving the mystery of sleep-, Tokyo, Mar. 2012.
23.
Hiroyoshi Sei, Kazuyoshi Kitaoka, Nobuhiro Fujiki, Noriyuki Shimizu, Sachiko Chikahisa, Hiroaki Fujihara, Tetsuya Shiuchi and A Nakai : Mice lacking heat shock factor 1 show evening-type sleep/wake rhythm, World sleep 2011, Kyoto, Oct. 2011.
24.
Sachiko Chikahisa, Noriyuki Shimizu, Kazuyoshi Kitaoka, Yohei Iwaki, Hiroaki Fujihara, Tetsuya Shiuchi and Hiroyoshi Sei : Sleep/wake regulation in PPAR knockout mice, World sleep 2011, Oct. 2011.
25.
Tetsuya Shiuchi, Shiki Okamoto, Chitoku Toda and Yasuhiko Minokoshi : Hypothalamic orexin stimulates feeding-associated glucose metabolism in skeletal muscle via sympathetic nervous system, The 11th International Congress of Obesity, Jul. 2010.
Noriyuki Shimizu, Sachiko Chikahisa, Tetsuya Shiuchi and Hiroyoshi Sei : Paternal psychological stress exposure prior to mating may cause an impairment of emotional behavior in the next generation via glucocorticoid system, 第46回日本神経科学大会, Aug. 2023.
6.
Tetsuya Shiuchi, Otsuka Airi, Chikahisa Sachiko, Shimizu Noriyuki and Sei Hiroyoshi : Effect of differences in feeding rhythm during gestation on offspring behavior, The 100th Anniversary Annual Meeting of The Physiological Society of Japan, Mar. 2023.
7.
Noriyuki Shimizu, Sachiko Chikahisa, Tetsuya Shiuchi and Hiroyoshi Sei : Exercise training of paternal mice subjected to continuous psychological stress prior to mating may modify changes in their offsprings emotional behaviors, 日本生理学会 第100回記念大会, Mar. 2023.
Noriyuki Shimizu, Sachiko Chikahisa, Tetsuya Shiuchi and Hiroyoshi Sei : Paternal exposure to psychological stress before mating may influence a formation of emotional behavior in next generation via effect of glucocorticoid, 第45回日本分子生物学会年会, Dec. 2022.
Tetsuya Shiuchi : Homeostatic coordination via alteration of hypothalamic energy sensor by feeding time. Planned Symposium-03 "Integration of sensory and metabolic signals by neuropeptide in hypothalamus", The 97th Annual Meeting of the Physiological Society of Japan, Apr. 2020.
Tetsuya Shiuchi, Keisuke Hashimoto, Ayaka Hashimoto, Airi Otsuka, Sachiko Chikahisa and Hiroyoshi Sei : Dopaminergic neuron activation via gut PPAR-alpha enhanced the motivation for wheel running in mice, NEURO2019, Jul. 2019.
Noriyuki Shimizu, Sachiko Chikahisa, Tetsuya Shiuchi, Airi Otsuka, Daisuke Tanioka and Hiroyoshi Sei : Paternal psychological stress just before mating influences a formation of emotional behavior in next generation offspring mice, The 41st Annual Meeting of the Japan Neuroscience Society, Jul. 2018.
31.
Daisuke Tanioka, Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi, Airi Otsuka and Hiroyoshi Sei : Social behavior is affected by mast cells activity in mice, The 41st Annual Meeting of the Japan Neuroscience Society, Jul. 2018.
32.
増田 拓也, Tetsuya Shiuchi, Sachiko Chikahisa, Noriyuki Shimizu and Hiroyoshi Sei : 中隔核でのドパミン作用と運動効率の関係, 第41回日本神経科学学会大会, Jul. 2018.
33.
大塚 愛理, Tetsuya Shiuchi and Hiroyoshi Sei : 社会敗北性ストレスはβ-アドレナリン受容体を介して血漿中FGF21を増加させる, 第41回日本神経科学学会大会, Jul. 2018.
Noriyuki Shimizu, Sachiko Chikahisa, Tetsuya Shiuchi, Daisuke Tanioka, Airi Otsuka and Hiroyoshi Sei : Paternal psychological stress causes an impairment of emotional behavior in offspring mice, The 95th Annual Meeting of the Physiological Society of Japan, Mar. 2018.
38.
Daisuke Tanioka, Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi, Airi Otsuka and Hiroyoshi Sei : The role of brain mast cells in mood and behavior, The 95th Annual Meeting of the Physiological Society of Japan, Mar. 2018.
Tetsuya Shiuchi, Noriyuki Shimizu, Airi Otsuka, Sachiko Chikahisa and Hiroyoshi Sei : Alteration of behavior in offspring born from mother lived in the different feeding rhythm during pregnancy, The 94th Annual Meeting of the Physiological Society of Japan, Mar. 2017.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa and Hiroyoshi Sei : Restricted high-fat diet is enough to improve social avoidance induced by social-defeat stress, The 39th Annual Meeting of the Japan Neuroscience Society, Jul. 2016.
64.
Noriyuki Shimizu, Yu Yoshioka, Takafumi Misaki, Yuki Kito, Sachiko Chikahisa, Tetsuya Shiuchi and Hiroyoshi Sei : Sleep depth is affected by acute running exercise in mice., The 39th Annual Meeting of the Japan Neuroscience Society, Jul. 2016.
65.
Tetsuya Shiuchi, Noriyuki Shimizu, Airi Otsuka, Sachiko Chikahisa and Hiroyoshi Sei : Behavior alteration on offspring born from mother lived in the different feeding rhythm during pregnancy, The 39th Annual Meeting of the Japan Neuroscience Society, Jul. 2016.
Noriyuki Shimizu, Yu Yoshioka, Takafumi Misaki, Sachiko Chikahisa, Tetsuya Shiuchi and Hiroyoshi Sei : Acute running exercise enhances sleep in mice, The 93rd Annual Meeting of the Physiological Society of Japan, Mar. 2016.
70.
Yuki Kito, Keisuke Hashimoto, Ayaka Hashimoto, Sachiko Chikahisa, Hiroyoshi Sei and Tetsuya Shiuchi : Exercise motivation is enhaced by peripheral PPAR-alpha stimulation, 93rd the Annual Meeting of the Physiological Society of Japan, Mar. 2016.
71.
Yumiko Miyatake and Tetsuya Shiuchi : The Effect of Voluntary Exercise of Metabolism-Related Signal Molecule, Ghrelin, 93rd the Annual Meeting of the Physiological Society of Japan, Mar. 2016.
72.
Airi Otsuka, Kanna Oura, Tetsuya Shiuchi, Sachiko Chikahisa and Hiroyoshi Sei : Relationship between feeding rhythm and sleep pressure, 93rd Annual Meeting of the Physiological Society of Japan, Mar. 2016.
Tetsuya Shiuchi : Hypothalamic regulation of energy metabolism by feeding rhythm, 92nd Annual Meeting of The Physiological Society of Japan, Mar. 2015.
79.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa, Junji Terao and Hiroyoshi Sei : Physical exercise reduces social avoidance induced by defeated stress, 92nd Annual Meeting of The Physiological Society of Japan, Mar. 2015.
Airi Otsuka, Tetsuya Shiuchi, Sachiko Chikahisa, Junji Terao and Hiroyoshi Sei : Effect of restricted high fat diet intake on behavior induced by social defeat stress, The 37th Annual Meeting of the Japan Neuroscience Society, Sep. 2014.
Tetsuya Shiuchi, Airi Otsuka, Kanna Oura, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Different feeding schedule affects sleep pressure, The 37th Annual Meeting of the Japan Neuroscience Society, Sep. 2014.
Tetsuya Shiuchi, Airi Otsuka, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Evening-based feeding habit impaires insulin sensitivity via central AgRP, 91th Annual Meeting of Physiological Society of Japan, Mar. 2014.
90.
Sachiko Chikahisa, Noriyuki Shimizu, Tetsuya Shiuchi and HIroyoshi Sei : Central ketone bodies regulate sleep homeostasis in mice, 91th Annual Meeting of Physiological Society of Japan, Mar. 2014.
91.
Airi Otsuka, Tetsuya Shiuchi, Kanna Oura, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Sei : Effect of feeding pattern on sleep depth, 91th Annual Meeting of Physiological Society of Japan, Mar. 2014.
Tetsuya Shiuchi, Akari Futami, Sachiko Chikahisa, Kanna Oura, Hiroaki Fujihara and Hiroyoshi Sei : Effect of feeding rhythm on hypothalamic regulation of energy metabolism, 第90回日本生理学会, Mar. 2013.
Tetsuya Shiuchi, Sachiko Chikahisa, Hiroaki Fujihara, Akari Futami and Hiroyoshi Sei : Effect of differential feeding rhythm on insulin sensitivity and its mechanism, 日本生理学会, Mar. 2012.