Faculty Profiles - SUGIYAMA Mariko

Papers - SUGIYAMA Mariko

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Elevated TSH level, TgAb and prior use of ramucirumab or TKIs as risk factors for thyroid dysfunction in PD-L1 blockade. International journal Open Access

Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Xin Zhou, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Takanori Ito, Toyone Kikumori, Megumi Inoue, Yuichi Ando, Norikazu Masuda, Hiroki Kawashima, Naozumi Hashimoto, Hiroshi Arima

The Journal of clinical endocrinology and metabolism Vol. 107 ( 10 ) page： E4115 - E4123 2022.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Thyroid dysfunction is frequently caused by treatment with anti-programmed cell death-1 ligand 1 antibodies (PD-L1-Abs) as well as anti-cancer drugs, including ramucirumab (RAM) and multi-targeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. METHODS: A total of 148 patients treated with PD-L1-Abs were evaluated for anti-thyroid antibodies at baseline and for thyroid function every six weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. RESULTS: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in eight and hypothyroidism without preceding thyrotoxicosis in seven). The prevalences of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs. 4/133 [3.0%], p < 0.05), positive anti-thyroglobulin antibodies (TgAb) at baseline (4/15 [26.7%] vs. 5/133 [3.8%], p < 0.05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs. 5/133 [3.8%], p < 0.05) were significantly higher in patients with versus without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with odds ratios of 7.098 (95% confidence interval [CI], 1.154-43.638), 11.927 (95% CI, 2.526-56.316) and 8.476 (95% CI, 1.592-45.115), respectively. CONCLUSIONS: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline and prior treatment with RAM or multi-TKIs.

DOI： 10.1210/clinem/dgac467

Inflammation in VTA Caused by HFD Induces Activation of Dopaminergic Neurons Accompanied by Binge-like Eating. International journal Open Access

Runan Sun, Mariko Sugiyama, Sixian Wang, Mitsuhiro Kuno, Tomoyuki Sasaki, Tomonori Hirose, Takashi Miyata, Tomoko Kobayashi, Taku Tsunekawa, Takeshi Onoue, Yoshinori Yasuda, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Hiroshi Arima

Nutrients Vol. 14 ( 18 ) 2022.9

Language：English Publishing type：Research paper (scientific journal)

Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

DOI： 10.3390/nu14183835

Protein Tyrosine Phosphatase 1B Deficiency Improves Glucose Homeostasis in Insulin-Dependent Diabetes Mellitus Treated with Leptin. International journal Open Access

Yoshihiro Ito, Runan Sun, Hiroshi Yagimuma, Keigo Taki, Akira Mizoguchi, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Hiroyuki Konishi, Hiroshi Kiyama, Hiroshi Arima, Ryoichi Banno

Diabetes Vol. 71 ( 9 ) page： 1902 - 1914 2022.9

Language：English Publishing type：Research paper (scientific journal)

Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of insulin-dependent diabetes mellitus (IDDM). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of IDDM was investigated using PTP1B deficient (KO) mice and a PTP1B inhibitor. IDDM wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared to non-IDDM WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-IDDM WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in IDDM WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in IDDM WT mice improved glucose metabolism to the same level as non-IDDM WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle via the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of IDDM with leptin, PTP1B deficiency or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for IDDM.

DOI： 10.2337/db21-0953

Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline. International journal Open Access

Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Masahiko Ando, Xin Zhou, Ayana Yamagami, Takeshi Onoue, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Keiko Wakahara, Kenji Yokota, Masashi Kato, Naoki Nishio, Chie Tanaka, Kazushi Miyata, Atsushi Ogura, Takanori Ito, Tsunaki Sawada, Tomoya Shimokata, Kaoru Niimi, Fumiharu Ohka, Masatoshi Ishigami, Momokazu Gotoh, Naozumi Hashimoto, Ryuta Saito, Hitoshi Kiyoi, Hiroaki Kajiyama, Yuichi Ando, Hideharu Hibi, Michihiko Sone, Masashi Akiyama, Yasuhiro Kodera, Hiroshi Arima

The Journal of clinical endocrinology and metabolism Vol. 107 ( 4 ) page： E1620 - E1630 2022.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. METHODS: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. RESULTS: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. CONCLUSIONS: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

DOI： 10.1210/clinem/dgab829

Functional lactotrophs in induced adenohypophysis differentiated from human iPS cells. Reviewed International journal Open Access

Natsuki Miyake, Takashi Nagai, Hidetaka Suga, Satoko Osuka, Takatoshi Kasai, Mayu Sakakibara, Mika Soen, Hajime Ozaki, Tsutomu Miwata, Tomoyoshi Asano, Mayuko Kano, Ayako Muraoka, Natsuki Nakanishi, Tomoko Nakamura, Maki Goto, Yoshinori Yasuda, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Akira Iwase, Naoko Inoshita, Hiroshi Arima, Hiroaki Kajiyama

Endocrinology Vol. 163 ( 3 ) 2022.3

Language：English Publishing type：Research paper (scientific journal)

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

DOI： 10.1210/endocr/bqac004

高脂肪食摂取に伴う中脳腹側被蓋野の炎症は絶食後の摂餌量を増加させる

孫汝楠, 杉山摩利子, 佐々木智之, 廣瀬友矩, 恒川卓, 高木博史, 坂野僚一, 有馬寛

肥満研究 Vol. 27 ( Suppl. ) page： 342 - 342 2022.3

Predicting non-insulin-dependent state in patients with slowly progressive insulin-dependent (type 1) diabetes mellitus or latent autoimmune diabetes in adults. Reply to Sugiyama K and Saisho Y [letter]. International journal Open Access

Eri Wada, Takeshi Onoue, Tamaki Kinoshita, Ayaka Hayase, Tomoko Handa, Masaaki Ito, Mariko Furukawa, Takayuki Okuji, Tomoko Kobayashi, Shintaro Iwama, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Motomitsu Goto, Hiroshi Arima

Diabetologia Vol. 65 ( 1 ) page： 252 - 253 2022.1

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study. International journal Open Access

Eri Wada, Takeshi Onoue, Tamaki Kinoshita, Ayaka Hayase, Tomoko Handa, Masaaki Ito, Mariko Furukawa, Takayuki Okuji, Tomoko Kobayashi, Shintaro Iwama, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Motomitsu Goto, Hiroshi Arima

Diabetologia Vol. 64 ( 10 ) page： 2183 - 2192 2021.10

Language：English Publishing type：Research paper (scientific journal)

AIMS/HYPOTHESIS: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. METHODS: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. RESULTS: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. CONCLUSIONS/INTERPRETATION: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.

DOI： 10.1007/s00125-021-05516-1

GABAB receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice. International journal Open Access

Runan Sun, Taku Tsunekawa, Tomonori Hirose, Hiroshi Yaginuma, Keigo Taki, Akira Mizoguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Bernhard Bettler, Hiroshi Arima

Scientific reports Vol. 11 ( 1 ) page： 19296 - 19296 2021.9

Language：English Publishing type：Research paper (scientific journal)

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

DOI： 10.1038/s41598-021-98590-9

Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice. International journal

Junki Kurimoto, Hiroshi Takagi, Takashi Miyata, Yuichi Hodai, Yohei Kawaguchi, Daisuke Hagiwara, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Katsuya Tanabe, Yukio Tanizawa, Hiroshi Arima

Pituitary Vol. 24 ( 4 ) page： 582 - 588 2021.8

Language：English Publishing type：Research paper (scientific journal)

Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1-/-) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic β-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1-/- mice. There were no differences in urine volumes between Wfs1-/- and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1-/- mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1-/- mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.

DOI： 10.1007/s11102-021-01135-6

Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice. International journal Open Access

Akira Mizoguchi, Ryoichi Banno, Runan Sun, Hiroshi Yaginuma, Keigo Taki, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Taku Nagai, Kiyofumi Yamada, Hiroshi Arima

Scientific reports Vol. 11 ( 1 ) page： 12873 - 12873 2021.6

Language：English Publishing type：Research paper (scientific journal)

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

DOI： 10.1038/s41598-021-92386-7

CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. International journal Open Access

Yoshinori Yasuda, Shintaro Iwama, Daisuke Sugiyama, Takayuki Okuji, Tomoko Kobayashi, Masaaki Ito, Norio Okada, Atsushi Enomoto, Sachiko Ito, Yue Yan, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Masahide Takahashi, Hiroyoshi Nishikawa, Hiroshi Arima

Science translational medicine Vol. 13 ( 593 ) 2021.5

Language：English Publishing type：Research paper (scientific journal)

Immune-related adverse events induced by anti-programmed cell death-1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

DOI： 10.1126/scitranslmed.abb7495

High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice. International journal

Akira Mizoguchi, Ryoichi Banno, Runan Sun, Hiroshi Yaginuma, Keigo Taki, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Hiroshi Arima

Neuroscience Vol. 461 page： 72 - 79 2021.5

Language：English Publishing type：Research paper (scientific journal)

The reward system plays an important role in the pathogenesis of not only drug addiction, but also diet-induced obesity. Recent studies have shown that insulin and leptin receptor signaling in the ventral tegmental area (VTA) regulate energy homeostasis and that their dysregulation is responsible for obesity and altered food preferences. Although a high-fat diet (HFD) induces inflammation that leads to insulin and leptin resistance in the brain, it remains unclear whether HFD induces inflammation in the VTA. In the present study, we placed male mice on a chow diet or HFD for 3, 7, and 28 days and evaluated the mRNA expression of inflammatory cytokines and microglial activation markers in the VTA. The HFD group showed significantly elevated mRNA expressions of IL1β at 3 days; tumor necrosis factor-alpha (TNFα), IL1β, IL6, Iba1, and CD11b at 7 days; and TNFα, IL1β, Iba1, and CD11b at 28 days. The changes in TNFα were also confirmed in immunohistochemical analysis. Next, after administration of chow or HFD for 7 days, we selected mice with equal weights in both groups. In experiments using these mice, Akt phosphorylation in the VTA was significantly decreased after intracerebroventricular injection of insulin, whereas no change in STAT3 phosphorylation was found with leptin. Taken together, these results suggest that HFD induces inflammation at least partly associated with microglial activation in the VTA leading to insulin resistance, independently of the energy balance. Our data provide new insight into the pathophysiology of obesity caused by a dysfunctional reward system under HFD conditions.

DOI： 10.1016/j.neuroscience.2021.02.009

Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons. International journal Open Access

Daisuke Hagiwara, Masayoshi Tochiya, Yoshinori Azuma, Tetsuro Tsumura, Yuichi Hodai, Yohei Kawaguchi, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Peptides Vol. 139 page： 170517 - 170517 2021.5

Language：English Publishing type：Research paper (scientific journal)

Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

DOI： 10.1016/j.peptides.2021.170517

Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors. International journal Open Access

Tomoko Kobayashi, Shintaro Iwama, Daisuke Sugiyama, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Sachiko Ito, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Hiroyoshi Nishikawa, Hiroshi Arima

Journal for immunotherapy of cancer Vol. 9 ( 5 ) 2021.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs). METHODS: In this case-control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles. RESULTS: Eleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls. CONCLUSIONS: This study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively. TRIAL REGISTRATION NUMBER: UMIN000019024.

DOI： 10.1136/jitc-2021-002493

食塩過剰摂取は高脂肪食によって惹起される膵β細胞増殖を抑制して耐糖能を悪化させる

滝啓吾, 高木博史, 廣瀬友矩, 孫汝楠, 柳沼裕史, 杉山摩利子, 伊藤禎浩, 坂野僚一, 有馬寛

日本内分泌学会雑誌 Vol. 97 ( 1 ) page： 321 - 321 2021.4

Dietary sodium chloride attenuates increased β-cell mass to cause glucose intolerance in mice under a high-fat diet. International journal Open Access

Keigo Taki, Hiroshi Takagi, Tomonori Hirose, Runan Sun, Hiroshi Yaginuma, Akira Mizoguchi, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Daisuke Sakano, Shoen Kume, Hiroshi Arima

PloS one Vol. 16 ( 3 ) page： e0248065 2021.3

Language：English Publishing type：Research paper (scientific journal)

Excessive sodium salt (NaCl) or fat intake is associated with a variety of increased health risks. However, whether excessive NaCl intake accompanied by a high-fat diet (HFD) affects glucose metabolism has not been elucidated. In this study, C57BL/6J male mice were fed a normal chow diet (NCD), a NCD plus high-NaCl diet (NCD plus NaCl), a HFD, or a HFD plus high-NaCl diet (HFD plus NaCl) for 30 weeks. No significant differences in body weight gain, insulin sensitivity, and glucose tolerance were observed between NCD-fed and NCD plus NaCl-fed mice. In contrast, body and liver weights were decreased, but the weight of epididymal white adipose tissue was increased in HFD plus NaCl-fed compared to HFD-fed mice. HFD plus NaCl-fed mice had lower plasma glucose levels in an insulin tolerance test, and showed higher plasma glucose and lower plasma insulin levels in an intraperitoneal glucose tolerance test compared to HFD-fed mice. The β-cell area and number of islets were decreased in HFD plus NaCl-fed compared to HFD-fed mice. Increased Ki67-positive β-cells, and increased expression levels of Ki67, CyclinB1, and CyclinD1 mRNA in islets were observed in HFD-fed but not HFD plus NaCl-fed mice when compared to NCD-fed mice. Our data suggest that excessive NaCl intake accompanied by a HFD exacerbates glucose intolerance, with impairment in insulin secretion caused by the attenuation of expansion of β-cell mass in the pancreas.

DOI： 10.1371/journal.pone.0248065

胆管癌に伴う閉塞性黄疸の解除後、約3ヵ月でインスリン離脱となった1例

木下珠希, 杉山摩利子, 有馬寛

糖尿病 Vol. 64 ( 2 ) page： 151 - 151 2021.2

Peripheral combination treatment of leptin and an SGLT2 inhibitor improved glucose metabolism in insulin-dependent diabetes mellitus mice Open Access

Hiroshi Yaginuma, Ryoichi Banno, Runan Sun, Keigo Taki, Akira Mizoguchi, Tomoko Kobayashi, Mariko Sugiyama, Taku Tsunekawa, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Hiroshi Arima

JOURNAL OF PHARMACOLOGICAL SCIENCES Vol. 147 ( 4 ) page： 340 - 347 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE PHARMACOLOGICAL SOC

We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 mu g/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin. (C) 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

DOI： 10.1016/j.jphs.2021.08.010

Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice. International journal Open Access

Yohei Kawaguchi, Daisuke Hagiwara, Takashi Miyata, Yuichi Hodai, Junki Kurimoto, Hiroshi Takagi, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Valery Grinevich, Hiroshi Arima

Scientific reports Vol. 10 ( 1 ) page： 19730 - 19730 2020.11

Language：English Publishing type：Research paper (scientific journal)

The immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

DOI： 10.1038/s41598-020-76839-z

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