Faculty Profiles - SUGIYAMA Mariko

Papers - SUGIYAMA Mariko

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Compensatory mechanisms underlying arginine vasopressin regulation in transient polyuria during pregnancy Open Access

Tsumura, T; Hagiwara, D; Naito, S; Kondo, Y; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Iwama, S; Suga, H; Banno, R; Arima, H

PEPTIDES Vol. 184 page： 171352 2025.2

Language：English Publisher：Peptides

Transient polyuria during pregnancy is reportedly caused by increased arginine vasopressin (AVP) degradation due to vasopressinase produced by the placenta. The mechanism underlying transient polyuria during pregnancy has not been established. In this study we measured urine volume, urine osmolality, and AVP transcriptional activity during pregnancy in wild-type and familial neurohypophysial diabetes insipidus (FNDI) mice. The FNDI mice were used as a partial AVP deficiency model. Vasopressinase was shown to be present in the placentas of pregnant mice. The Avp hnRNA level in the supraoptic nucleus, which is indicative of AVP transcriptional activity, was upregulated in wild-type and FNDI mice during late pregnancy. FNDI mice, but not wild-type mice, had a significant increase in urine volume and a decrease in urine osmolality during pregnancy. These data suggest that an increase in urine volume during pregnancy only occurs when the compensatory increase in AVP release is insufficient to counteract degradation by vasopressinase.

DOI： 10.1016/j.peptides.2025.171352

Guidance on Energy Intake Based on Resting Energy Expenditure and Physical Activity: Effective for Reducing Body Weight in Patients with Obesity Open Access

Handa, T; Onoue, T; Maeda, R; Mizutani, K; Suzuki, K; Kobayashi, T; Miyata, T; Sugiyama, M; Hagiwara, D; Iwama, S; Suga, H; Banno, R; Arima, H

NUTRIENTS Vol. 17 ( 2 ) 2025.1

Language：English Publisher：Nutrients

Objective: In treating obesity, energy intake control is essential to avoid exceeding energy expenditure. However, excessive restriction of energy intake often leads to resting energy expenditure (REE) reduction, increasing hunger and making weight loss difficult. This study aimed to investigate whether providing nutritional guidance that considers energy expenditure based on the regular evaluation of REE and physical activity could effectively reduce body weight (BW) in patients with obesity. Methods: A single-arm, prospective interventional study was conducted on 20 patients with obesity (body mass index ≥ 25 kg/m<sup>2</sup>) at the Nagoya University Hospital for 24 weeks. REE and physical activity were regularly assessed, and the recommended energy intake was adjusted based on the values. The primary outcome was the change in BW, and the secondary outcomes included changes in REE and hunger ratings, which were assessed using a visual analog scale. Results: Eighteen participants completed the study, demonstrating a significant reduction in BW after 24 weeks (−5.34 ± 6.76%, p < 0.0001). No significant changes were observed in REE or hunger ratings. No adverse events were reported throughout the study period. Conclusions: Guidance on energy intake based on REE and physical activity was effective for reducing BW in patients with obesity without decreasing REE or increasing hunger. This approach may reduce the burden on patients with obesity while losing BW.

DOI： 10.3390/nu17020202

A deep learning approach to predict differentiation outcomes in hypothalamic-pituitary organoids Open Access

Tomoyoshi Asano, Hidetaka Suga, Hirohiko Niioka, Hiroshi Yukawa, Mayu Sakakibara, Shiori Taga, Mika Soen, Tsutomu Miwata, Hiroo Sasaki, Tomomi Seki, Saki Hasegawa, Sou Murakami, Masatoshi Abe, Yoshinori Yasuda, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Yoshinobu Baba, Hiroshi Arima

Communications Biology Vol. 7 ( 1 ) page： 1468 2024.12

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

We use three-dimensional culture systems of human pluripotent stem cells for differentiation into pituitary organoids. Three-dimensional culture is inherently characterized by its ability to induce heterogeneous cell populations, making it difficult to maintain constant differentiation efficiency. That is why the culture process involves empirical aspects. In this study, we use deep-learning technology to create a model that can predict from images of organoids whether differentiation is progressing appropriately. Our models using EfficientNetV2-S or Vision Transformer, employing VENUS-coupled RAX expression, predictively class bright-field images of organoids into three categories with 70% accuracy, superior to expert-observer predictions. Furthermore, the model obtained by ensemble learning with the two algorithms can predict RAX expression in cells without RAX::VENUS, suggesting that our model can be deployed in clinical applications such as transplantation.

DOI： 10.1038/s42003-024-07109-1

Voluntary exercise suppresses inflammation and improves insulin resistance in the arcuate nucleus and ventral tegmental area in mice on a high-fat diet. International journal Open Access

Tomoyuki Sasaki, Mariko Sugiyama, Mitsuhiro Kuno, Takashi Miyata, Tomoko Kobayashi, Yoshinori Yasuda, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Physiology & behavior Vol. 287 page： 114703 - 114703 2024.12

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

A high-fat diet (HFD) causes inflammation with an increase in microglial activity in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA), resulting in insulin resistance in both regions. This leads to a deterioration in glucose and energy metabolism. The effect of voluntary exercise on HFD-induced inflammation in the central nervous system (CNS) remains unclear. To clarify the effects of voluntary exercise on the CNS, 8-week-old male C57BL6 mice were fed a chow diet (CHD) or HFD for 4 weeks; each group was further divided into running exercise (EX+) on a wheel and no exercise (EX-) groups. The expression of the inflammatory cytokine, tumor necrosis factor alpha (TNFα), in the ARC and VTA was significantly increased in the HFD/EX- group, with an increase of microglial activity noted, compared to the CHD/EX- group. The expression of TNFα was significantly suppressed, with a decrease of microglial activity, in the HFD/EX+ compared to HFD/EX- group. Insulin resistance in the ARC and VTA was improved with the suppression of TNFα expression. The HFD/EX- group showed significant weight gain and impaired glucose metabolism compared to the CHD/EX- group. The HFD/EX+ group showed an improvement in glucose and energy metabolism compared to the HFD/EX- group. In addition, voluntary wheel running suppressed HFD-induced inflammation in the ARC, with a decrease in microglial activity observed independently of weight changes. Our data suggest that voluntary exercise prevents obesity and improves glucose metabolism by suppressing inflammation in the ARC and VTA under HFD conditions.

DOI： 10.1016/j.physbeh.2024.114703

Development of pituitary dysfunction and destructive thyroiditis is associated with better survival in non-small cell lung cancer patients treated with programmed cell death-1 inhibitors: a prospective study with immortal time bias correction. International journal Open Access

Koji Suzuki, Tomoko Kobayashi, Tetsushi Izuchi, Koki Otake, Masahiko Ando, Tomoko Handa, Takashi Miyata, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Megumi Inoue, Makoto Ishii, Hiroshi Arima, Shintaro Iwama

Frontiers in endocrinology Vol. 15 page： 1490042 - 1490042 2024.11

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

BACKGROUND: Immune-related adverse events (irAEs) are reported to be associated with better overall survival (OS) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. However, there may be a bias in that patients who develop irAEs must survive long enough to experience the irAEs, and no prospective studies adjusting for immortal time bias (ITB) have examined the relationship between OS and pituitary dysfunction or the two different types of thyroid dysfunction: destructive thyroiditis and hypothyroidism without prior thyrotoxicosis (isolated hypothyroidism). METHODS: Patients with NSCLC who received nivolumab or pembrolizumab at Nagoya University Hospital between November 2, 2015 and February 1, 2023 were enrolled. Endocrine irAEs were prospectively assessed during scheduled evaluations of hormone levels. The association between irAE development and survival when considering ITB was examined by time-dependent Cox regression analysis. RESULTS: Of the 194 patients included, 11 (5.7%), 10 (5.2%), and 5 (2.6%) developed pituitary dysfunction, destructive thyroiditis, and isolated hypothyroidism, respectively. The development of pituitary dysfunction (HR 0.36, 95% CI 0.13-0.98, p = 0.045) and destructive thyroiditis (HR 0.31, 95% CI 0.10-0.97, p = 0.044), but not isolated hypothyroidism (HR 1.15, 95% CI 0.42-3.20, p = 0.786), was significantly associated with longer OS. CONCLUSION: NSCLC patients developing pituitary dysfunction and destructive thyroiditis showed better OS even after adjusting for ITB, suggesting that these irAEs indicate a better prognosis.

DOI： 10.3389/fendo.2024.1490042

Thyroid autoantibodies at baseline predict longer survival in non-small cell lung cancer patients treated with anti-programmed cell death-1 blockade: a prospective study Open Access

Okuji, T; Iwama, S; Kobayashi, T; Yasuda, Y; Ito, M; Yamagami, A; Ando, M; Hase, T; Shibata, H; Hatta, T; Zhou, X; Onoue, T; Kawaguchi, Y; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Ando, Y; Hashimoto, N; Arima, H

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 86 ( 3 ) page： 452 - 463 2024.8

Language：English Publisher：Nagoya Journal of Medical Science

The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.

DOI： 10.18999/nagjms.86.3.452

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study. International journal Open Access

Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Tetsushi Izuchi, Koji Suzuki, Koki Otake, Yoshinori Yasuda, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Naoki Nishio, Shoichiro Mori, Tomoya Shimokata, Tomoyasu Sano, Kaoru Niimi, Nobuhisa Yoshikawa, Shusuke Akamatsu, Yuichi Ando, Masashi Akiyama, Michihiko Sone, Makoto Ishii, Hiroshi Arima

Cancer immunology, immunotherapy : CII Vol. 73 ( 8 ) page： 146 - 146 2024.6

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

BACKGROUND: Anti-programmed cell death-1 (ligand-1) antibody [PD-(L)1-Ab] can cause destructive thyroiditis and/or hypothyroidism. In addition, tyrosine kinase inhibitors (TKIs) frequently induce hypothyroidism. The aim of this prospective study is to examine the incidence and clinical characteristics of thyroid dysfunction induced by combination therapy of a PD-(L)1-Ab and TKI [PD-(L)1-Ab/TKI]. METHODS: A total of 757 patients treated with PD-(L)1-Ab or PD-(L)1-Ab/TKI were evaluated for anti-thyroid antibodies (ATAs) at baseline and for thyroid function for 48 weeks after treatment initiation and then observed until the last visit. RESULTS: The cumulative incidences of destructive thyroiditis [4/23 (17.4%) vs. 45/734 (6.1%) patients, p < 0.001], isolated hypothyroidism [10/23 (43.5%) vs. 29/734 (4.0%) patients, p < 0.001], and all thyroid dysfunction [14/23 (60.9%) vs. 74/734 (10.1%) patients, p < 0.001] were significantly higher in the PD-(L)1-Ab/TKI group than PD-(L)1-Ab group, respectively. All patients positive for ATAs at baseline developed thyroid dysfunction after PD-(L)1-Ab/TKI treatment, a significantly higher incidence than that in those negative for ATAs at baseline [4/4 (100%) vs. 10/19 (52.6%) patients, p = 0.026]. CONCLUSIONS: The addition of TKIs increased the risk of thyroid dysfunction induced by PD-(L)1-Ab, with the risk being higher in patients positive for baseline ATAs.

DOI： 10.1007/s00262-024-03733-2

Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade Open Access

Ayana Yamagami, Shintaro Iwama, Tomoko Kobayashi, Xin Zhou, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Tetsushi Izuchi, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Endocrine Journal Vol. 71 ( 5 ) page： 515 - 526 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Endocrine Society

<p>Anti-thyroglobulin antibodies (TgAb) and/or anti-thyroid peroxidase antibodies (TPOAb) positivity at baseline is a risk marker for thyroid immune-related adverse events (thyroid-irAEs) in anti-programmed cell death-1 antibody (PD-1-Ab) treatment; however, it is unknown if TgAb and TPOAb titers are associated with clinical characteristics of thyroid-irAEs. Among 586 patients treated with PD-1-Ab at Nagoya University Hospital between 2 November 2015 and 30 September 2021, 57 patients developed thyroid-irAEs (thyrotoxicosis [<i>n</i> = 38]; hypothyroidism without prior thyrotoxicosis {isolated hypothyroidism} [<i>n</i> = 19]) in whom thyroid function, and TgAb and TPOAb titers were determined at baseline and at the onset. The changes in TgAb (median, 54.8 <i>vs.</i> 0.2 IU/mL; <i>p</i> = 0.002) and TPOAb titers (31.6 <i>vs.</i> 0 IU/mL; <i>p</i> = 0.032) from baseline to onset of developing thyroid-irAEs were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism. Higher TgAb and TPOAb titers, and the TgAb titer at baseline were associated with an earlier onset of thyrotoxicosis and higher peak free thyroxine levels, respectively. Twenty-eight patients who developed hypothyroidism after thyrotoxicosis had higher TgAb (54.5 <i>vs.</i> 10.7 IU/mL; <i>p</i> = 0.011) and TPOAb titers at baseline (46.1 <i>vs.</i> 9.0 IU/mL; <i>p</i> < 0.001) and greater changes in TgAb (61.7 <i>vs.</i> 7.8 IU/mL; <i>p</i> = 0.025) and TPOAb titers (52.8 <i>vs.</i> –0.8 IU/mL; <i>p</i> < 0.001) than patients who did not develop hypothyroidism. The TgAb titer at baseline and changes in the TgAb and TPOAb titers were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism, suggesting that the magnitude of the thyroid autoimmune response reflects the clinical types of thyroid-irAEs.</p>

DOI： 10.1507/endocrj.EJ23-0480

Improved glycemic control after the use of flash glucose monitoring accompanied by improved treatment satisfaction in patients with non-insulin-treated type 2 diabetes: A post-hoc analysis of a randomized controlled trial. International journal Open Access

Ayaka Hayase, Takeshi Onoue, Tomoko Kobayashi, Eri Wada, Tomoko Handa, Tamaki Kinoshita, Ayana Yamagami, Yoshinori Yasuda, Shintaro Iwama, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yachiyo Kuwatsuka, Masahiko Ando, Motomitsu Goto, Hiroshi Arima

Primary care diabetes Vol. 17 ( 6 ) page： 575 - 580 2023.12

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

AIMS: In our previously reported randomized controlled trial in patients with noninsulin-treated type 2 diabetes, the use of flash glucose monitoring (FGM) improved glycated hemoglobin (HbA1c), and the improvement was sustained after the cessation of glucose monitoring. In this post-hoc analysis, we examined data from our trial to identify the factors that influenced FGM efficacy. METHODS: We analyzed data for 48 of 49 participants of the FGM group who completed the trial to clarify the changes in various parameters and factors related to HbA1c improvement with the use of FGM. RESULTS: Analyses of the FGM data during the 12-week FGM provision period showed that the weekly mean blood glucose levels considerably decreased as early as at 1 week compared with the baseline values, and this decline continued for 12 weeks. An enhancement in the Diabetes Treatment Satisfaction Questionnaire regarding "willingness to continue the current treatment" score was significantly associated with the improvement in HbA1c at 12 (p = 0.009) and 24 weeks (p = 0.012). CONCLUSIONS: Glycemic control was improved soon after FGM initiation, accompanied by improved satisfaction with continuation of the current treatment in patients with noninsulin-treated type 2 diabetes.

DOI： 10.1016/j.pcd.2023.09.009

Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation Open Access

Taga, S; Suga, H; Nakano, T; Kuwahara, A; Inoshita, N; Kodani, Y; Nagasaki, H; Sato, Y; Tsumura, Y; Sakakibara, M; Soen, M; Miwata, T; Ozaki, H; Kano, M; Watari, K; Ikeda, A; Yamanaka, M; Takahashi, Y; Kitamoto, S; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Yasuda, Y; Hagiwara, D; Iwama, S; Tomigahara, Y; Kimura, T; Arima, H

STEM CELL REPORTS Vol. 18 ( 8 ) page： 1657 - 1671 2023.8

Language：English Publisher：Stem Cell Reports

Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

DOI： 10.1016/j.stemcr.2023.05.002

線条体ニューロンにおけるPTP1Bは高脂肪食に対する報酬効果を増強する

久納光皓, 坂野僚一, 王思嫻, 佐々木智之, 孫汝楠, 廣瀬友矩, 杉山摩利子, 高木博史, 有馬寛

日本内分泌学会雑誌 Vol. 99 ( 1 ) page： 321 - 321 2023.5

高脂肪食摂取により生じる視床下部弓状核と中脳腹側被蓋野の炎症は自発運動により抑制される

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

日本内分泌学会雑誌 Vol. 99 ( 1 ) page： 322 - 322 2023.5

Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells. International journal Open Access

Tsutomu Miwata, Hidetaka Suga, Yohei Kawaguchi, Mayu Sakakibara, Mayuko Kano, Shiori Taga, Mika Soen, Hajime Ozaki, Tomoyoshi Asano, Hiroo Sasaki, Takashi Miyata, Yoshinori Yasuda, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hiroshi Arima

Stem cell reports Vol. 18 ( 4 ) page： 869 - 883 2023.4

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

When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX+ cells from mature organoids. The isolated RAX+ cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX+ hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.

DOI： 10.1016/j.stemcr.2023.02.006

Dapagliflozinは脂質と食塩の過剰摂取によって生じる耐糖能異常を改善する

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

糖尿病 Vol. 66 ( Suppl.1 ) page： S - 232 2023.4

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency. Open Access

Junki Kurimoto, Hiroshi Takagi, Takashi Miyata, Yohei Kawaguchi, Yuichi Hodai, Tetsuro Tsumura, Daisuke Hagiwara, Tomoko Kobayashi, Yoshinori Yasuda, Mariko Sugiyama, Takeshi Onoue, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Takeshi Katsuki, Fumiaki Ando, Shinichi Uchida, Hiroshi Arima

Endocrine journal Vol. 70 ( 3 ) page： 295 - 304 2023.3

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Endocrine Society

The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophysial diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

DOI： 10.1507/endocrj.EJ22-0339

Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study. International journal Open Access

Tomoko Handa, Takeshi Onoue, Tomoko Kobayashi, Eri Wada, Ayaka Hayase, Tamaki Kinoshita, Ayana Yamagami, Yoshinori Yasuda, Shintaro Iwama, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Motomitsu Goto, Hiroshi Arima

Archives of endocrinology and metabolism Vol. 67 ( 2 ) page： 233 - 241 2023.3

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

OBJECTIVE: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. RESULTS: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (-4.7 ± 2.0 kg, P < 0.001) and 2 weeks (-5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x - 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. CONCLUSION: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process.

DOI： 10.20945/2359-3997000000532

放射線治療とパシレオチドの併用が奏功したクッシング病の1例

村瀬萌絵, 安田康紀, 杉山摩利子, 永田雄一, 竹内和人, 井下尚子, 有馬寛

日本内分泌学会雑誌 Vol. 98 ( 5 ) page： 1401 - 1401 2023.3

Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP/CRH neurons in mice. International journal Open Access

Yohei Kawaguchi, Daisuke Hagiwara, Tetsuro Tsumura, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshinori Yasuda, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Valery Grinevich, Hiroshi Arima

Journal of neuroendocrinology Vol. 35 ( 1 ) page： e13223 2023.1

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

Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin-releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy-associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.

DOI： 10.1111/jne.13223

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency Open Access

Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Kawaguchi Yohei, Hodai Yuichi, Tsumura Tetsuro, Hagiwara Daisuke, Kobayashi Tomoko, Yasuda Yoshinori, Sugiyama Mariko, Onoue Takeshi, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Katsuki Takeshi, Ando Fumiaki, Uchida Shinichi, Arima Hiroshi

ENDOCRINE JOURNAL Vol. 70 ( 3 ) page： 295 - 304 2023

Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state. International journal Open Access

Hajime Ozaki, Hidetaka Suga, Mayu Sakakibara, Mika Soen, Natsuki Miyake, Tsutomu Miwata, Shiori Taga, Takashi Nagai, Mayuko Kano, Kazuki Mitsumoto, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Ryoichi Banno, Genzo Iguchi, Yutaka Takahashi, Keiko Muguruma, Haruhisa Inoue, Hiroshi Arima

Scientific reports Vol. 12 ( 1 ) page： 17381 - 17381 2022.10

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

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

DOI： 10.1038/s41598-022-22405-8

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