| 1. |
Hiroshi Nakao, Maki Yokomoto-Umakoshi, Kohta Nakatani, Hironobu Umakoshi, Masatoshi Ogata, Tazuru Fukumoto, Hiroki Kaneko, Norifusa Iwahashi, Masamichi Fujita, Tatsuki Ogasawara, Yayoi Matsuda, Ryuichi Sakamoto, Yoshihiro Izumi, Takeshi Bamba, Yoshihiro Ogawa, Adrenal steroid metabolites and bone status in patients with adrenal incidentalomas and hypercortisolism, eBioMedicine, 10.1016/j.ebiom.2023.104733, 104733-104733, 2023.08. |
| 2. |
Tatsuki Ogasawara, Yoichi Fujii, Nobuyuki Kakiuchi, Yusuke Shiozawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Katsuki Ootani, Etsuro Ito, Tomoaki Tanaka, Kenichiro Watanabe, Yusaku Yoshida, Noriko Kimura, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Genetic analysis of pheochromocytoma and paraganglioma complicating cyanotic congenital heart disease., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgac362, 107, 9, 2545-2555, 2022.06, CONTEXT: Pheochromocytoma and paraganglioma (PPGL) may appear as a complication of cyanotic congenital heart disease (CCHD-PPGL) with frequent EPAS1 mutations, suggesting a close link between EPAS1 mutations and tissue hypoxia in CCHD-PPGL pathogenesis. OBJECTIVE: Our aim is to further investigate the role of EPAS1 mutations in the hypoxia-driven mechanism of CCHD-PPGL pathogenesis, particularly focusing on metachronous and/or multifocal CCHD-PPGL tumors. METHODS: We performed whole exome sequencing (WES) for somatic and germline mutations in 15 PPGL samples from 7 CCHD patients, including 3 patients with metachronous and/or multifocal tumors, together with an adrenal medullary hyperplasia (AMH) sample. RESULTS: We detected EPAS1 mutations in 15 out of 16 PPGL/AMH samples from 7 cases. Conspicuously, all EPAS1 mutations in each of three cases with multifocal or metachronous tumors were mutually independent and typical examples of parallel evolution, which is suggestive of strong positive selection of EPAS1-mutated clones. Compared to 165 TCGA non-CCHD-PPGL samples, CCHD-PPGL/AMH samples were enriched for 11p deletions (13/16) and 2p amplifications (4/16). Of particular note, the multiple metachronous PPGL tumors with additional copy number abnormalities developed 18-23 years after the resolution of hypoxemia, suggesting that CCHD-induced hypoxic environments are critical for positive selection of EPAS1 mutants in early life, but may no longer be required for development of PPGL in later life. CONCLUSIONS: Our results highlight a key role of activated HIF2α due to mutated EPAS1 in positive selection under hypoxic environments, although hypoxemia itself may not necessarily be required for the EPAS1-mutated clones to progress to PPGL.. |
| 3. |
Mitsuhide Naruse, Takuyuki Katabami, Hirotaka Shibata, Masakatsu Sone, Katsutoshi Takahashi, Akiyo Tanabe, Shoichiro Izawa, Takamasa Ichijo, Michio Otsuki, Masao Omura, Yoshihiro Ogawa, Yutaka Oki, Isao Kurihara, Hiroki Kobayashi, Ryuichi Sakamoto, Fumitoshi Satoh, Yoshiyu Takeda, Tomoaki Tanaka, Kouichi Tamura, Mika Tsuiki, Shigeatsu Hashimoto, Tomonobu Hasegawa, Takanobu Yoshimoto, Takashi Yoneda, Koichi Yamamoto, Hiromi Rakugi, Norio Wada, Aya Saiki, Youichi Ohno, Tatsuya Haze, Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021., Endocrine journal, 10.1507/endocrj.EJ21-0508, 69, 4, 327-359, 2022.04, Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.. |
| 4. |
Hiroki Kaneko, Hironobu Umakoshi, Masatoshi Ogata, Norio Wada, Takamasa Ichijo, Shohei Sakamoto, Tetsuhiro Watanabe, Yuki Ishihara, Tetsuya Tagami, Norifusa Iwahashi, Tazuru Fukumoto, Eriko Terada, Shunsuke Katsuhara, Maki Yokomoto-Umakoshi, Yayoi Matsuda, Ryuichi Sakamoto, Yoshihiro Ogawa, Machine learning-based models for predicting clinical outcomes after surgery in unilateral primary aldosteronism., Scientific reports, 10.1038/s41598-022-09706-8, 12, 1, 5781-5781, 2022.04, Unilateral subtype of primary aldosteronism (PA) is a common surgically curable form of endocrine hypertension. However, more than half of the patients with PA who undergo unilateral adrenalectomy suffer from persistent hypertension, which may discourage those with PA from undergoing adrenalectomy even when appropriate. The aim of this retrospective cross-sectional study was to develop machine learning-based models for predicting postoperative hypertensive remission using preoperative predictors that are readily available in routine clinical practice. A total of 107 patients with PA who achieved complete biochemical success after adrenalectomy were included and randomly assigned to the training and test datasets. Predictive models of complete clinical success were developed using supervised machine learning algorithms. Of 107 patients, 40 achieved complete clinical success after adrenalectomy in both datasets. Six clinical features associated with complete clinical success (duration of hypertension, defined daily dose (DDD) of antihypertensive medication, plasma aldosterone concentration (PAC), sex, body mass index (BMI), and age) were selected based on predictive performance in the machine learning-based model. The predictive accuracy and area under the curve (AUC) for the developed model in the test dataset were 77.3% and 0.884 (95% confidence interval: 0.737-1.000), respectively. In an independent external cohort, the performance of the predictive model was found to be comparable with an accuracy of 80.4% and AUC of 0.867 (95% confidence interval: 0.763-0.971). The duration of hypertension, DDD of antihypertensive medication, PAC, and BMI were non-linearly related to the prediction of complete clinical success. The developed predictive model may be useful in assessing the benefit of unilateral adrenalectomy and in selecting surgical treatment and antihypertensive medication for patients with PA in clinical practice.. |
| 5. |
Shunsuke Katsuhara, Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Yayoi Matsuda, Norifusa Iwahashi, Hiroki Kaneko, Masatoshi Ogata, Tazuru Fukumoto, Eriko Terada, Ryuichi Sakamoto, Yoshihiro Ogawa, Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab862, 107, 4, e1477-e1487, 2022.03, CONTEXT: Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. OBJECTIVE: We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. METHODS: Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. RESULTS: One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. CONCLUSION: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.. |
| 6. |
成瀬 光栄, 方波見 卓行, 柴田 洋孝, 曽根 正勝, 高橋 克敏, 田辺 晶代, 伊澤 正一郎, 一城 貴政, 大月 道夫, 大村 昌夫, 小川 佳宏, 沖 隆, 栗原 勲, 小林 洋輝, 坂本 竜一, 佐藤 文俊, 武田 仁勇, 田中 知明, 田村 功一, 立木 美香, 橋本 重厚, 長谷川 奉延, 吉本 貴宣, 米田 隆, 山本 浩一, 楽木 宏実, 和田 典男, 佐伯 絢, 大野 洋一, 土師 達也, 岡本 健太郎, 成瀬 光栄, 川島 彰透, 藤井 雄一, 難波 多挙, 益崎 裕章, 斎藤 能彦, 横尾 隆, 向山 政志, 桑鶴 良平, 宮崎 康, 関 博之, 辻 光, 猿田 享男, 平田 結喜緒, 島本 和明, 宮森 勇, 西川 哲男, 相馬 正義, 柳瀬 敏彦, 一般社団法人日本内分泌学会, 一般社団法人日本内分泌学会, 「原発性アルドステロン症診療ガイドライン策定と診療水準向上」委員会, 特定非営利活動法人日本高血圧学会, 一般社団法人日本腎臓学会, 一般社団法人日本内分泌外科学会, 一般社団法人日本妊娠高血圧学会, 厚生労働省科学研究費補助金難治性疾患等政策研究事業副腎ホルモン産生異常症に関する調査研究班, 国際医療研究開発費「難治性副腎腫瘍の疾患レジストリと診療実態に関する検討」研究班, 日本医療研究開発機構(難治性疾患実用化研究事業)「重症型原発性アルドステロン症の診療の質向上に資するエビデンス構築(JPAS)」研究班および「難治性副腎疾患の診療に直結するエビデンス創出(JRAS)」研究班, 原発性アルドステロン症診療ガイドライン2021, 日本内分泌学会雑誌, 97, Suppl., i-53, 2021.10. |
| 7. |
Satoko Oda, Kenji Ashida, Makiko Uchiyama, Shohei Sakamoto, Nao Hasuzawa, Ayako Nagayama, Lixiang Wang, Hiromi Nagata, Ryuichi Sakamoto, Junji Kishimoto, Koji Todaka, Yoshihiro Ogawa, Yoichi Nakanishi, Masatoshi Nomura, An Open-label Phase I/IIa Clinical Trial of 11β-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab450, 106, 10, e3865-e3880, 2021.09, CONTEXT: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. OBJECTIVE: To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients. DESIGN: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. SETTING: Kyushu University Hospital, Kurume University Hospital, and related facilities. PATIENTS: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. INTERVENTION: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. MAIN OUTCOME MEASURES: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. RESULTS: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P = 0.033] and -2.7% [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P |
| 8. |
Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Norifusa Iwahashi, Yayoi Matsuda, Hiroki Kaneko, Masatoshi Ogata, Tazuru Fukumoto, Eriko Terada, Yui Nakano, Ryuichi Sakamoto, Yoshihiro Ogawa, Protective Role of DHEAS in Age-related Changes in Bone Mass and Fracture Risk., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab459, 106, 11, E4580-E4592, 2021.06, PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95% CI, 0.081-0.158; P = 9 × 10-10), and decreased fracture (odds ratio, 0.989; 95% CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.. |
| 9. |
Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Norifusa Iwahashi, Yayoi Matsuda, Hiroki Kaneko, Masatoshi Ogata, Tazuru Fukumoto, Eriko Terada, Yui Nakano, Ryuichi Sakamoto, Yoshihiro Ogawa, Protective Role of DHEAS in Age-related Changes in Bone Mass and Fracture Risk: A Mendelian Randomization Study., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab459, 2021.06, PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (μmol/L) increase in serum DHEAS concentrations was associated with SD increase in estimated BMD at the heel (estimate, 0.120; 95% confidence interval [CI], 0.081-0.158; P = 9 × 10 -10), and decreased fracture (odds ratio [OR], 0.989; 95%CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and IGF-1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Baysian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.. |
| 10. |
Hiroki Kaneko, Hironobu Umakoshi, Masatoshi Ogata, Norio Wada, Norifusa Iwahashi, Tazuru Fukumoto, Maki Yokomoto-Umakoshi, Yui Nakano, Yayoi Matsuda, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Machine learning based models for prediction of subtype diagnosis of primary aldosteronism using blood test., Scientific reports, 10.1038/s41598-021-88712-8, 11, 1, 9140-9140, 2021.05, Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1%). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.. |
| 11. |
Tazuru Fukumoto, Hironobu Umakoshi, Masatoshi Ogata, Maki Yokomoto-Umakoshi, Yayoi Matsuda, Misato Motoya, Hiromi Nagata, Yui Nakano, Norifusa Iwahashi, Hiroki Kaneko, Norio Wada, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Significance of Discordant Results Between Confirmatory Tests in Diagnosis of Primary Aldosteronism., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgaa812, 106, 2, e866-e874, 2021.01, CONTEXT: Current clinical guidelines recommend confirmation of a positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results. OBJECTIVE: The aim of the present study was to explore the role of 2 confirmatory tests in subtype diagnosis of PA. DESIGN AND SETTING: A retrospective cross-sectional study was conducted at two referral centers. PARTICIPANTS AND METHODS: We identified 360 hypertensive patients who underwent both a captopril challenge test (CCT) and a saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS). MAIN OUTCOME MEASURE: The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests was measured. RESULTS: Of patients studied, 127 were positive for both CCT and SIT (double-positive), whereas 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5%] vs 72/127 [56.7%], P |
| 12. |
Hironobu Umakoshi, Ryuichi Sakamoto, Yayoi Matsuda, Maki Yokomoto-Umakoshi, Hiromi Nagata, Tazuru Fukumoto, Masatoshi Ogata, Yoshihiro Ogawa, Role of aldosterone and potassium levels in sparing confirmatory tests in primary aldosteronism, Journal of Clinical Endocrinology and Metabolism, 10.1210/clinem/dgz148, 105, 4, 1284-1289, 2020.04, © Endocrine Society 2019. All rights reserved. Context: The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. Objective: This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. Design and Setting: A retrospective cross-sectional study in a single referral center. Participants: This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. Main Outcome Measure: Diagnostic value of PAC and serum potassium in confirmation of PA. Results: Of the studied patients, 252 of 327 (77%) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80%) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76% vs. 17%, P <.001 conclusion: confirmatory tests in pa could be spared patients who have typical features of and these had a high probability unilateral on avs.. id="gencho_ronbuns10127780" class="qir_handle_link"> |
| 13. |
Ryuichi Sakamoto, Eri Matsubara, Masatoshi Nomura, Lixiang Wang, Yuta Kawahara, Toshihiko Yanase, Hajime Nawata, Ryoichi Takayanagi, Roles for corticotropin-releasing factor receptor type 1 in energy homeostasis in mice., Metabolism: clinical and experimental, 10.1016/j.metabol.2013.08.005, 62, 12, 1739-48, 2013.12, OBJECTIVE: Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic β cells, and its activation potentiates glucose-stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. MATERIALS/METHODS: We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. RESULTS: When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the β cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. CONCLUSIONS: Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis.. |
| 14. |
Masatoshi Nomura, Ryuichi Sakamoto, Hidetaka Morinaga, Lixiang Wang, Chizu Mukasa, Ryoichi Takayanagi, Activin stimulates CYP19A gene expression in human ovarian granulosa cell-like KGN cells via the Smad2 signaling pathway., Biochemical and biophysical research communications, 10.1016/j.bbrc.2013.05.124, 436, 3, 443-8, 2013.07, Activin, a transforming growth factor β family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development.. |
| 15. |
Lixiang Wang, Masatoshi Nomura, Yutaka Goto, Kimitaka Tanaka, Ryuichi Sakamoto, Ichiro Abe, Shohei Sakamoto, Atsushi Shibata, Patricio L. M. Enciso, Masahiro Adachi, Keizo Ohnaka, Hisaya Kawate, Ryoichi Takayanagi, Smad2 Protein Disruption in the Central Nervous System Leads to Aberrant Cerebellar Development and Early Postnatal Ataxia in Mice, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M111.223271, 286, 21, 18766-18774, 2011.05, Smad2 is a critical mediator of TGF-beta signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control.. |
