Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Journal of clinical endocrinology and metabolism  

CONTEXT: Positive antithyroglobulin (TgAb) and/or antithyroid peroxidase antibodies (TPOAb) at baseline indicate a high risk of thyroid immune-related adverse events (irAEs) induced by antiprogrammed cell death-1 antibodies (anti-PD-1-Ab). However, whether the positivity patterns of both antibodies are associated with the risk of thyroid irAEs is unknown. OBJECTIVE: The aim of the present study was to clarify the association of the pattern of TgAb and TPOAb positivity at baseline with the risk of thyroid irAEs induced by anti-PD-1-Ab. METHODS: Patients (n = 516) were evaluated for TgAb and TPOAb at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after initiating anti-PD-1-Ab. RESULTS: Fifty-one (9.9%) patients developed thyroid irAEs (thyrotoxicosis in 34, hypothyroidism without prior thyrotoxicosis in 17). Twenty-five patients subsequently developed hypothyroidism following thyrotoxicosis. The cumulative incidence of thyroid irAEs differed among 4 groups classified by the presence of TgAb/TPOAb at baseline (group 1: TgAb-(-)/TPOAb-(-), 4.6% [19/415]; group 2: TgAb-(-)/TPOAb-(+), 15.8% [9/57]; group 3: TgAb-(+)/TPOAb-(-), 42.1% [8/19]; group 4: TgAb-(+)/TPOAb-(+), 60.0% [15/25]) as follows: groups 1 vs 2-4 (P ≤ .001) and groups 2 vs 3 (P = .008) and 4 (P < .001). There were different incidences of thyrotoxicosis (groups 1-4, 3.1%, 5.3%, 31.6%, 48.0%, respectively; P < .001) in groups 1 vs 3 and 4, and groups 2 vs 3 and 4, and of hypothyroidism (groups 1-4: 2.9%, 15.8%, 31.6%, 60.0%, respectively; P < .001) in groups 1 vs 2 to 4, and groups 2 vs 4. CONCLUSION: The risk of thyroid irAEs was affected by the pattern of TgAb and TPOAb positivity at baseline; there were high risks of thyrotoxicosis in patients with TgAb-(+) and of hypothyroidism in patients with TgAb-(+) and those with TPOAb-(+).

DOI： 10.1210/clinem/dgad231

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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

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Hyperglycemia impairs immune response; however, it remains unknown whether the anti-tumor effects of anti-programmed cell death-1 antibody (PD-1-Ab) treatment are changed in hyperglycemic conditions. We analyzed the effect of PD-1-Ab on tumor growth in streptozotocin-induced diabetic mice (STZ-mice) subcutaneously inoculated with MC38 (a colon carcinoma cell line). Furthermore, we assessed the expression of chemokines by polymerase chain reaction (PCR) array in tumor-draining lymph nodes (dLNs) of these mice and MC38 cells cultured in different glucose concentrations. The suppressive effect of PD-1-Ab on tumor growth was attenuated. This was accompanied by fewer tumor-infiltrating CD8+ T cells, and STZ-mice had fewer tumor-infiltrating CD11c+ dendritic cells (DCs) than normoglycemic mice. mRNA expression levels of CXCL9, a chemokine recruiting CD8+ T cells, were lower in dLNs of STZ-mice than in normoglycemic mice after PD-1-Ab treatment, and its protein was expressed in DCs. In MC38 cells cultured with 25 mM glucose, mRNA expression of CCL7, a chemokine recruiting DCs, was decreased compared to cells cultured with 5 mM glucose. These results suggest that the STZ-induced hyperglycemia impairs the effect of PD-1-Ab treatment on MC38 tumor growth, and is accompanied by reduced infiltration of DCs and CD8+ T cells and decreased expression of CCL7 and CXCL9.

DOI： 10.1038/s41598-023-33049-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

DOI： 10.3389/fimmu.2023.1165004

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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

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DOI： 10.1016/j.stemcr.2023.02.006

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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

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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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

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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Authorship：Corresponding author   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

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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

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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

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Best Practice and Research: Clinical Endocrinology and Metabolism  

Immune-related adverse events (irAEs) are caused by immune checkpoint inhibitors in several organs including the endocrine glands. Thyroid dysfunction (thyroid irAEs) is often observed among endocrine irAEs and is induced by blockade of programmed cell death 1 (PD-1), programmed death ligand 1, or PD-1 plus cytotoxic T-lymphocyte antigen 4. Endocrinologically, destructive thyroiditis or hypothyroidism is observed in most cases, whereas hyperthyroidism (Graves' disease) is rare. Most patients who develop destructive thyroiditis or hypothyroidism subsequently require thyroid hormone replacement therapy. Thyroid irAE development is associated with prolonged survival in patients with non-small cell lung carcinoma. The incidence of thyroid irAEs is higher in patients who are positive versus negative for anti-thyroid antibodies at baseline, suggesting that these antibodies can predict thyroid irAE development. Cytotoxic T cells, especially CD4 T cells, are reportedly involved in the development of destructive thyroiditis. In this review, we describe the clinical features, potential biomarkers, and mechanism of thyroid irAEs.

DOI： 10.1016/j.beem.2022.101660

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1210/clinem/dgab829

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Endocrinology (United States)  

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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Endocrinology and Metabolism  

Background: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. Methods: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. Results: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P= 0.022; 11/14 vs. 7/26, P= 0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. Conclusion: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

DOI： 10.3803/EnM.2021.1282

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

DOI： 10.1007/s00125-021-05610-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Pharmacological Sciences  

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 μg/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.

DOI： 10.1016/j.jphs.2021.08.010

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

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. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s00125-021-05516-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

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

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Science translational medicine  

DOI： 10.1126/scitranslmed.abb7495

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

DOI： 10.1016/j.neuroscience.2021.02.009

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

DOI： 10.1016/j.peptides.2021.170517

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/jitc-2021-002493

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本内分泌学会  

<p>The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8–18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.</p>

DOI： 10.1507/endocrj.EJ20-0769

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Endocrinology and Metabolism  

DOI： 10.3803/EnM.2021.1007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLoS ONE  

DOI： 10.1371/journal.pone.0248065

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

DOI： 10.1007/s11102-021-01135-6

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1507/endocrj.EJ20-0436

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DOI： 10.1038/s41598-020-76839-z

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DOI： 10.1016/j.isci.2020.101648

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DOI： 10.1136/bmjdrc-2019-001115

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neuint.2020.104733

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DOI： 10.1507/endocrj.EJ19-0569

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

DOI： 10.1038/s41416-020-0736-7

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

DOI： 10.1016/j.celrep.2019.12.009

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM). METHODS: A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint. RESULTS: Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05). CONCLUSIONS: In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone. CLINICAL TRIALS REGISTRATION: UMIN000019024.

DOI： 10.1136/jitc-2020-000779

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DOI： 10.1371/journal.pone.0228004

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DOI： 10.1507/endocrj.EJ19-0224

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DOI： 10.1016/j.isci.2019.09.032

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DOI： 10.1016/j.scr.2019.101572

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DOI： 10.1210/en.2019-00105.

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DOI： 10.1507/endocrj.EJ18-0545

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DOI： 10.1111/cas.13800

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DOI： 10.1016/j.neulet.2018.06.013

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DOI： 10.1002/path.5046

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DOI： 10.1507/endocrj.EJ17-0399

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DOI： 10.1210/js.2017-00432

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DOI： 10.1016/j.neulet.2017.06.014

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DOI： 10.1016/j.bbrc.2017.05.019

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

DOI： 10.1016/j.ebiom.2017.01.007

PubMed

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

<p>  免疫チェックポイント阻害薬で認められる免疫関連有害事象（immune-related adverse events; irAEs）は全身の臓器で認められ，大腸炎，肝炎，間質性肺炎，皮膚炎，神経・筋障害，内分泌障害などが報告されている．死亡に至る重篤例もあることから適切な対応が重要である．irAEsとして障害される内分泌器官は下垂体，甲状腺，副腎皮質，膵，副甲状腺が挙げられ，それぞれ異なる対応を要する．下垂体障害の頻度は細胞傷害性T細胞抗原（cytotoxic T-lymphocyte-associated antigen; CTLA）-4に対する抗体であるイピリムマブで4-10％程度，programmed cell death（PD）-1に対する抗体で1％未満と報告されている．下垂体前葉機能障害および下垂体腫大を呈する症例は臨床的に下垂体炎と考えられる．内分泌学的には副腎皮質刺激ホルモン（ACTH）の障害が最も高頻度で認められ，診断が遅れると副腎クリーゼとなり得る重篤な副作用である．これまでに報告された抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎の症例を検討した結果，両者の臨床的特徴には相違点があることが解ってきた．本講演では，抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎について臨床的特徴をそれぞれ解説し，両者の相違点について考察する．</p>

DOI： 10.2177/jsci.40.264a

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

DOI： 10.1155/2017/1543149

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

DOI： 10.2177/jsci.40.90

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

DOI： 10.1007/s11102-016-0780-8

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DOI： 10.1371/journal.pone.0164544

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DOI： 10.1016/j.expneurol.2016.08.007

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<p>  免疫チェックポイント阻害剤はT細胞の活性化を負に制御する分子に対するモノクローナル抗体で，細胞傷害性T細胞抗原（CTLA）4に対する抗体であるイピリムマブ（Ipi）とprogrammed cell death-1に対する抗体であるニボルマブが本邦でも近年使用開始された．これらの薬剤は，優れた抗腫瘍効果の一方で，自己免疫機序が想定される重篤な副作用を発症させ，特に，肝炎，腸炎，皮膚炎，内分泌障害が好発する．内分泌副作用として，下垂体炎，甲状腺機能異常症，副腎炎，1型糖尿病などが報告されており，薬剤によりその発症頻度は異なる．特に我々は，従来まれな疾患と考えられてきた下垂体炎が，Ipi使用者において約10％もの頻度で発症することに着目し，抗マウスCTLA4抗体をSJLマウスに連続投与することで下垂体に炎症細胞浸潤を呈する抗CTLA4抗体誘発下垂体炎マウスモデルを作成した．本マウスにおける病態解析を進め，抗CTLA4抗体は下垂体に発現するCTLA4に直接結合し，補体活性化を介したII型アレルギー反応により下垂体に炎症を誘発する可能性を報告した．さらに，Ipiにより下垂体炎を発症した患者血清中に抗下垂体抗体が存在することを明らかにし，臨床における抗下垂体抗体の診断的有用性を示した．本講演では抗CTLA4抗体による下垂体炎の発症メカニズムおよび実際の症例を紹介するとともに，現在名古屋大学で行っている臨床研究についても紹介したい．</p>

DOI： 10.2177/jsci.39.350b

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

DOI： 10.1681/ASN.2014121196

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DOI： 10.1210/jc.2014-4209

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DOI： 10.1002/ijc.28973

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DOI： 10.1507/endocrj.EJ14-0369

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DOI： 10.1038/ki.2014.119

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DOI： 10.1210/jc.2014-1049

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1126/scitranslmed.3008002

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DOI： 10.1210/jc.2013-2411

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DOI： 10.1210/jc.2013-1912

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DOI： 10.1089/thy.2012.0554

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DOI： 10.1210/en.2012-1236

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DOI： 10.1007/s12020-011-9549-z

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DOI： 10.1002/glia.21114

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DOI： 10.1111/j.1365-2826.2009.01894.x

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DOI： 10.1089/thy.2006.0121

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Language：Japanese

Event date： 2023.7

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Event date： 2021.4

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<p>  免疫チェックポイント阻害薬で認められる免疫関連有害事象（immune-related adverse events; irAEs）は全身の臓器で認められ，大腸炎，肝炎，間質性肺炎，皮膚炎，神経・筋障害，内分泌障害などが報告されている．死亡に至る重篤例もあることから適切な対応が重要である．irAEsとして障害される内分泌器官は下垂体，甲状腺，副腎皮質，膵，副甲状腺が挙げられ，それぞれ異なる対応を要する．下垂体障害の頻度は細胞傷害性T細胞抗原（cytotoxic T-lymphocyte-associated antigen; CTLA）-4に対する抗体であるイピリムマブで4-10％程度，programmed cell death（PD）-1に対する抗体で1％未満と報告されている．下垂体前葉機能障害および下垂体腫大を呈する症例は臨床的に下垂体炎と考えられる．内分泌学的には副腎皮質刺激ホルモン（ACTH）の障害が最も高頻度で認められ，診断が遅れると副腎クリーゼとなり得る重篤な副作用である．これまでに報告された抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎の症例を検討した結果，両者の臨床的特徴には相違点があることが解ってきた．本講演では，抗PD-1抗体または抗CTLA-4抗体による下垂体障害・下垂体炎について臨床的特徴をそれぞれ解説し，両者の相違点について考察する．</p>

Event date： 2017.5

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Event date： 2016.9

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

<p>  免疫チェックポイント阻害剤はT細胞の活性化を負に制御する分子に対するモノクローナル抗体で，細胞傷害性T細胞抗原（CTLA）4に対する抗体であるイピリムマブ（Ipi）とprogrammed cell death-1に対する抗体であるニボルマブが本邦でも近年使用開始された．これらの薬剤は，優れた抗腫瘍効果の一方で，自己免疫機序が想定される重篤な副作用を発症させ，特に，肝炎，腸炎，皮膚炎，内分泌障害が好発する．内分泌副作用として，下垂体炎，甲状腺機能異常症，副腎炎，1型糖尿病などが報告されており，薬剤によりその発症頻度は異なる．特に我々は，従来まれな疾患と考えられてきた下垂体炎が，Ipi使用者において約10％もの頻度で発症することに着目し，抗マウスCTLA4抗体をSJLマウスに連続投与することで下垂体に炎症細胞浸潤を呈する抗CTLA4抗体誘発下垂体炎マウスモデルを作成した．本マウスにおける病態解析を進め，抗CTLA4抗体は下垂体に発現するCTLA4に直接結合し，補体活性化を介したII型アレルギー反応により下垂体に炎症を誘発する可能性を報告した．さらに，Ipiにより下垂体炎を発症した患者血清中に抗下垂体抗体が存在することを明らかにし，臨床における抗下垂体抗体の診断的有用性を示した．本講演では抗CTLA4抗体による下垂体炎の発症メカニズムおよび実際の症例を紹介するとともに，現在名古屋大学で行っている臨床研究についても紹介したい．</p>