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青谷 大介アオタニ ダイスケ

所属部署医学研究科消化器・代謝内科学分野
職名講師
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Last Updated :2020/06/02

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  • Generation of leptin-deficient Lep(mkyo)/Lep(mkyo) rats and identification of leptin-responsive genes in the liver, Megumi Aizawa-Abe, Ken Ebihara, Chihiro Ebihara, Tomoji Mashimo, Akiko Takizawa, Tsutomu Tomita, Toru Kusakabe, Yuji Yamamoto, Daisuke Aotani, Sachiko Yamamoto-Kataoka, Takeru Sakai, Kiminori Hosoda, Tadao Serikawa, Kazuwa Nakao, PHYSIOLOGICAL GENOMICS, 45, (17) 786 - 793,   2013年09月, 査読有り, Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver.
  • Leptin activates hepatic 5′-AMP-activated protein kinase through sympathetic nervous system and α1-adrenergic receptor: A potential mechanism for improvement of fatty liver in lipodystrophy by leptin, L. Miyamoto, K. Ebihara, T. Kusakabe, D. Aotani, S. Yamamoto-Kataoka, T. Sakai, M. Aizawa-Abe, Y. Yamamoto, J. Fujikura, T. Hayashi, K. Hosoda, K. Nakao, Journal of Biological Chemistry, 287, (48) 40441 - 40447,   2012年11月, 査読有り
  • Functional Magnetic Resonance Imaging Analysis of Food-Related Brain Activity in Patients with Lipodystrophy Undergoing Leptin Replacement Therapy, Daisuke Aotani, Ken Ebihara, Nobukatsu Sawamoto, Toru Kusakabe, Megumi Aizawa-Abe, Sachiko Kataoka, Takeru Sakai, Hitomi Iogawa, Chihiro Ebihara, Junji Fujikura, Kiminori Hosoda, Hidenao Fukuyama, Kazuwa Nakao, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 97, (10) 3663 - 3671,   2012年10月, 査読有り, Context: Lipodystrophy is a disease characterized by a paucity of adipose tissue and low circulating concentrations of adipocyte-derived leptin. Leptin-replacement therapy improves eating and metabolic disorders in patients with lipodystrophy. Objective: The aim of the study was to clarify the pathogenic mechanism of eating disorders in lipodystrophic patients and the action mechanism of leptin on appetite regulation. Subjects and Interventions: We investigated food-related neural activity using functional magnetic resonance imaging in lipodystrophic patients with or without leptin replacement therapy and in healthy controls. We also measured the subjective feelings of appetite. Results: Although there was little difference in the enhancement of neural activity by food stimuli between patients and controls under fasting, postprandial suppression of neural activity was insufficient in many regions of interest including amygdala, insula, nucleus accumbens, caudate, putamen, and globus pallidus in patients when compared with controls. Leptin treatment effectively suppressed postprandial neural activity in many of these regions of interest, whereas it showed little effect under fasting in patients. Consistent with these results, postprandial formation of satiety feeling was insufficient in patients when compared with controls, which was effectively reinforced by leptin treatment. Conclusions: This study demonstrated the insufficiency of postprandial suppression of food-related neural activity and formation of satiety feeling in lipodystrophic patients, which was effectively restored by leptin. The findings in this study emphasize the important pathological role of leptin in eating disorders in lipodystrophy and provide a clue to understanding the action mechanism of leptin in human, which may lead to development of novel strategies for prevention and treatment of obesity. (J Clin Endocrinol Metab 97: 3663-3671, 2012)
  • Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice, Toru Kusakabe, Ken Ebihara, Takeru Sakai, Licht Miyamoto, Daisuke Aotani, Yuji Yamamoto, Sachiko Yamamoto-Kataoka, Megumi Aizawa-Abe, Junji Fujikura, Kiminori Hosoda, Kazuwa Nakao, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 302, (8) E924 - E931,   2012年04月, 査読有り, Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice. Am J Physiol Endocrinol Metab 302: E924-E931, 2012. First published January 24, 2012; doi:10.1152/ajpendo.00198.2011.-Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic beta-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 mu g.kg(-1).day(-1)), amylin (A; 100 mu g.kg(-1).day(-1)), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPK alpha 2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.
  • Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet, T. Kusakabe, H. Tanioka, K. Ebihara, M. Hirata, L. Miyamoto, F. Miyanaga, H. Hige, D. Aotani, T. Fujisawa, H. Masuzaki, K. Hosoda, K. Nakao, DIABETOLOGIA, 52, (4) 675 - 683,   2009年04月, 査読有り, We have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity. To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 mu g/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight](-1) h(-1)) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined. Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of alpha 2 AMPK activity in skeletal muscle. Pair-feeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction. This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.
  • Central pontine and extrapontine myelinolysis associated with type 2 diabetic patient with hypokalemia, M Shintani, M Yamashita, A Nakano, D Aotani, K Maeda, T Yamamoto, H Nishimura, DIABETES RESEARCH AND CLINICAL PRACTICE, 68, (1) 75 - 80,   2005年04月, 査読有り, Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with the demyelination of extrapontine areas of the central nervous system. Although the etiology and pathogenesis are unclear, CPM is usually associated with hyponatremia or its rapid correction, and chronic alcoholism is also a common underlying condition. We observed a 43-year-old man with diabetes mellitus who developed central pontine and extrapontine myelinolysis with no apparent evidence of hyponatremia, serum hyperosmolality or associated rapid correction, or history of alcohol abuse. On admission, the patient was lethargic with dysarthria, dysphagia, and mild tetraparesis and his face and lower extremities were severely edematous. Laboratory examination showed normoglycemia and normonatremia, although hypokalemia, elevated HbA(1c), and nephrotic syndrome were also present. Magnetic resonance imaging (MRI) revealed abnormal signal intensity in the pons, the deep layers of the cerebral cortex, and the adjacent white matter consistent with central pontine and extrapontine myelinolysis. Generalized edema was reduced by the use of diuretics and extracorporeal ultrafiltration without significant changes of serum sodium or osmolality. His consciousness level and paresis gradually improved within a few weeks. Our patient is a rare case of CPM associated with diabetes without apparent evidence of sodium or glucose imbalances. (c) 2004 Elsevier Ireland Ltd. All rights reserved.


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