論文 - 渡辺　光博

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.

Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J.

Nature 439   484 - 489 2006年

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways1,2, are ligands for the G-protein-coupled receptor (GPCR) TGR53,4 and activate nuclear hormone receptors such as farnesoid X receptor α (FXR-α; NR1H4)5,6,7. FXR-α regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2)8,9 that inhibits the activity of other nuclear receptors. The FXR-α-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c10. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-α, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA–TGR5–cAMP–D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

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Vitamin D and energy homeostasis: of mice and men.

Bouillon R, Carmeliet G, Lieben L, Watanabe M, Perino A, Auwerx J, Schoonjans K, Verstuyf A.

Nature Rev Endocrinol 10 （ (2) ） 79 - 87 2013年11月

研究論文（学術雑誌）, 共著, 査読有り

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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.

Um SH, Frigerio F. Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G.

Nature 431   200 - 205 2004年

研究論文（学術雑誌）, 共著, 査読有り

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Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.

Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J.

J Clin Invest 113   1408 - 1418 2004年

研究論文（学術雑誌）, 共著, 査読有り

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Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure.

Watanabe M, Horai Y, Houten S M., Morimoto K, Sugizaki T, Arita E, Mataki C, Sato H, Tanigawara Y, Schoonjans K, Itoh H, Auwerx J

Journal of Biological Chemistry 286 （ 30 ） 26913-26920 2011年07月

研究論文（学術雑誌）, 共著, 査読有り

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Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure

Watanabe M, Morimoto M, Houten S, Kaneko-Iwasaki N, Sugizaki T, Horai Y, Mataki C, Sato H, Murahashi K, Arita E, Schoonjans K, Suzuki T, Itoh H and Auwerx J.

PLOS ONE 7 （ 8 ）  2012年08月

研究論文（学術雑誌）, 共著, 査読有り

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Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis.

Anakk S. Watanabe M. Ochsner SA, McKenna NJ, Finegold MJ, Moore DD.

Journal of Clinical Investigation 121 （ 1 ） 86-95 2011年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0021-9738

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Cysteine sulfinic acid decarboxylase regulation: A role for farnesoid X receptor and small heterodimer partner in murine hepatic taurine metabolism

Kerr TA, Matsumoto Y, Matsumoto H, Xie Y, Hirschberger LL, Stipanuk MH, Anakk S, Moore DD, Watanabe M, Kennedy S, Davidson NO.

Hepatology Research 44 （ 10 ） E218 - 28 2014年10月

研究論文（学術雑誌）, 共著, 査読有り

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Sodium ferrous citrate and 5-aminolevulinic acid improve type 2 diabetes by maintaining muscle and mitochondrial health

Naho Kitamura, Shiyang Zhang, Jean-David Morel, Utana Nagano, Tanon Taworntawat, Shotaro Hosoda, Anna Nakamura, Yoko Ogawa, Giorgia Benegiamo, Johan Auwerx, Kazuo Tsubota, Yoko Yokoyama, Mitsuhiro Watanabe

Obesity (Silver Spring) vol.31 （ 4 ） 1038 - 1049 2023年04月

学位論文（博士）, 最終著者, 査読有り

　概要を見る

Objective
Improving mitochondrial function is a promising strategy for intervention in type 2 diabetes mellitus. This study investigated the preventive effects of sodium ferrous citrate (SFC) and 5-aminolevulinic acid phosphate (ALA) on several metabolic dysfunctions associated with obesity because they have been shown to alleviate abnormal glucose metabolism in humans.

Methods
Six-week-old male C57BL/6J mice were fed with a normal diet, a high-fat diet, or a high-fat diet supplemented with SFC and ALA for 15 weeks.

Results
The simultaneous supplementation of SFC + ALA to high-fat diet-fed mice prevented loss of muscle mass, improved muscle strength, and reduced obesity and insulin resistance. SFC + ALA prevented abnormalities in mitochondrial morphology and reverted the diet effect on the skeletal muscle transcriptome, including the expression of glucose uptake and mitochondrial oxidative phosphorylation-related genes. In addition, SFC + ALA prevented the decline in mitochondrial DNA copy number by enhancing mitochondrial DNA maintenance and antioxidant transcription activity, both of which are impaired in high-fat diet-fed mice during long-term fasting.

Conclusions
These findings suggest that SFC + ALA supplementation exerts its preventive effects in type 2 diabetes mellitus via improved skeletal muscle and mitochondrial health, further validating its application as a promising strategy for the prevention of obesity-induced metabolic disorders.

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Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways

Kitamura N., Yokoyama Y., Taoka H., Nagano U., Hosoda S., Taworntawat T., Nakamura A., Ogawa Y., Tsubota K., Watanabe M.

Scientific Reports （Scientific Reports）  11 （ 1 ） 10753 2021年05月

研究論文（学術雑誌）, 共著

　概要を見る

Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

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Asperuloside Improves Obesity and Type 2 Diabetes through Modulation of Gut Microbiota and Metabolic Signaling

Nakamura A., Yokoyama Y., Tanaka K., Benegiamo G., Hirayama A., Zhu Q., Kitamura N., Sugizaki T., Morimoto K., Itoh H., Fukuda S., Auwerx J., Tsubota K., Watanabe M.

iScience （iScience）  23 （ 9 ）  2020年09月

研究論文（学術雑誌）, 共著

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Human Metabolism; Microbiome

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Agaricus brasiliensis KA21 May Prevent Diet-Induced Nash through Its Antioxidant, Anti-Inflammatory, and Anti-Fibrotic Activities in the Liver

Nakamura A., Zhu Q., Yokoyama Y., Kitamura N., Uchida S., Kumadaki K., Tsubota K., Watanabe M.

Foods （Foods）  8 （ 11 ）  2019年11月

研究論文（学術雑誌）, 共著

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Non-alcoholic steatohepatitis (NASH) is a progressive disease that occurs in the liver. As the number of people with NASH has increased, effective prevention and treatment strategies are needed. Agaricus brasiliensis KA21 (AGA) is a mushroom native to Brazil and is considered a healthy food because of its purported health benefits, including its antioxidant properties. In this study, we focused on the oxidative stress that accompanies the onset of NASH and examined whether AGA can prevent NASH development through its antioxidant activity. We used a mouse model of NASH in which pathogenesis was promoted by dietary induction. Supplementation with AGA attenuated the development of hepatic fibrosis, which is a characteristic feature of late-stage NASH. This effect appeared to be mechanistically linked to an AGA-promoted reduction in hepatic oxidative stress. These results demonstrate a novel role for AGA in NASH prevention.

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Melon GliSODin® prevents diet-induced NASH onset by reducing fat synthesis and improving liver function

Nakamura A., Kitamura N., Yokoyama Y., Uchida S., Kumadaki K., Tsubota K., Watanabe M.

Nutrients （Nutrients）  11 （ 8 ） E1779 2019年08月

　概要を見る

A high-calorie diet causes fat accumulation and oxidative stress in the liver, leading to fatty liver and eventually non-alcoholic steatohepatitis (NASH). Melon GliSODin® is used as a nutritional supplement because of its antioxidant activity. This study aimed to assess the antioxidant activity of Melon GliSODin® and its effectiveness in preventing NASH, which primarily results from oxidative stress. Furthermore, we verified the protective effect of Melon GliSODin® by administering it to a mouse model of diet-induced NASH. Melon GliSODin® suppressed liver fibrosis and fat accumulation, which is characteristic of the NASH phenotype. Gene expression analysis confirmed the suppression of fat synthesis and activation of antioxidative mechanisms. These results show that Melon GliSODin® mitigates NASH onset at the molecular level, suggesting its potential application as a NASH preventive agent.

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Vegetarian diets and glycemic control in diabetes: a systematic review and meta-analysis.

Yokoyama Y, Barnard ND, Levin SM, Watanabe M.

Cardiovascular Diagonosis Therapy 4 （ (5) ） 373 - 382 2014年10月

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Metabolic Effects of Bee Larva-Derived Protein in Mice: Assessment of an Alternative Protein Source

Yoko Yokoyama, Kawori Shinohara, Naho Kitamura, Anna Nakamura, Ai Onoue, Kazuki Tanaka, Akiyoshi Hirayama, Wanping Aw, Shigeru Nakamura, Yoko Ogawa, Shinji Fukuda, Kazuo Tsubota, Mitsuhiro Watanabe

Foods.  10 （ 11 ） 2642 2021年11月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り

　概要を見る

Food crises caused by growing global population or environmental changes are predicted in the near future; therefore, sustainable solutions are needed. Edible insects, which are rich in protein and can save feed and environmental resources, have the potential to be a sustainable alternative protein source. However, there is limited evidence on the impact on health. In this study, we investigated the biological effects of ingesting bee larva by examining their effects on amino acid, lipid, and glucose metabolism in animal models. In our animal experiments, the replacement of casein as a protein source, with edible insects, did not seem to cause any deficiency in murine amino acid levels in the plasma and liver. Metabolomic analysis of plasma metabolites showed decreased 3-methylhistidine and increased nicotinamide in the bee larva-derived protein-fed mice. Decreased levels of plasma 3-metylhistidine, an indicator of muscle degradation, implies that replacement to bee-larva protein from casein did not cause muscle degradation in vivo. We further investigated effects of increased plasma nicotinamide on peripheral tissue and found an increase in expression levels of genes involved in glucose uptake in muscle and thermogenesis in adipose tissue. These data imply that bee larva is a potential sustainable, safe and healthy alternative protein source.

Keywords: bee larva; edible insects; metabolite; nutrition balance; protein.

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A high-salt/high fat diet alters circadian locomotor activity and glucocorticoid synthesis in mice

Yokoyama Y., Nakamura T.J., Yoshimoto K., Ijyuin H., Tachikawa N., Oda H., Shiraishi R., Shinohara K., Kumadaki K., Honda S., Nakamura A., Kitamura N., Tsubota K., Watanabe M.

PLoS ONE （PLoS ONE）  15 （ 5 ） e0233386 2020年05月

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　概要を見る

Salt is an essential nutrient; however, excessive salt intake is a prominent public health concern worldwide. Various physiological functions are associated with circadian rhythms, and disruption of circadian rhythms is a prominent risk factor for cardiovascular diseases, cancer, and immune disease. Certain nutrients are vital regulators of peripheral circadian clocks. However, the role of a high-fat and high-salt (HFS) diet in the regulation of circadian gene expression is unclear. This study aimed to investigate the effect of an HFS diet on rhythms of locomotor activity, caecum glucocorticoid secretion, and clock gene expression in mice. Mice administered an HFS diet displayed reduced locomotor activity under normal light/dark and constant dark conditions in comparison with those administered a normal diet. The diurnal rhythm of caecum glucocorticoid secretion and the expression levels of glucocorticoid-related genes and clock genes in the adrenal gland were disrupted with an HFS diet. These results suggest that an HFS diet alters locomotor activity, disrupts circadian rhythms of glucocorticoid secretion, and downregulates peripheral adrenal gland circadian clock genes.

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Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice.

Fajas L, Annicotte JS, Miard S, Sarruf D, Watanabe M, Auwerx J.

J Clin Invest. 113 （ 9 ） 1288 - 1295 2004年05月

研究論文（学術雑誌）, 共著, 査読有り

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Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.

Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J.

Proc Natl Acad Sci U S A. 100 （ 26 ） 15924 - 15929 2003年12月

研究論文（学術雑誌）, 共著, 査読有り

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Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice.

Koutnikova H, Cock TA, Watanabe M, Houten SM, Champy MF, Dierich A, Auwerx J.

Proc Natl Acad Sci U S A. 100 （ 24 ） 14457 - 14462 2003年11月

研究論文（学術雑誌）, 共著, 査読有り

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Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation.

Picard F, Watanabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J.

Proc Natl Acad Sci U S A. 99 （ 24 ） 15644 - 15648 2002年11月

研究論文（学術雑誌）, 共著, 査読有り

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