Search for the novel molecules involved in brown adipocyte activation

• Project/Area Number: 18K16208
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kumamoto University
• Principal Investigator: Sakaguchi Masaji 熊本大学, 大学院生命科学研究部(医), 助教 (90625774)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 糖尿病 / インスリン抵抗性 / 褐色脂肪組織 / インスリンシグナル / ミトコンドリア / 再生 / 肥満 / ２型糖尿病 / 2型糖尿病 / インスリン受容体 / 臓器連関

Outline of Final Research Achievements

In order to identify the molecules involved in the activation of brown adipose tissues, we employed the proteomics analysis using the serum from the inducible adipocyte-specific IR and IGF1R knockout mice. We selected the candidate molecules that altered significantly and confirmed their differences in comparison with those of controls by the qPCR. We tentatively designated this molecule brown adipocyte activator (BAF) that derived from the liver. The addition of BAF induced the proliferation of brown adipocyte progenitor cells in vitro, promoted mitochondrial activity. BAF was also shown to act on white adipocytes, inducing beige adipocyte. These results confirmed that BAF is a novel soluble factor involved in activating both white and brown adipocytes. To furthermore investigate the impact of BAF in vivo, we created liver-specific BAF transgenic mice (BAF-Tg).

Academic Significance and Societal Importance of the Research Achievements

BAFはメタボリックシンドロームにおける肝臓‐脂肪の臓器連関に深く関わっていると考えられ、糖尿病治療の新規分子標的として期待できる。BAFの作用機序の解明をすすめると同時に、in vivoでの機能解析をすすめていくことで、今後の臨床応用への展望を開く可能性がある。本成果報告として、褐色脂肪前駆細胞の増殖及び再生を誘導する新規生理活性因子を網羅的に検索し、候補分子BAFを確定することができた。今後、褐色脂肪細胞前駆細胞の分化、増殖を誘導する因子（BAF）の作用機序を明らかにしていきたい。

Research Products

• [Journal Article] The Amount of Residual Incretin Regulates the Pancreatic β-cell Function and Glucose Homeostasis (2021)
  • Author(s): Kondo T, Kitano S, Miyakawa N, Watanabe T, Goto R, Sato M, Hanatani S, Sakaguchi M, Igata M, Kawashima J, Motoshima H, Matsumura T, Araki E.
  • Journal Title: Internal Medicine Volume: 60 Issue: 9 Pages: 1433-1442
  • DOI: 10.2169/internalmedicine.6026-20
  • NAID: 130008033306
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-05-01
  • Peer Reviewed / Open Access
• [Journal Article] Leptin Receptor Signaling Regulates Protein Synthesis Pathways and Neuronal Differentiation in Pluripotent Stem Cells (2020)
  • Author(s): Gupta Manoj K.、Vethe Heidrun、Softic Samir、Rao Tata Nageswara、Wagh Vilas、Shirakawa Jun、Barsnes Harald、Vaudel Marc、Takatani Tomozumi、Kahraman Sevim、Sakaguchi Masaji、Martinez Rachael、Hu Jiang、Bj?rlykke Yngvild、Raeder Helge、Kulkarni Rohit N.
  • Journal Title: Stem Cell Reports Volume: 15 Issue: 5 Pages: 1067-1079
  • DOI: 10.1016/j.stemcr.2020.10.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid and dramatic glucose‐lowering effect of bromocriptine in an inadequately controlled type2 diabetes patient with prolactinoma (2020)
  • Author(s): Igata Motoyuki、Yagi Yoshitaka、Hanatani Satoko、Sakaguchi Masaji、Ishii Norio、Yoshinaga Kayo、Kawashima Junji、Motoshima Hiroyuki、Araki Eiichi
  • Journal Title: Journal of Diabetes Investigation Volume: 12 Issue: 4 Pages: 668-671
  • DOI: 10.1111/jdi.13369
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of the PI 3-kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress-dependent apoptosis. (2020)
  • Author(s): Winnay JN, Solheim MH, Sakaguchi M, Njolstad PR, Kahn CR.
  • Journal Title: FASEB J. Volume: 34 Issue: 9 Pages: 12521-12532
  • DOI: 10.1096/fj.202000892r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat. (2019)
  • Author(s): Leiria LO, Wang CH, Lynes MD, Yang K, Shamsi F, Sato M, Sugimoto S, Chen EY, Bussberg V, Narain NR, Sansbury BE, Darcy J, Huang TL, Kodani SD, Sakaguchi M, Rocha AL, Schulz TJ, Bartelt A, Hotamisligil GS, Hirshman MF, van Leyen K, Goodyear LJ, Bluher M, Cypess AM, Kiebish MA, Spite M, Tseng YH.
  • Journal Title: Cell Metabolism Volume: 30 Issue: 4 Pages: 768-783
  • DOI: 10.1016/j.cmet.2019.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism. (2019)
  • Author(s): Li ME, Lauritzen HPMM, O'Neill BT, Wang CH, Cai W, Brandao BB, Sakaguchi M, Tao R, Hirshman MF, Softic S, Kahn CR.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 3412-3412
  • DOI: 10.1038/s41467-019-11265-y
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of the efficacy and safety of once-daily insulin degludec/insulin aspart (IDegAsp) and long-acting second-generation basal insulin (insulin degludec and insulin glargine 300 units/mL) in insulin-naïve Japanese adults with type 2 diabetes: a pilot, randomized, controlled study (2019)
  • Author(s): Shimoda Seiya、Sakamoto Wakana、Hokamura Ayaka、Matsuo Yasuto、Sekigami Taiji、Ichimori Shinji、Iwashita Shinsuke、Ishii Norio、Otsu Kae、Yoshimura Ryohei、Nishiyama Toshihiko、Sakaguchi Masaji、Nishida Kenro、Araki Eiichi
  • Journal Title: Endocrine Journal Volume: 66 Issue: 8 Pages: 745-752
  • DOI: 10.1507/endocrj.EJ19-0179
  • NAID: 130007696455
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets (2019)
  • Author(s): Goto Rieko、Kondo Tatsuya、Ono Kaoru、Kitano Sayaka、Miyakawa Nobukazu、Watanabe Takuro、Sakaguchi Masaji、Sato Miki、Igata Motoyuki、Kawashima Junji、Motoshima Hiroyuki、Matsumura Takeshi、Shimoda Seiya、Araki Eiichi
  • Journal Title: Journal of Clinical Medicine Volume: 8 Issue: 5 Pages: 674-674
  • DOI: 10.3390/jcm8050674
  • Peer Reviewed / Open Access
• [Journal Article] FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism. (2019)
  • Author(s): Sakaguchi M, Cai W, Wang CH, Cederquist CT, Damasio M, Homan EP, Batista T, Ramirez AK, Gupta MK, Steger M, Wewer Albrechtsen NJ, Singh SK, Araki E, Mann M, Enerback S, Kahn CR.
  • Journal Title: Nat Commun. Volume: 10 Issue: 1 Pages: 1582-1582
  • DOI: 10.1038/s41467-019-09418-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo. (2019)
  • Author(s): Batista TM, Garcia-Martin R, Cai W, Konishi M, O'Neill BT, Sakaguchi M, Kim JH, Jung DY, Kim JK, Kahn CR.
  • Journal Title: Cell Rep. Volume: 12 Issue: 12 Pages: 3429-3443
  • DOI: 10.1016/j.celrep.2019.02.081
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Membrane metallo-endopeptidase (Neprilysin) regulates inflammatory response and insulin signaling in white preadipocytes. (2019)
  • Author(s): Ramirez AK, Dankel S, Cai W, Sakaguchi M, Kasif S, Kahn CR.
  • Journal Title: Mol Metab. Volume: 22 Pages: 21-36
  • DOI: 10.1016/j.molmet.2019.01.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of hepatic HSP72 on insulin signaling (2019)
  • Author(s): Kitano Sayaka、Kondo Tatsuya、Matsuyama Rina、Ono Kaoru、Goto Rieko、Takaki Yuki、Hanatani Satoko、Sakaguchi Masaji、Igata Motoyuki、Kawashima Junji、Motoshima Hiroyuki、Matsumura Takeshi、Kai Hirofumi、Araki Eiichi
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism Volume: 316 Issue: 2 Pages: E305-E318
  • DOI: 10.1152/ajpendo.00215.2018
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism (2019)
  • Author(s): Takahashi H, Alves C, Stanford K, Middelbeek R, Nigro P, Ryan R, Xue R, Sakaguchi M, Lynes M, So K, Mul J, Lee M. Y, Balan E, Pan H, Dreyfuss J, Hirshman M, Azhar M, Hannukainen J, Kalliokoski K, Nielsen S, Pedersen B, Kahn C.R, Tseng YH, Nuutila P, Goodyear L.
  • Journal Title: Nat Metab. Volume: 1 Issue: 2 Pages: 291-293
  • DOI: 10.1038/s42255-018-0030-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Insulin regulates astrocyte gliotransmission and modulates behavior. (2018)
  • Author(s): Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, Li ME, Yu R, Kleinridders A, Pothos EN, Kahn CR.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 7 Pages: 2914-2926
  • DOI: 10.1172/jci99366
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. (2018)
  • Author(s): Altindis E, Cai W, Sakaguchi M, Zhang F, GuoXiao W, Liu F, De Meyts P, Gelfanov V, Pan H, DiMarchi R, Kahn CR.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 115 Issue: 10 Pages: 2461-2466
  • DOI: 10.1073/pnas.1721117115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of microRNA that represses IRS-1 expression in liver. (2018)
  • Author(s): Ono K, Igata M, Kondo T, Kitano S, Takaki Y, Hanatani S, Sakaguchi M, Goto R, Senokuchi T, Kawashima J, Furukawa N, Motoshima H, Araki E
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: 0191553-0191553
  • DOI: 10.1371/journal.pone.0191553
  • Peer Reviewed / Open Access
• [Presentation] Regulation of Phosphorylation Status in Insulin Signaling via α4 Is Necessary for Adipocyte Maintenance and Lipid Dynamics. (2020)
  • Author(s): Sakaguchi M, Okagawa S, Okubo Y, Kitano S, Igata M, Kondo T, Araki E.
  • Organizer: The 80th ADA scientific meeting
  • Int'l Joint Research
• [Presentation] The essential role of the α4 for insulin signalling in metabolic regulation and maintenance of brown adipocyte. (2020)
  • Author(s): Sakaguchi M, Okagawa S, Okubo Y, Igata M, Kondo T, Araki E.
  • Organizer: 56th Annual Meetng of the European Association of the Study of Diabetes.
  • Int'l Joint Research
• [Presentation] 白色および褐色脂肪組織のインスリン抵抗性に関わる新規経路α4 の全身代謝制御の解析. (2020)
  • Author(s): 阪口雅司，岡川章太，大久保侑馬，北野さやか，井形元維，河島淳司，近藤龍也，荒木栄一
  • Organizer: 第63回日本糖尿病学会年次学術集会
• [Presentation] FoxK1 and FoxK2 are positive regulators for IR and IGF1R signalling in cell proliferation and metabolism. (2019)
  • Author(s): Sakaguchi M, Araki E, Mann M, Enerback S, Kahn CR
  • Organizer: 55th Annual Meetng of the European Association of the Study of Diabetes.
  • Int'l Joint Research
• [Presentation] Unique role of the α4 component for S6-kinase activity in Metabolic Regulation and anti- Apoptotic effect in Brown Adipose Tissue (2019)
  • Author(s): Sakaguchi M, Okagawa S, Kondo T, Kitano S,Araki E.
  • Organizer: The 79th ADA scientific meeting,
  • Int'l Joint Research
• [Presentation] Molecular mechanism for adipose tissue dynamics (2019)
  • Author(s): 阪口雅司
  • Organizer: AASD-MDIA 2019
  • Int'l Joint Research / Invited
• [Presentation] 脂肪細胞の機能を制御するインスリンシグナル伝達経路 (2018)
  • Author(s): 阪口雅司, C Ronald Kahn, 荒木栄一
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] インスリン抵抗性下における白色及び褐色脂肪組織の維持及び再生 (2018)
  • Author(s): 阪口雅司, C Ronald Kahn, 荒木栄一
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 脂肪組織のダイナミックス. (2018)
  • Author(s): 阪口雅司, 荒木栄一
  • Organizer: 第56回日本糖尿病学会 九州地方会
  • Invited
• [Presentation] FoxK1/K2 are new important components of IR and IGF1R signaling and control of cell proliferation and metabolism. (2018)
  • Author(s): Sakaguchi M, Cai W, Wang C, Homan P. E, Batista T, Araki E, Kahn C. R.
  • Organizer: The 78th ADA scientific meeting,
  • Int'l Joint Research
• [Book] 医学の歩み (2020)
  • Author(s): 阪口雅司, 大久保侑馬, 岡川章太, 荒木栄一
  • Total Pages: 4
  • Publisher: 医歯薬出版
• [Book] Medical Science Digest (2020)
  • Author(s): 1.阪口雅司, 大久保侑馬, 岡川章太, 荒木栄一
  • Total Pages: 3
  • Publisher: ニュー・サイエンス社
• [Book] Diabetes Strategy (2019)
  • Author(s): 阪口雅司
  • Total Pages: 6
  • Publisher: 先端医学社
• [Book] インスリン受容体異常症(A型，B型) (2019)
  • Author(s): 阪口雅司, 荒木栄一
  • Total Pages: 7
  • Publisher: 日本臨牀社
• [Book] Islet Equality (2018)
  • Author(s): 阪口雅司
  • Total Pages: 2
  • Publisher: メディカルレビュー社
• [Book] Diabetes Journal (糖尿病と代謝) (2018)
  • Author(s): 阪口雅司, 荒木栄一
  • Total Pages: 3
  • Publisher: 協和企画
• [Book] 糖尿病学2018 (2018)
  • Author(s): 阪口雅司, 荒木栄一
  • Total Pages: 8
  • Publisher: 診断と治療社
  • ISBN: 9784787823472
• [Book] 臨床と研究 (2018)
  • Author(s): 阪口雅司, 荒木栄一
  • Total Pages: 8
  • Publisher: 大道学館