Project Programs

 

Associate Professor Takahisa NAKAMURA



Our lab’s primary interest is the pathogenesis of obesity and metabolic diseases such as type 2 diabetes, nonalcoholic steatohepatitis (NASH), and cardiovascular disease (CVD). We are specifically interested in the role of cellular and circulating RNA networks in the regulation of immunometabolism in the development and progression of these diseases. We have established a variety of mouse and cell culture models to study inflammatory and metabolic responses regulated by cellular and circulating RNA networks that lead us to find novel therapeutic approaches targeting the RNA networks for treating such diseases.

Research Topics:
•Determining endogenous pathogenic dsRNAs in chronic inflammation.
•Investigating circulating RNA that mediate intercellular communication.
•Analyzing roles of hepatic miRNA networks in the regulation of inflammation and metabolism.

Published Study:
Peer reviewed articles
Kim A, Shah A, Nakamura T. “Extracellular Vesicles: A potential novel regulator of obesity and its associated complications.” Children. 2018 Nov 15;5(11), PubMed ID: 30445758.

Salem ESB, Murakami K, Takahashi T, Bernhard E, Borra, V, Bethi M, Nakamura T*. “Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-Radioactive L-Azidohomoalanine Labeling Method.” Journal of Visualized Experiments. 2018 Oct 23; 140. PubMed ID: 30417869.

Zhang C, Seo J, Murakami K, Salem ESB, Bernhard E, Borra V, Choi K, Yuan CL, Chan C, Chen X, Huang T, Weirauch MT, Divanovic S, Qi NR, Thomas HE, Mercer CA, Siomi H, Nakamura T*. “Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology.” Nature Communications. 2018 Sep 10; 9(1): 3658, PubMed ID: 30201950.

Peng J, Li Y, Deng S, Holland J, Yates E, Chen J, Gu H, Wang X, Essandoh K, Mu X, McNamara RK, Peng T, Jegga AG, Nakamura T*, Huang K*, Perez-Tilve D*, Fan G*. “An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.” Cell Reports. 2018 June 19; 23(12):3607-3620, PubMed ID: 29925002.

Yamazaki T, Li W, Yang L, Li P, Cao H, Motegi SI, Udey MC, Bernhard E, Nakamura T, Mukouyama YS. “Whole-mount adult ear skin imaging reveals defective neuro-vascular branching morphogenesis in obese and type 2 diabetic mouse models” Sci Rep. 2018 Jan 11;8(1):430, PubMed ID: 29323138.

Zhang C, Seo J, Nakamura T*. “Cellular approaches in investigating Argonaute 2-dependent RNA silencing.” Methods Mol Biol. 2018 1680: 205-215, PubMed ID: 29030851. *

Youssef OA, Safran SA, Nakamura T, Nix DA, Hotamisligil GS, Bass BL. “A potential role for snoRNAs in PKR activation during metabolic stress.” Proc Natl Acad Sci U S A. 2015 Apr; 112 (16): 5023-5028, PubMed ID: 25848059.

Nakamura T*, Kunz RC, Zhang C, Kimura T, Yuan CL, Baccaro B, Namiki, Y, Gygi SP, Hotamisligil GS*. “A critical role of PKR complexes with TRBP in immunometabolic regulation and eIF2alpha phosphorylation in obesity.” Cell Reports. 2015 Apr 14;11(2):295-307, PubMed ID: 25843719.

Nakamura T, Arduini A, Baccaro B, Furuhashi M, Hotamisligil GS. “Small molecule inhibitors of PKR improve glucose homeostasis in obese, diabetic mice.” Diabetes. 2014 Feb; 63 (2): 526-534, PubMed ID: 24150608.

Lu B, Nakamura T, Inouye K, Valdes-Ferrer SI, Olofsson PS, Li J, Wang H, Erlandsson-Harris, Andersson U, Yang H, Chavan SS, Hotamisligil GS, Tracey KJ. “PKR is required for NLRP3 inflammasome activation and HMGB1 release.” Nature. 2012 Aug 30; 488 (7413): 670-4, PubMed ID: 22801494.

Morita M. Oike Y, Nagashima T, Kadomatsu T, Tabata M, Suzuki T, Nakamura T, Yoshida N, Okada M, Yamamoto T. “Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3(+/-) mice.” EMBO J. 2011 Sep 6; 30 (22): 4678-4691, PubMed ID: 21897366.

Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS. “Double-stranded RNA-dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis.” Cell. 2010 Feb 5; 140 (3): 338-348, PubMed ID: 20144759.

Murohashi M, Nakamura T, Tanaka S, Ichise T, Yoshida N, Yamamoto T, Shibuya M, Schlessinger J, Gotoh N. “An FGF-FRS2alpha-Cdx2 Axis in Trophoblast Stem Cells Induces Bmp4 to Regulate Proper Growth of Early Mouse Embryos.” Stem Cells. 2009 Nov 3; 28 (1): 113-121, PubMed ID: 19890878.

Horiuchi M, Takeuchi K, Noda N, Muroya N, Suzuki T, Nakamura T, Kawamura-Tsuzuku J, Takahasi K, Yamamoto T, Inagaki F. “Structural basis for the antiproliferative activity of the Tob-hCaf1 complex.” J Biol Chem. 2009 May 8; 284 (19): 13244-13255, PubMed ID: 19276069.

Yoneda M, Suzuki T, Nakamura T, Ajima R, Yoshida Y, Kakuta S, Sudo K, Iwakura Y, Shibutani M, Mitsumori K, Yokota J, Yamamoto T. “Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma.” Cancer Science. 2009 Feb; 100 (2): 225-232, PubMed ID: 19068083.

Hirata T, Amiya S, Akiya M, Takei O, Sakai T, Nakamura T, Tsuzuku JK, Yamamoto T, Hatakeyama R. “Chemical Modification of Carbon Nanotube Based Bio-Nanosensor by Plasma Activation.” Jpn J Applied Physics. 2008 Apr 18; 47 (4): 2068-2071, Accession Number: WOS:000255449000033.

Ajima R, Akiyama T, Usui M, Yoneda M, Yoshida Y, Nakamura T, Minowa O, Noda M, Tanaka S, Noda T, Yamamoto T. “Osteoporotic bone formation in mice lacking tob2; involvement of Tob2 in RANK ligand expression and osteoclasts differentiation.” FEBS Lett. 2008 Apr 16; 582 (9): 1313-8, PubMed ID: 18358842.

Morita M, Suzuki T, Nakamura T, Yokoyama K, Miyasaka T, Yamamoto T. “Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1 mRNA level and impairs cell growth.” Mol Cell Biol. 2007 Jul; 27 (13): 4980-90, PubMed ID: 17452450.

Washio-Oikawa K, Nakamura T, Usui M, Yoneda M, Ezura Y, Ishikawa I, Nakashima K, Noda T, Yamamoto T, Noda M. “Cnot7-null mice exhibit high bone mass phenotype and modulation of BMP actions.” J Bone Miner Res. 2007 Aug; 22 (8): 1217-23, PubMed ID: 17451368.

Kawa S, Ito C, Toyama Y, Maekawa M, Tezuka T, Nakamura T, Nakazawa T, Yokoyama K, Yoshida N, Toshimori K, Yamamoto T. “Azoospermia in mice with targeted disruption of the Brek/Lmtk2 (brain-enriched kinase/lemur tyrosine kinase 2) gene.” Proc Natl Acad Sci U S A. 2006 Dec 19; 103 (51): 19344-9, PubMed ID: 17158803.

Washio-Oikawa K, Nakamura T, Usui M, Yoneda M, Ezura Y, Ishikawa I, Nakashima K, Yamamoto T, Noda M. “Expression analysis of LacZ gene placed in the locus of Cnot7 exhibits its activity in osteoblasts in vivo and in mineralized nodules in vitro.” J Cell Biochem. 2006 Oct 1; 99 (2): 538-44, PubMed ID: 16639713.

Ogawa T, Ito C, Nakamura T, Tamura Y, Yamamoto T, Noda T, Kubota Y, Toshimori K. “Abnormal sperm morphology caused by defects in Sertoli cells of Cnot7 knockout mice.” Arch Histol Cytol. 2004 Nov; 67 (4): 307-14, PubMed ID: 15700538.

Nakamura T, Yao R, Ogawa T, Suzuki T, Ito C, Tsunekawa N, Inoue K, Ajima R, Miyasaka T, Yoshida Y, Ogura A, Toshimori K, Noce T, Yamamoto T, Noda T. “Oligo-astheno- teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta.” Nat Genet. 2004 May; 36 (5): 528-33, PubMed ID: 15107851.

Goto J, Tezuka T, Nakazawa T, Tsukamoto N, Nakamura T, Ajima R, Yokoyama K, Ohta T, Ohki M, Yamamoto T. “Altered gene expression in the adult brain of fyn-deficient mice.” Cell Mol Neurobiol. 2004 Feb; 24 (1): 149-59, PubMed ID: 15049519.

Kimura H*, Nakamura T*, Ogawa T, Tanaka S, Shiota K. “Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways.” Nucleic Acids Res, 2003 Jun 15; 31 (12): 3101-13, PubMed ID: 12799438. *These authors contributed equally to this work.

Yoshida Y*, Nakamura T*, Komoda M, Satoh H, Suzuki T, Tsuzuku JK, Miyasaka T, Yoshida EH, Umemori H, Kunisaki RK, Tani K, Ishii S, Mori S, Suganuma M, Noda T, Yamamoto T. “Mice lacking a transcriptional corepressor Tob are predisposed to cancer.” Genes Dev. 2003 May 15; 17 (10): 1201-6, PubMed ID: 12756225. *These authors contributed equally to this work.

Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. “Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation.” Genes Dev. 2002 Jun 1; 16 (11): 1356-70, PubMed ID: 12050114.

Yoshida Y, Hosoda E, Nakamura T, Yamamoto T. “Association of ANA, a member of the antiproliferative Tob family proteins, with a Caf1 component of the CCR4 transcriptional regulatory complex.” Jpn J Cancer Res. 2001 Jun; 92 (6): 592-6, PubMed ID: 11429045.

 
Non-peer reviewed articles (Book chapter/Review/Commentary)
Nakamura T. “Role of double-stranded RNA pathways in Immunometabolism in Obesity.” Springer: Chronic Inflammation – Mechanisms and Regulation. 2016; 277-290, ISBN: 978- 4-431-56068-5 (Review).

Nakamura T. “The Role of dsRNA pathways in inflammation and cancer in obesity” Journal of Clinical and Experimental Medicine. 2016 Jun; 257 (12): 1245-1250 (Review in Japanese).

Nakamura T. “dsRNA in immunometabolism” Oncotarget. 2015 Aug; 6 (24): 19940-19941, PubMed ID: 26343371 (Review).

Nakamura T. “Molecular mechanism of double-stranded RNA pathway-mediated immunometabolic regulation” BIO Clinica: Lipid metabolism and signaling. 2015 Aug; 30 (9): 838-842 (Review in Japanese).

Nakamura T. “Role of double-stranded RNA pathways in immune-metabolic regulation” BIO Clinica Special Edition: Chronic inflammation in endocrinology and metabolism. 2015 Feb; 4 (1): 104-108 (Review in Japanese).

Nakamura T. “Molecular basis of chronic inflammatory responses and metabolic diseases in obesity” Experimental Medicine. 2014 Feb; 32 (3): 380-385 (Review in Japanese).

Nakamura T. “Revisiting Metformin” Science Translation Medicine. 5 (172), p172ec31, 2013 (Commentary).

Nakamura T. “Microbes and Type 1 Diabetes” Science Translation Medicine. 5 (168), p168ec14, 2013 (Commentary).

Nakamura T. “Resveratrol: Too Early to Bring Out the Wine?” Science Translation Medicine. 4 (164), p164ec228, 2012 (Commentary).

Nakamura T. “Weighty Considerations” Science Translation Medicine. 4 (160), p160ec209, 2012 (Commentary).

Nakamura T. “A Warning Bell Tolls for Type 1 Diabetes” Science Translation Medicine. 4 (156), p156ec189, 2012 (Commentary).

Nakamura T. “Microbial Manipulation of Metabolism” Science Translation Medicine. 4 (148), p148ec153, 2012 (Commentary).

Nakamura T. “Mitochondrial Workout” Science Translation Medicine. 4 (144), p144ec134, 2012 (Commentary).

Nakamura T. “You Are What and When You Eat” Science Translation Medicine. 4 (141), p141ec116, 2012 (Commentary).

Nakamura T. “Perceiving Your Appetite” Science Translation Medicine. 4 (136), p136ec97, 2012 (Commentary).

Nakamura T. “Bypassing Alzheimer’s Diseases” Science Translation Medicine. 4 (132), p132ec79, 2012 (Commentary).

Nakamura T. “Bypassing Alzheimer’s Diseases” Science Translation Medicine. 4 (132), p132ec79, 2012 (Commentary).

Nakamura T. “Diseases of Resistance” Science Translation Medicine. 4 (128), p128ec60, 2012 (Commentary).

Nakamura T. “What’s Up with BAT?” Science Translation Medicine. 4 (125), p125ec45, 2012 (Commentary).

Nakamura T and Hotamisligil GS. “Impact of qualitative alterations of lipid on metabolism in obesity” Experimental Medicine. 2012 Feb; 30 (3): 435-440 (Review in Japanese)

Nakamura T and Hotamisligil GS. “Obesity, ER stress, and metabolic disease” Experimental Medicine. 2009 Mar; 27 (4): 498-504 (Review in Japanese).