Laboratory of Molecular Physiology on Energy Metabolism


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INTRODUCTION

The Laboratory of Molecular Physiology on Energy Metabolism was established in 2008, supported by the funds from Sunny Health Holdings and Sunny Health Co., Ltd., and is in close collaboration with the Department of Metabolic Diseases. The goal of this research program is to understand the pathophysiology of overnutrition-related diseases including metabolic syndrome and diabetes, the basis of which is considered to be insulin resistance closely associated with the imbalance of energy metablism.

Project Associate Professor: Naoya Yahagi, MD, PhD

Address：7-3-1, Hongo, Bunkyoku, Tokyo 1138655, Japan
Phone：+81-3-3815-5411（ext.33129）

Email：

RESEARCH DESCRIPTION

We focus on the molecular mechanisms of insulin resistance, especially from the standpoint of lipid metabolism.
For the better understanding of the basic pathogenesis of overnutrition and insulin resistance, we are proposing a new concept of "adipose capacity"; insulin resistance can be considered as a physiological response against the overload of nutrients beyond the "adipose capacity". To clarify the molecular basis of this concept is one of our major goals.

（Members）

Project Associate Professor: Naoya Yahagi, MD, PhD
Project Research Associate: Hironori Waki, MD, PhD
Postdoctoral Fellow: Yoshihiko Izumida, MD, PhD
Postdoctoral Fellow: Yoshinori Takeuchi, PhD

SPECIFIC THEMES

Elucidation of mechanisms of negative feedback regulation to understand the molecular basis of "adipose capacity", especially from the viewpoint of the involvement of tumor suppressors such as p53.
In vivo Ad-luc promoter analyses utilizing in vivo imaging system (IVIS).
Development of TFEL (transcription factor expression library) to entirely elucidate the transcriptional regulatory network of nutrient metabolism.
cis-to-trans (C2T) analyses of the transcriptional network based on TFEL.
Importance of the quality of fat besides the quantity.
New approach from chemical biology to the molecular physiology on energy metabolism.
Epigenetic regulation in the control of differentiation and energy metabolism of adipocytes.
Autonomic nerve system in the regulatory mechanisms of adipo-hepatic balancing.

PUBLICATIONS

Izumida Y, Yahagi N, Takeuchi Y, Nishi M, Shikama A, Takarada A, Masuda Y, Kubota M, Matsuzaka T, Nakagawa Y, Iizuka Y, Itaka K, Kataoka K, Shioda S, Niijima A, Yamada T, Katagiri H, Nagai R, Yamada N, Kadowaki T, Shimano H.
Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization.
Nat Commun 4:2316, 2013. [Full text]
Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T, Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K, Osuga JI, Gotoda T, Ishibashi S, Itaka K, Kataoka K, Nagai R, Yamada N, Kadowaki T, Shimano H.
Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit.
J Biol Chem 285:11681-91, 2010. [Abstract]
Park KW, Waki H, Kim WK, Davies BS, Young SG, Parhami F, Tontonoz P.
The small molecule phenamil induces osteoblast differentiation and mineralization.
Mol Cell Biol 29:3905-14, 2009. [Abstract]
Sekiya M, Yahagi N, Tamura Y, Okazaki H, Igarashi M, Ohta K, Takanashi M, Kumagai M, Takase S, Nishi M, Takeuchi Y, Izumida Y, Kubota M, Ohashi K, Iizuka Y, Yagyu H, Gotoda T, Nagai R, Shimano H, Yamada N, Kadowaki T, Ishibashi S, Osuga JI.
Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep(ob)(/)(ob) mice.
Biochem Biophys Res Commun 387:511-5, 2009. [Abstract]
Davies BS, Waki H, Beigneux AP, Farber E, Weinstein MM, Wilpitz DC, Tai LJ, Evans RM, Fong LG, Tontonoz P, Young SG.
The expression of GPIHBP1, an endothelial cell binding site for lipoprotein lipase and chylomicrons, is induced by PPARγ.
Mol Endocrinol 22:2496-504, 2008. [Abstract]
Park KW, Waki H, Villanueva CJ, Monticelli LA, Hong C, Kang S, Macdougald OA, Goldrath AW, Tontonoz P.
Id2 is a small molecule-inducible modulator of PPARγ expression and adipocyte differentiation.
Mol Endocrinol 22:2038-48, 2008. [Abstract]
Sekiya M, Osuga J, Yahagi N, Okazaki H, Tamura Y, Igarashi M, Takase S, Harada K, Okazaki S, Iizuka Y, Ohashi K, Yagyu H, Okazaki M, Gotoda T, Nagai R, Kadowaki T, Shimano H, Yamada N, Ishibashi S.
Hormone-sensitive lipase is involved in hepatic cholesterol ester hydrolysis.
J Lipid Res 49:1829-38, 2008. [Abstract]
Inoue N, Yahagi N, Yamamoto T, Ishikawa M, Watanabe K, Matsuzaka T, Nakagawa Y, Takeuchi Y, Kobayashi K, Takahashi A, Suzuki H, Hasty AH, Toyoshima H, Yamada N, Shimano H.
Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity and insulin resistance.
J Biol Chem 283:21220-9, 2008. [Abstract]
Matsuzaka T, Shimano H, Yahagi N, Kato T, Atsumi A, Yamamoto T, Inoue N, Ishikawa M, Okada S, Ishigaki N, Iwasaki H, Iwasaki Y, Karasawa T, Kumadaki S, Matsui T, Sekiya M, Ohashi K, Hasty AH, Nakagawa Y, Takahashi A, Suzuki H, Yatoh S, Sone H, Toyoshima H, Osuga JI, Yamada N.
Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance.
Nature Medicine 13:1193-1202, 2007. [Abstract]
Waki H, Park KW, Mitro N, Pei L, Damoiseaux R, Wilpitz DC, Reue K, Saez E, Tontonoz P.
The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARgamma expression.
Cell Metabolism 5:357-70, 2007. [Abstract]
Takeuchi Y, Yahagi N, Nakagawa Y, Matsuzaka T, Shimizu R, Sekiya M, Iizuka Y, Ohashi K, Gotoda T, Yamamoto M, Nagai R, Kadowaki T, Yamada N, Osuga JI, Shimano H.
In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-1c expression.
Biochem Biophys Res Commun 363:329-35, 2007. [Abstract]
Sekiya M, Yahagi N, Matsuzaka T, Takeuchi Y, Nakagawa Y, Takahashi H, Okazaki H, Iizuka Y, Ohashi K, Gotoda T, Ishibashi S, Nagai R, Yamazaki T, Kadowaki T, Yamada N, Osuga JI, Shimano H.
Sterol regulatory element-binding protein (SREBP) -1-independent regulation of lipogenic gene expression in adipocytes.
J Lipid Res 48:1581-91, 2007. [Abstract]
Kato T, Shimano H, Yamamoto T, Yokoo T, Endo Y, Ishikawa M, Matsuzaka T, Nakagawa Y, Kumadaki S, Yahagi N, Takahashi A, Sone H, Suzuki H, Toyoshima H, Hasty AH, Takahashi S, Gomi H, Izumi T, Yamada N.
Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.
Cell Metabolism 4:143-54, 2006. [Abstract]
Nakagawa Y, Shimano H, Yoshikawa T, Ide T, Tamura M, Furusawa M, Yamamoto T, Inoue N, Matsuzaka T, Takahashi A, Hasty AH, Suzuki H, Sone H, Toyoshima H, Yahagi N, Yamada N.
TFE3, a novel transcription factor for hepatic IRS-2 and insulin signals, ameliorates diabetes.
Nature Medicine 12:107-13, 2006. [Abstract]
Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P.
NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism.
Nature Medicine 12:1048-55, 2006. [Abstract]
Waki H, Yamauchi T, Kamon J, Kita S, Ito Y, Hada Y, Uchida S, Tsuchida A, Takekawa S, Kadowaki T.
Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1.
Endocrinology 146:790-6, 2005. [Abstract]
Inoue N, Shimano H, Nakakuki M, Matsuzaka T, Nakagawa Y, Yamamoto T, Sato R, Takahashi A, Sone H, Yahagi N, Suzuki H, Toyoshima H, Yamada N.
Lipid synthetic transcription factor SREBP-1a activates p21 WAF1/CIP1, a universal cyclin-dependent kinase inhibitor.
Mol Cell Biol 25:8938-47, 2005. [Abstract]
Najima Y, Yahagi N, Takeuchi Y, Matsuzaka T, Sekiya M, Nakagawa Y, Amemiya-Kudo M, Okazaki H, Okazaki S, Tamura Y, Iizuka Y, Ohashi K, Harada K, Gotoda T, Nagai R, Kadowaki T, Ishibashi S, Yamada N, Osuga JI, Shimano H.
High mobility group protein-B1 (HMGB1) interacts with sterol regulatory element-binding proteins (SREBPs) to enhance their DNA binding.
J Biol Chem 280:27523-32, 2005. [Abstract]
Yahagi N, Shimano H, Hasegawa K, Ohashi K, Matsuzaka T, Najima Y, Sekiya M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Nagai R, Ishibashi S, Kadowaki T, Makuuchi M, Ohnishi S, Osuga JI, Yamada N.
Coordinate activation of lipogenic enzymes in hepatocellular carcinoma.
Eur J Cancer 41:1316-22, 2005. [Abstract]
Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki M, Yamamoto T, Nakagawa Y, Takahashi A, Suzuki H, Sone H, Toyoshima H, Fukamizu A, Yamada N.
SREBPs suppress IRS-2-mediated insulin signalling in the liver.
Nature Cell Biology 6:351-7, 2004. [Abstract]
Yahagi N, Shimano H, Matsuzaka T, Sekiya M, Najima Y, Okazaki S, Okazaki H, Tamura Y, Iizuka Y, Inoue N, Nakagawa Y, Takeuchi Y, Ohashi K, Harada K, Gotoda T, Nagai R, Kadowaki T, Ishibashi S, Osuga JI, Yamada N.
p53 involvement in the pathogenesis of fatty liver disease.
J Biol Chem 279:20571-5, 2004. [Abstract]
Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Tomita S, Sekiya M, Hasty A, Nakagawa Y, Sone H, Toyoshima H, Ishibashi S, Osuga J, Yamada N.
Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice.
Diabetes 53:560-9, 2004. [Abstract]
Yahagi N, Shimano H, Matsuzaka T, Najima Y, Sekiya M, Nakagawa Y, Ide T, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Gotoda T, Nagai R, Kimura S, Ishibashi S, Osuga JI, Yamada N.
p53 activation in adipocytes of obese mice.
J Biol Chem 278:25395-400, 2003. [Abstract]
Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, Kimura S, Nagai R, Kadowaki T.
Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.
J Biol Chem 278:40352-63, 2003. [Abstract]
Sekiya M, Yahagi N, Matsuzaka T, Najima Y, Nakakuki M, Nagai R, Ishibashi S, Osuga J, Yamada N, Shimano H.
Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.
Hepatology 38:1529-39, 2003. [Abstract]
Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N.
Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice.
J Biol Chem 277:19353-7, 2002. [Abstract]

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