Professor, Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine
Position
Director of the GCOE program
Education and Career
Graduated from University of Tokyo, Faculty of Medicine, 1974
Professor, Yamaguchi University School of Medicine, 1994
Major research area : Diabetes and Obesity
Pancreatic beta cell survival and ER stress
Metabolic information highway connecting organs for coordinated metabolic regulation
Type 2 diabetes is caused by complex interactions between insulin resistance in peripheral tissues and impaired insulin secretion from pancreatic β-cells. Recent studies have shown decreased b cell mass to be a common feature of subjects with type 2 diabetes mellitus. Susceptibility to stress-induced apoptosis may underlie b cell loss. We previously showed that Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. We further established a wfs1-deficient mouse, which exhibited impaired glucose homeostasis accompanied by progressive reduction of b-cell mass, a model of Wolfram syndrome. We showed that WFS1 protein deficiency activates the ER stress response specifically in β-cells, causing b-cell loss through increased apoptosis and impaired cell cycle progression. In addition, we demonstrated that ATF4-mediated induction of the translational repressor 4E-BP1 promotes β-cell survival under chronic ER stress, which is a potential therapeutic target for diabetes.
We also demonstrated, for the fist time, that, in addition to humoral actors including adipocytokines, neuronal signals originating from peripheral tissues including adipose tissues and liver to the brain constitute an important metabolic regulatory system. The brain obtains a variety of metabolic information from peripheral organs/tissues through humoral and neuronal pathways, resulting in cooperative metabolic regulation among tissues/organs throughout the body. Our novel signaling findings, metabolic information highways, may help protect the humans from the metabolic disturbances such as metabolic syndrome in this over-nutrition era.
Publication
Oka Y, Asano T, Shibasaki Y, Lin J-L, Tsukuda K, Katagiri H, Akanuma Y and Takaku F. C-terminal truncated glucose transporter is locked into an inward-facing form without transport activity. Nature 345: 550-553, 1990
Katagiri H, Asano T, Ishihara H, Inukai K, Anai M, Miyazaki J-I, Tsukuda K, Kikuchi M, Yazaki Y and Oka Y. Nonsense mutation of the glucokinase gene in late-onset non-insulin dependent diabetes mellitus. Lancet 340(8831): 1316-1317, 1992
Oka Y, Katagiri H, Yazaki Y, Murase T and Kobayashi T. Mitochondrial gene mutation in islet cell antibody-positive diabetics who were initially non-insulin-dependent. Lancet 342: 527-528, 1993
Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bewnal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K, Sobue G, Oka Y, Permutt MA. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nature Genetics 20: 143-148, 1998
Takeda K, Inoue H, Tanizawa Y, Matsuzaki Y, Oba J, Watanabe Y, Shinoda K, Oka Y. WFS1 (Wolfram syndrome 1) gene product: Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 10: 477-484, 2001
Ishihara H, Takeda S, Tamura A, Takahashi R, Yamaguchi S, Takei D, Yamada T, Inoue H, Soga H, Katagiri H, Tanizawa Y, Oka Y. Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet 13:1159-1170, 2004
Yamada T, Katagiri H, Ishigaki Y, Ogihara T, Imai J, Uno K, Hasegawa Y, Gao J, Ishihara H, Niijima A, Mano H, Aburatani H, Asano T, Oka Y. Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: neuronal involvement in food intake regulation. Cell Metabolism 3: 223-9, 2006
Uno K, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Imai J, Hasegawa Y, Gao J, Kaneko K, Iwasaki H, Ishihara H, Sasano H, Inukai K, Mizuguchi H, Asano T, Shiota M, Nakazato M, Oka Y. Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science 312: 1656-9, 2006.
Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, Munakata Y, Satake C, Katagiri H, Tashiro F, Aburatani H, Tsukiyama-Kohara K, Miyazaki J, Sonenberg N, and Oka Y. ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress. Cell Metabolism 7(3):269-76, 2008
Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H, Uno K, Hasegawa Y, Gao J, Kaneko K, Ishihara H, Niijima A, Nakazato M, Asano T, Minokoshi Y and Oka Y. Regulation of pancreatic β cell mass by neuronal signals from the liver. Science, in press 2008
