TY - JOUR
T1 - Increased Expression of the Sterol Regulatory Element-binding Protein-1 Gene in Insulin Receptor Substrate-2-/- Mouse Liver
AU - Tobe, Kazuyuki
AU - Suzuki, Ryo
AU - Aoyama, Masashi
AU - Yamauchi, Toshimasa
AU - Kamon, Junji
AU - Kubota, Naoto
AU - Terauchi, Yasuo
AU - Matsui, Junji
AU - Akanuma, Yasuo
AU - Kimura, Satoshi
AU - Tanaka, Jun
AU - Abe, Manabu
AU - Ohsumi, Jun
AU - Nagai, Ryozo
AU - Kadowaki, Takashi
PY - 2001/10/19
Y1 - 2001/10/19
N2 - Insulin receptor substrate (IRS)-2-/- mice develop diabetes because of insulin resistance in the liver and failure to undergo β-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2 -/- mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citratelyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2-/- mice assures the physiological importance of SREBP-1 gene induction. IRS-2 -/- mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2-/- mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2-/- mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.
AB - Insulin receptor substrate (IRS)-2-/- mice develop diabetes because of insulin resistance in the liver and failure to undergo β-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2 -/- mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citratelyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2-/- mice assures the physiological importance of SREBP-1 gene induction. IRS-2 -/- mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2-/- mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2-/- mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.
UR - http://www.scopus.com/inward/record.url?scp=0035914361&partnerID=8YFLogxK
U2 - 10.1074/jbc.C100160200
DO - 10.1074/jbc.C100160200
M3 - 学術論文
C2 - 11546755
AN - SCOPUS:0035914361
SN - 0021-9258
VL - 276
SP - 38337
EP - 38340
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -