Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver.
Insulin receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-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 citrate-lyase, 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.
Tobe
K
K
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Suzuki
R
R
Aoyama
M
M
Yamauchi
T
T
Kamon
J
J
Kubota
N
N
Terauchi
Y
Y
Matsui
J
J
Akanuma
Y
Y
Kimura
S
S
Tanaka
J
J
Abe
M
M
Ohsumi
J
J
Nagai
R
R
Kadowaki
T
T
D001275:ATP Citrate (pro-S)-Lyase / Q000096:biosynthesis; D000367:Age Factors; D000818:Animals; D015152:Blotting, Northern; D001835:Body Weight; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D064429:Fatty Acid Synthases / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000096:biosynthesis*; D051780:Sterol Regulatory Element Binding Protein 1; D013997:Time Factors; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D020738:Leptin; D010750:Phosphoproteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D064429:Fatty Acid Synthases; D001275:ATP Citrate (pro-S)-Lyase; D005947:Glucose