PMID- 15448592
OWN - NLM
STAT- MEDLINE
DCOM- 20050624
LR  - 20151119
IS  - 1234-1010 (Print)
IS  - 1234-1010 (Linking)
VI  - 10
IP  - 10
DP  - 2004 Oct
TI  - Enhancement of insulin signaling through inhibition of tissue lipid accumulation 
      by activation of peroxisome proliferator-activated receptor (PPAR) alpha in obese 
      mice.
PG  - BR388-95
AB  - BACKGROUND: The aim of the present study was to investigate the effect of 
      PPARalpha activation on insulin signaling and lipid accumulation in the liver and 
      skeletal muscle of insulin-resistant (ob/ob) mice. MATERIAL/METHODS: A known 
      subtype-selective PPARalpha agonist, Wy-14,643, was administered to lean and 
      ob/ob mice at 30 mg/kg/day for 4 weeks. Insulin (100 units/kg) or saline was 
      injected into the portal vein of anesthetized mice. The liver and skeletal 
      muscles were used for the detection of tyrosine phosphorylation of the insulin 
      receptor (IR) and insulin receptor substrates (IRSs), as well as for the 
      determination of both IRS-associated PI3-K activity and lipid content; in 
      addition, the measurement of mRNA levels of PPAR-regulated genes was carried out. 
      RESULTS: The PPARalpha agonist lowered plasma levels of glucose, insulin, 
      triglycerides, and free fatty acids in ob/ob mice. Several PPARalpha-upregulated 
      genes related to the transport and oxidation of fatty acids in the liver were 
      increased by treatment with the agonist. The PPARalpha agonist significantly 
      increased IR- and IRS-tyrosine phosphorylation and IRS-associated PI3-K activity 
      in the liver and muscle of ob/ob mice, without exerting the same effects in lean 
      mice. Moreover, these effects in ob/ob mice were accompanied by decreased 
      triglyceride and fatty acyl-CoA contents in the liver and skeletal muscle. 
      CONCLUSIONS: The present results suggest that inhibition of lipid accumulation by 
      hepatic PPARalpha activation leads to an improvement in impaired insulin 
      signaling in muscle tissue as well as in the liver of insulin-resistant mice.
FAU - Ide, Tomohiro
AU  - Ide T
AD  - Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
FAU - Tsunoda, Masaki
AU  - Tsunoda M
FAU - Mochizuki, Toshiro
AU  - Mochizuki T
FAU - Murakami, Koji
AU  - Murakami K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040923
PL  - United States
TA  - Med Sci Monit
JT  - Medical science monitor : international medical journal of experimental and 
      clinical research
JID - 9609063
RN  - 0 (Biomarkers)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (PPAR alpha)
RN  - 0 (Phosphoproteins)
RN  - 0 (Pyrimidines)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - 86C4MRT55A (pirinixic acid)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Gene Expression Regulation/drug effects
MH  - Insulin/blood/*pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - *Lipid Metabolism
MH  - Liver/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Obese
MH  - Muscles/drug effects/*metabolism
MH  - Obesity/*metabolism
MH  - PPAR alpha/agonists/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphotyrosine/metabolism
MH  - Pyrimidines/pharmacology
MH  - Receptor, Insulin/metabolism
MH  - Signal Transduction/*drug effects
EDAT- 2004/09/28 05:00
MHDA- 2005/06/25 09:00
CRDT- 2004/09/28 05:00
PHST- 2004/04/01 00:00 [received]
PHST- 2004/06/29 00:00 [accepted]
PHST- 2004/09/28 05:00 [pubmed]
PHST- 2005/06/25 09:00 [medline]
PHST- 2004/09/28 05:00 [entrez]
AID - 5401 [pii]
PST - ppublish
SO  - Med Sci Monit. 2004 Oct;10(10):BR388-95. Epub 2004 Sep 23.