Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle.
Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes and may be causally associated with increases in intramuscular fatty acid metabolites. Fatty acid transport protein 1 (FATP1) is an acyl-CoA synthetase highly expressed in skeletal muscle and modulates fatty acid uptake and metabolism by converting fatty acids into fatty acyl-CoA. To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on insulin action in FATP1 KO mice. Whole-body adiposity, adipose tissue expression of adiponectin, intramuscular fatty acid metabolites, and insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet. In contrast, FATP1 deletion protected the KO mice from fat-induced insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity. These findings demonstrate an important role of intramuscular fatty acid metabolites in causing insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA. jason.k.kim@yale.edu
Jason K
JK
Kim
Ruth E
RE
Gimeno
Takamasa
T
Higashimori
Hyo-Jeong
HJ
Kim
Hyejeong
H
Choi
Sandhya
S
Punreddy
Robin L
RL
Mozell
Guo
G
Tan
Alain
A
Stricker-Krongrad
David J
DJ
Hirsch
Jonathan J
JJ
Fillmore
Zhen-Xiang
ZX
Liu
Jianying
J
Dong
Gary
G
Cline
Andreas
A
Stahl
Harvey F
HF
Lodish
Gerald I
GI
Shulman
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction
D052242:Adiponectin; D001786:Blood Glucose; D002352:Carrier Proteins; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D011506:Proteins; C493569:Slc27a1 protein, mouse; C493572:Slc27a4 protein, mouse; D005947:Glucose