The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance.
Peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1beta) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here, we evaluated the role of PGC-1beta in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1beta in liver and adipose tissue. PGC-1beta ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1beta ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin-stimulated states. Furthermore, PGC-1beta ASO increased insulin-stimulated whole-body glucose disposal due to a threefold increase in glucose uptake in white adipose tissue. These data support an important role for PGC-1beta in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1beta inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis.
Nagai
Yoshio
Y
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-8012, USA.
Yonemitsu
Shin
S
Erion
Derek M
DM
Iwasaki
Takanori
T
Stark
Romana
R
Weismann
Dirk
D
Dong
Jianying
J
Zhang
Dongyan
D
Jurczak
Michael J
MJ
Löffler
Michael G
MG
Cresswell
James
J
Yu
Xing Xian
XX
Murray
Susan F
SF
Bhanot
Sanjay
S
Monia
Brett P
BP
Bogan
Jonathan S
JS
Samuel
Varman
V
Shulman
Gerald I
GI
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004032:Diet; D005632:Fructose / Q000008:administration & dosage / Q000378:metabolism*; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D005632:Fructose