The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance.

Abstract

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.

• Authors: Yoshio Nagai, Shin Yonemitsu, Derek M Erion, Takanori Iwasaki, Romana Stark, Dirk Weismann, Jianying Dong, Dongyan Zhang, Michael J Jurczak, Michael G Löffler, James Cresswell, Xing Xian Yu, Susan F Murray, Sanjay Bhanot, Brett P Monia, Jonathan S Bogan, Varman Samuel, Gerald I Shulman
• Journal: Cell metabolism (Cell Metab) Vol. 9 Issue 3 Pg. 252-64 (Mar 2009) ISSN: 1932-7420 [Electronic] United States
• PMID: 19254570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Oligonucleotides, Antisense
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• RNA-Binding Proteins
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Transcription Factors
• Fructose

Topics

• Adipose Tissue (metabolism)
• Animals
• Diet
• Fructose (administration & dosage, metabolism)
• Gene Expression
• Hepatocytes (cytology, metabolism)
• Humans
• Insulin Resistance (physiology)
• Liver (cytology, metabolism)
• Male
• Mice
• Oligonucleotides, Antisense (genetics, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA-Binding Proteins (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)
• Transcription Factors (genetics, metabolism)