The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance

Yoshio Nagai; Shin Yonemitsu; Derek M Erion; Takanori Iwasaki; Romana Stark; Dirk Weismann; Jianying Dong; Dongyan Zhang; Michael J Jurczak; Michael G Loffler; James Cresswell; Xingxian Yu; Susan F Murray; Sanjay Bhanot; Brett P Monia; Jonathan S Bogan; Varman T Samuel; Gerald I Shulman

doi:10.1016/j.cmet.2009.01.011

The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance

Yoshio Nagai, Shin Yonemitsu, Derek M Erion, Takanori Iwasaki, Romana Stark, Dirk Weismann, Jianying Dong, Dongyan Zhang, Michael J Jurczak, Michael G Loffler, James Cresswell, Xingxian Yu, Susan F Murray, Sanjay Bhanot, Brett P Monia, Jonathan S Bogan, Varman T Samuel, Gerald I Shulman

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

Peroxisome proliferator-activated receptor ? coactivator-1 ? (PGC-1?) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here, we evaluated the role of PGC-1? in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1? in liver and adipose tissue. PGC-1? ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1? ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin-stimulated states. Furthermore, PGC-1? 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-1? in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1? inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis.

Original language	English
Pages (from-to)	252 - 264
Number of pages	13
Journal	Cell Metabolism
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2009.01.011
Publication status	Published - 2009
Externally published	Yes

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Nagai, Y., Yonemitsu, S., Erion, D. M., Iwasaki, T., Stark, R., Weismann, D., Dong, J., Zhang, D., Jurczak, M. J., Loffler, M. G., Cresswell, J., Yu, X., Murray, S. F., Bhanot, S., Monia, B. P., Bogan, J. S., Samuel, V. T., & Shulman, G. I. (2009). The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance. Cell Metabolism, 9(3), 252 - 264. https://doi.org/10.1016/j.cmet.2009.01.011

@article{e107d94d3af541238a3cee1265b38fbe,

title = "The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance",

abstract = "Peroxisome proliferator-activated receptor ? coactivator-1 ? (PGC-1?) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here, we evaluated the role of PGC-1? in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1? in liver and adipose tissue. PGC-1? ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1? ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin-stimulated states. Furthermore, PGC-1? 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-1? in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1? inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis.",

author = "Yoshio Nagai and Shin Yonemitsu and Erion, {Derek M} and Takanori Iwasaki and Romana Stark and Dirk Weismann and Jianying Dong and Dongyan Zhang and Jurczak, {Michael J} and Loffler, {Michael G} and James Cresswell and Xingxian Yu and Murray, {Susan F} and Sanjay Bhanot and Monia, {Brett P} and Bogan, {Jonathan S} and Samuel, {Varman T} and Shulman, {Gerald I}",

year = "2009",

doi = "10.1016/j.cmet.2009.01.011",

language = "English",

volume = "9",

pages = "252 -- 264",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Elsevier",

number = "3",

}

Nagai, Y, Yonemitsu, S, Erion, DM, Iwasaki, T, Stark, R, Weismann, D, Dong, J, Zhang, D, Jurczak, MJ, Loffler, MG, Cresswell, J, Yu, X, Murray, SF, Bhanot, S, Monia, BP, Bogan, JS, Samuel, VT & Shulman, GI 2009, 'The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance', Cell Metabolism, vol. 9, no. 3, pp. 252 - 264. https://doi.org/10.1016/j.cmet.2009.01.011

TY - JOUR

T1 - The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance

AU - Nagai, Yoshio

AU - Yonemitsu, Shin

AU - Erion, Derek M

AU - Iwasaki, Takanori

AU - Stark, Romana

AU - Weismann, Dirk

AU - Dong, Jianying

AU - Zhang, Dongyan

AU - Jurczak, Michael J

AU - Loffler, Michael G

AU - Cresswell, James

AU - Yu, Xingxian

AU - Murray, Susan F

AU - Bhanot, Sanjay

AU - Monia, Brett P

AU - Bogan, Jonathan S

AU - Samuel, Varman T

AU - Shulman, Gerald I

PY - 2009

Y1 - 2009

N2 - Peroxisome proliferator-activated receptor ? coactivator-1 ? (PGC-1?) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here, we evaluated the role of PGC-1? in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1? in liver and adipose tissue. PGC-1? ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1? ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin-stimulated states. Furthermore, PGC-1? 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-1? in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1? inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis.

AB - Peroxisome proliferator-activated receptor ? coactivator-1 ? (PGC-1?) is known to be a transcriptional coactivator for SREBP-1, the master regulator of hepatic lipogenesis. Here, we evaluated the role of PGC-1? in the pathogenesis of fructose-induced insulin resistance by using an antisense oligonucletoide (ASO) to knockdown PGC-1? in liver and adipose tissue. PGC-1? ASO improved the metabolic phenotype induced by fructose feeding by reducing expression of SREBP-1 and downstream lipogenic genes in liver. PGC-1? ASO also reversed hepatic insulin resistance induced by fructose in both basal and insulin-stimulated states. Furthermore, PGC-1? 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-1? in the pathogenesis of fructose-induced insulin resistance and suggest that PGC-1? inhibition may be a therapeutic target for treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis.

UR - http://www.sciencedirect.com.ezproxy.lib.monash.edu.au/science/article/pii/S1550413109000369

U2 - 10.1016/j.cmet.2009.01.011

DO - 10.1016/j.cmet.2009.01.011

M3 - Article

SN - 1550-4131

VL - 9

SP - 252

EP - 264

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator-1 ? in the Pathogenesis of Fructose-Induced Insulin Resistance

Abstract

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