The Role of Peroxisome Proliferator-Activated Receptor γ Coactivator-1 β in the Pathogenesis of Fructose-Induced Insulin Resistance
Open accessAbstract
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.
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Liver fructose metabolism in the fed state generates lipogenic substrates in an unregulated fashion, driving hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates insulin signaling, leading to hepatic insulin resistance.
“For example, liver fructose metabolism in the fed state generates lipogenic substrates in an unregulated fashion, which drives hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates the insulin signaling pathway, leading to hepatic insulin resistance [16], [17].”
From The relationship of sugar to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data (2013) · cites this paper as [17]
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“in an unregulated fashion, which drives hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates the insulin signaling pathway, leading to hepatic insulin resistance [16,17].”
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- Authors
- Nagai, Y., Yonemitsu, S., Erion, D. M., Iwasaki, T., Stark, R., Weismann, D., Dong, J., Zhang, D., Jurczak, M. J., Löffler, M. G., Cresswell, J., Yu, X. X., Murray, S. F., Bhanot, S., Monia, B. P., Bogan, J. S., Samuel, V., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 9
- Issue
- 3
- Pages
- 252-264
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3131094
- OpenAlex
- W2063518484
- Cited by
- 203
- References
- 42
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 9 · 2022: 9 · 2021: 15 · 2020: 6 · 2019: 10 · 2018: 9 · 2017: 11 · 2016: 13 · 2015: 19 · 2014: 15 · 2013: 14 · 2012: 21
- FWCI
- 14.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, U24DK059635, R01DK075772, R24DK085638, P30DK045735)
- National Center for Research Resources (K23RR017404, K23 RR-17404)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- PGC-1β, fructose-induced insulin resistance, SREBP1, hepatic lipogenesis, antisense oligonucleotide knockdown, hepatic insulin resistance, glucose disposal, non-alcoholic fatty liver disease, hypertriglyceridemia, de novo lipogenesis, liver, adipose tissue
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adipose Tissue, Animals, Diet, Fructose, Humans, Insulin Resistance, Liver, Male, Transcription Factors, Gene Expression, Oligonucleotides, Antisense, RNA-Binding Proteins, Rats, Sprague-Dawley, Hepatocytes, Mice, Rats, Sterol Regulatory Element Binding Protein 1
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