Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids
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Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives. Whether this downregulation is a cause or effect of early aberrations in the development of insulin resistance, such as disturbances in fat metabolism, is unknown. We examined whether lipid-induced insulin resistance was associated with downregulation of expression of skeletal muscle genes involved in oxidative metabolism and mitochondrial biogenesis in humans.Materials and methods Nine healthy lean male subjects underwent a 6-h hyperinsulinaemic-euglycaemic clamp with simultaneous infusion of either a lipid emulsion or glycerol as a control. Blood was sampled at regular time points and muscle biopsies were taken before and after every test. Intramuscular triacylglycerol (IMTG) content was determined by Oil Red O staining and gene expression was measured by quantitative PCR.Results Lipid infusion resulted in a approximately 2.7-fold increase in plasma NEFA levels and a 31+/-6% decrease in insulin sensitivity (p=0.001). The infusion of lipids resulted in a approximately 1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to approximately 53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to approximately 61, 77 and approximately 52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p<0.05).Conclusions/interpretation Acute elevation of plasma NEFA levels, leading to muscular fat accumulation and insulin resistance, downregulates PPARGC1A, PPARGC1B and PPARA expression, suggesting that the decrease in PPARGC1 expression observed in the (pre)diabetic state may be the result, rather than the cause of lipid-induced insulin resistance.
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Acute elevation of plasma FFA by lipid infusion is accompanied by downregulation of PGC1α and other genes involved in mitochondrial metabolism.
“Furthermore, we showed that the acute elevation of plasma FFA by lipid infusion is accompanied by downregulation of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and other genes involved in mitochondrial metabolism (9).”
From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [9]
PGC-1α expression and the insulin-stimulated increase in skeletal muscle ATP synthesis were reduced upon lipid infusion.
“PGC-1α expression (9) and the insulin-stimulated increase in skeletal muscle ATP synthesis (10) were reduced upon lipid infusion.”
From Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance (2010) · cites this paper as [9]
Acute elevation of circulating fatty acid levels decreases the expression of PGC1α and β alongside other genes involved in mitochondrial metabolism.
“The negative impact of fat oversupply to skeletal muscle has been confirmed by acute elevation of circulating fatty acid levels, which also decreased the expression of PGC 1α and β alongside other genes involved in mitochondrial metabolism (Richardson et al., 2005; Hoeks et al., 2006)”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Hoeks et al., 2006
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Self-citation
- Authors
- Hoeks, J., Hesselink, M. K. C., Russell, A. P., Mensink, M., Saris, W. H. M., Mensink, R. P., & Schrauwen, P.
- Affiliations
- Maastricht University (NL)
- Clinique Romande de Réadaptation (CH)
- Venue
- Diabetologia
- Published
- 2006-08-01
- Volume
- 49
- Issue
- 10
- Pages
- 2419-2426
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2044175256
- Cited by
- 74
- References
- 30
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 1 · 2017: 3 · 2016: 1 · 2014: 4 · 2013: 7 · 2012: 5
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Own your potential (DEAKIN) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Koninklijke Nederlandse Akademie van Wetenschappen
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Wageningen University and Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PPAR-gamma coactivator 1, PGC-1α, PPARGC1B, PPARα, insulin resistance, lipid-induced insulin resistance, fatty acids, skeletal muscle, mitochondrial biogenesis, UCP3, free fatty acids, hyperinsulinemic-euglycemic clamp, type 2 diabetes, oxidative metabolism
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adult, Blood Glucose, Carrier Proteins, Emulsions, Fatty Acids, Nonesterified, Heat-Shock Proteins, Humans, Insulin Resistance, Male, Reference Values, Transcription Factors, Glucose Clamp Technique, Body Mass Index, RNA-Binding Proteins, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, PPAR alpha
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