Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle
Open accessAbstract
The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-gamma cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 +/- 0.02 to 1.73 +/- 0.43 mm and decreased insulin-stimulated glucose disposal from 8.82 +/- 0.69 to 6.67 +/- 0.66 mg/kg.min, both with p < 0.05. PGC-1 mRNA, along with mRNAs for a number of nuclear encoded mitochondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation.
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Both acute (4-hour) and chronic (4-day) physiological elevation of plasma free fatty acid concentration in insulin-sensitive individuals impairs insulin signalling and causes skeletal muscle insulin resistance.
“Both acute (4 hours) and chronic (4 days) physiologic elevation of plasma FFA concentration in insulin sensitive individuals impairs insulin signaling and causes insulin resistance in skeletal muscle [28, 62–68].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [67]
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 Richardson et al., 2005
Several conditions associated with susceptibility to insulin resistance, including obesity, lipid accumulation, and aging, have all been associated with reduced nuclear-encoded OXPHOS gene expression.
“Several conditions associated with susceptibility to insulin resistance, including obesity, lipid accumulation, and aging, have all been associated with reduced nuclearencoded OXPHOS gene expression.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [129]
Reduced OXPHOS gene expression has been observed in response to lipid infusion.
“Reduced OXPHOS gene expression has been observed in response to genetic and nutritional obesity (127), short-term high-fat feeding (even in humans) (128), lipid infusion (129), and lipid loading of myotubes (127).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [129]
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References 44 · Cited by 259
Research works printed but not linked: 3
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- Authors
- Richardson, D. K., Kashyap, S., Bajaj, M., Cusi, K., Mandarino, S. J., Finlayson, J., DeFronzo, R. A., Jenkinson, C. P., & Mandarino, L. J.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Mandarino, Lawrence J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 280
- Issue
- 11
- Pages
- 10290-10297
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2001369189
- Cited by
- 259
- References
- 44
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 17 · 2020: 16 · 2019: 7 · 2018: 10 · 2017: 13 · 2016: 6 · 2015: 11 · 2014: 10 · 2013: 11 · 2012: 11
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (DK24092)
- National Institutes of Health (DK24092)
- University of Texas Health Science Center at San Antonio
- National Institute of Diabetes and Digestive and Kidney Diseases (DK47936, DK66483, DK 24092, R01DK047936, R01DK066483, R01DK079195)
- National Center for Research Resources (M01RR001346)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- 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
- free fatty acids, lipid infusion, triglyceride emulsion, skeletal muscle, PGC-1, nuclear-encoded mitochondrial genes, extracellular matrix genes, connective tissue growth factor, collagen expression, insulin resistance, insulin-stimulated glucose disposal, inflammation
- MeSH terms
- Adult, Biopsy, Cell Nucleus, Collagen, Extracellular Matrix, Fatty Acids, Fatty Acids, Nonesterified, Female, Gene Expression Regulation, Humans, Image Processing, Computer-Assisted, Inflammation, Insulin, Male, Microscopy, Fluorescence, Middle Aged, Mitochondria, Muscles, Nucleic Acid Hybridization, Radioimmunoassay, RNA, Messenger, Time Factors, Transcription Factors, Immunoblotting, Models, Statistical, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Lipid Metabolism
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