Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity
Open accessAbstract
Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1alpha expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1alpha is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1alpha and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1alpha was moderately (approximately 2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1alpha overexpression resulted in increased expression of hepatocyte nuclear factor-4alpha and the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. PGC-1alpha overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1alpha overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1alpha overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IkappaB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1alpha overexpression in liver and muscle suggests that PGC-1alpha is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.
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These same animals displayed increased liver gluconeogenic enzyme levels and impaired insulin suppression of hepatic glucose production, thus nullifying the potentially beneficial effect of modest muscle PGC-1α overexpression on whole-body glucose homeostasis.
“However, these same animals displayed increased liver gluconeogenic enzyme levels and impaired insulin suppression of hepatic glucose production, thus nullifying the potentially beneficial effect of modest muscle PGC-1␣ overexpression on whole-body glucose homeostasis.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [262]
This modest PGC-1α overexpression was accompanied by decreased levels of ROS and inflammatory signaling.
“Importantly, this modest PGC-1␣ overexpression also was accompanied by decreased levels of ROS and inflammatory signaling.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [262]
Transgenic mice expressing human PGC-1α driven by its own promoter displayed a modest (30% higher than basal) increase in mRNA expression of several OXPHOS genes, fiber type switching, and enhanced muscle insulin sensitivity.
“Similarly, transgenic mice expressing human PGC-1␣ driven by its own promoter displayed a modest (30% higher than basal) increase in mRNA expression of several OXPHOS genes, fiber type switching, and enhanced muscle insulin sensitivity (262).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [262]
Modest overexpression of PGC-1α and transgenic overexpression of PGC-1β increase oxidative metabolism and insulin sensitivity.
“Taken together, these studies suggest that modest overexpression of PGC-1␣ (261, 262) and transgenic overexpression of PGC-1 (271, 272) increase oxidative metabolism and insulin sensitivity.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [262]
Whole-body PGC-1α transgenic expression driven by its own promoter increased mitochondrial DNA by 200-300% (Ward, 2009).
“1 200 -300%”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [262]
PGC-1α transgenic expression increases OXPHOS mRNA and protein levels, with increases ranging from 130% to 500% across transgenic models.
“180% 1 COXIV | protein | 130% 1 mRNA | | 150 -200% | 1 mRNA | | | 150 -250% | 1 mRNA | | | | 170 -300% | 1 mRNA | 200 -500% | 1 mRNA and | protein”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [262]
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- Authors
- Liang, H., Balas, B., Tantiwong, P., Dube, J., Goodpaster, B. H., O'Doherty, R. M., DeFronzo, R. A., Richardson, A., Musi, N., & Ward, W. F.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Pittsburgh (US)
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-04
- Volume
- 296
- Issue
- 4
- Pages
- E945-E954
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC2670619
- OpenAlex
- W2134307023
- Cited by
- 81
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 1 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 11 · 2013: 6 · 2012: 6
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institute on Aging (1P30- AG13319, R37AG026557, AG013319, AG-26557, AG-028294, P30AG013319)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-058855, R01DK080157, DK 24092, R01DK058855, DK-080157)
- Topics
- 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
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- PGC-1α, hepatic insulin resistance, skeletal muscle insulin sensitivity, type 2 diabetes, gluconeogenesis, glucose production, HNF4α, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, Akt phosphorylation, muscle fiber type shift, reactive oxygen species, NF-κB signaling, high-fat diet, fasting, glucose homeostasis, transgenic mice
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Feeding Behavior, Female, Gluconeogenesis, Heat-Shock Proteins, Humans, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Transcription Factors, Up-Regulation, Reactive Oxygen Species, Muscle, Skeletal, Genes, Mitochondrial, Lipid Metabolism, Mice
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