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Mitochondrial gene expression and increased oxidative metabolism: Role in increased lifespan of fat-specific insulin receptor knock-out mice
Open accessAbstract
Caloric restriction, leanness and decreased activity of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling are associated with increased longevity in a wide range of organisms from Caenorhabditis elegans to humans. Fat-specific insulin receptor knock-out (FIRKO) mice represent an interesting dichotomy, with leanness and increased lifespan, despite normal or increased food intake. To determine the mechanisms by which a lack of insulin signaling in adipose tissue might exert this effect, we performed physiological and gene expression studies in FIRKO and control mice as they aged. At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression in white adipose tissue (WAT) of FIRKO mice from 6 to 36 months of age revealed persistently high expression of the nuclear-encoded mitochondrial genes involved in glycolysis, tricarboxylic acid cycle, beta-oxidation and oxidative phosphorylation as compared to expression of the same genes in WAT from controls that showed a tendency to decline in expression with age. These changes in gene expression were correlated with increased cytochrome c and cytochrome c oxidase subunit IV at the protein level, increased citrate synthase activity, increased expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and PGC-1beta, and an increase in mitochondrial DNA in WAT of FIRKO mice. Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.
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“Moreover, WAT-specific insulin receptor deficiency was shown to protect mice from obesity, independently of food intake [270,271].”
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“Expression of genes with protein products involved in key metabolic processes, such as glycolysis, the TCA cycle, β-oxidation and OXPHOS were increased in 2.5–3.0-year-old FIRKO mice compared with age-matched control mice28.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [28]
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“For example, mice with adipose tissue-specific ablation of the insulin receptor (FIRKO mice) display high levels of mitochondrial genes involved in fatty acid oxidation and OXPHOS over the lifespan of the animals (201).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [201]
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Metadata
- Authors
- Katic, M., Kennedy, A. R., Leykin, I., Norris, A., McGettrick, A., Gesta, S., Russell, S. J., Bluher, M., Maratos‐Flier, E., & Kahn, C. R.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Joslin Diabetes Center (US)
- University of Iowa (US)
- Corresponding author
- Kahn, C. Ronald
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2007-09-24
- Volume
- 6
- Issue
- 6
- Pages
- 827-839
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC5715809
- OpenAlex
- W1960692735
- Cited by
- 141
- References
- 73
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 10 · 2020: 9 · 2019: 4 · 2018: 2 · 2017: 10 · 2016: 5 · 2015: 14 · 2014: 7 · 2013: 9 · 2012: 11
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01dk069983-05, DK31036)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031036, R01DK031036, R01DK056113, DK31036, P01DK056116, R01-DK-069983, DK-60837, R01DK060837)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- lifespan extension, mitochondrial gene expression, oxidative metabolism, white adipose tissue, insulin signaling, caloric restriction, aging, PGC-1α, PGC-1β, mitochondrial DNA, cytochrome c, citrate synthase, respiratory exchange ratio, basal metabolic rate, leanness
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Citrate (si)-Synthase, Citric Acid Cycle, Electron Transport Complex IV, DNA, Mitochondrial, Electron Transport, Glycolysis, Longevity, Mitochondria, Oxidation-Reduction, Receptor, Insulin, Thinness, Transcription Factors, Trans-Activators, Gene Expression, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Cytochromes c, Genes, Mitochondrial, Mice, Adipose Tissue, White
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