Mitochondrial gene expression and increased oxidative metabolism: Role in increased lifespan of fat-specific insulin receptor knock-out mice

Joslin Diabetes Center, One Joslin Place and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Aging cell (Impact Factor: 6.34). 01/2008; 6(6):827-39. DOI: 10.1111/j.1474-9726.2007.00346.x
Source: PubMed


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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Available from: Steven J Russell, Nov 21, 2014
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    • "Interestingly, dwarf mice have increased mitochondrial respiration and increased metabolism per body weight, indicating that decreased GH signaling may beneficially affect mitochondrial flexibility by increasing the capacity for fat oxidation [73] [74]. Similarly, fat-specific insulin receptor knockout mice, which also have extended lifespan, have increased expression of PGC-1α and PGC-1β, enhanced mitochondrial gene expression, and boosted oxidative metabolism in white adipose tissue [75] "
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    • "One of the promising targets is adipose insulin signaling pathway. Consistent with this, fat-specific disruption of this signaling pathway led to extended lifespan and improved metabolism (Bluher et al., 2003; Katic et al., 2007). Another possible target for aging is the mTORC1 signaling pathway in adipose tissues. "
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