Role of Insulin Action and Gene Expression in Adipose Tissue in Aging





C.R. Kahn, M. Katic, M. Bluher

Joslin Diabetes Center and Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA



Defects in the insulin signalling pathway in lower organisms, such as C. elegans and Drosophila, have been associated with increased longevity. Caloric restriction has also been shown to increase longevity in organisms ranging from yeast to mammals. To further explore these associations, we studied mice with a fat specific knockout of the insulin receptor (FIRKO mice), since they have reduced fat mass in the presence of normal or increased food intake and also have a selective defect in insulin action in adipose tissue. We found that both male and female FIRKO mice had an increase in mean lifespan of approximately 134 days (18%), with parallel increases in median and maximum lifespan. Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signalling.

To better understand the link between insulin action and longevity and the potential role of insulin action as a modifier of the response to oxidative stress, we performed gene expression analysis, using RNA isolated from adipose tissue of FIRKO and control mice of different ages (6 months, 1.5 years and 2.5-3 years old animals of each genotype) using Affymetrix microarrays. Of the 22,626 probes/ESTs represented, 1,256 were significantly different in young FIRKO vs. young control mice (708 increased and 548 decreased) and 2,213 were significant in old FIRKO compared to old controls (954 increased and 1,259 decreased), at p< 0.05 level. GenMapp and MappFinder analysis revealed that the most significantly and co-ordinately changed group represented genes encoding mitochondrial proteins. Further analysis identified two distinct groups of genes. Group 1 was comprised of 17 genes with differential expression in young (6 months old) FIRKO vs. control mice. These include glucose phosphate isomerase 1, acetyl - coenzyme A acyltransferase 2, thioredoxin reductase 2, pyruvate dehydrogenase, and cytochrome c oxidase subunits Vb and VIIc. Group 2, which consisted of 58 genes differentially expressed in 2.5 to 3 year-old animals, included acetyl coenzyme A dehydrogenase, citrate synthase, succinate dehydrogenase, malate dehydrogenase, aldolase 1, aconitase 2, NADH deydrogenase (ubiquinone) 1, NADH dehydrogenase (ubiquinone) flavoprotein 1 and 2, ubiquinol--cytochrome c reductase, cytochrome c and cytochrome c oxidase subunits VIa, VIb, VIc and 8a, and ATP synthase, subunit . There was no change in mitochondrially-encoded genes or changes in NRF-1 or PGC-1. However, there was a 50% decrease in expression of mitochondrial transcription factor A in young FIRKO mice.

Our results showing increased expression of genes involved in glycolysis and oxidative phosphorylation in old FIRKO mice, taken together with recent data in humans suggesting decreased mitochondrial activity with aging, suggests that maintaining a high level of mitochondrial function and gene expression in adipose tissue with aging may promote a long-lived phenotype.




Key words: insulin receptor, oxidative phosphorylation, gene expression, adipose tissue







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