Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice.
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.
Katic
Masa
M
Joslin Diabetes Center, One Joslin Place and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Kennedy
Adam R
AR
Leykin
Igor
I
Norris
Andrew
A
McGettrick
Aileen
A
Gesta
Stephane
S
Russell
Steven J
SJ
Bluher
Matthias
M
Maratos-Flier
Eleftheria
E
Kahn
C Ronald
CR
D052436:Adipose Tissue, White / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D002952:Citric Acid Cycle / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis; D004579:Electron Transport / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D015870:Gene Expression; D050259:Genes, Mitochondrial / Q000235:genetics*; D006019:Glycolysis / Q000235:genetics; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011972:Receptor, Insulin / Q000235:genetics; D013851:Thinness / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D011972:Receptor, Insulin