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

Abstract

SummaryCaloric 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. Fatspecific 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, β β β β -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 γ γ γ γ coactivator 1 α α α α (PGC-1 α α α α ) and PGC-1 β β β β , 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.

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

“…Additionally, increased ROS production in WAT can lead to increased oxidative stress in the blood, causing harmful events to occur in various other organs (Furukawa et al ., 2004). Certain genetically modified animals living longer than controls were reported to exhibit activated mitochondrial biogenesis in WAT (Chiu et al ., 2004; Katic et al ., 2007). The relationship between oxidative stress and lifespan is still controversial.…”

Conditional Knock-out Reveals a Requirement for O-Linked N-Acetylglucosaminase (O-GlcNAcase) in Metabolic Homeostasis

“…RER is a sensitive measure of metabolic rate and has been reported to be altered as the result of a number of loss of function mutations in the mouse (73)(74)(75). An increased basal metabolic rate and RER were observed in fat-specific insulin receptor knock-out mice (76). In an Akt1 knock-out model, mice exhibited elevated energy expenditure without an obvious increase in RER (75).…”

Paradoxical Effect of Mitochondrial Respiratory Chain Impairment on Insulin Signaling and Glucose Transport in Adipose Cells

“…A possible relationship between mitochondrial levels and adipose tissue function has been inferred from results in animals and humans indicating that alterations in mitochondrial levels correlate with changes in insulin sensitivity (9,10,(15)(16)(17)(18)(19)(20)(21)(22)(23). In this report we have turned to a simple model, 3T3-L1 adipocytes, to determine whether a direct relationship between mitochondrial function and insulin sensitivity might indeed exist.…”