Wednesday, 8 July 2015

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Christopher E. Wall, Jamie Whyte, Jae M. Suh, Ronald M. Evans et al.

The POLG mutator mouse is a well-known model of premature aging. They express a proofreading-deficient version of POLG, causing them to introduce point-mutations and deletions in their mitochondrial genome. The aging phenotype is visible from 9 months onwards, and yet most mutations accumulate during embryogenesis. This study sought to characterise younger mutator mice, which bare much of the mtDNA damage of older mice, but relatively little respiratory chain dysfunction, and without a progerioid phenotype.

To do this, the authors challenged the mice with a high-fat diet (HFD). The expectation was that these mice would fair poorly under such a diet, but surprisingly the mice appeared healthier than controls. POLG mice were highly resistant to weight gain, and had much lower insulin levels relative to controls. These mice also had a substantially higher mitochondrial content and oxygen consumption rate in their brown adipose tissue, once given a HFD. POLG mice on a normal diet have an abnormally low body temperature (by ~4°C), but HFD allowed the mice to recover normal core temperature, through aerobic thermogenesis.  

The gene FGF21, which is thought to mediate the benefits of caloric restriction (but also signals mitochondrial stress), was substantially upregulated in POLG mice in both HFD and normal diets. Thus, the authors suggest that young POLG mice are in a metabolic state of starvation. Since calorie restriction is associated with longevity, they suggest that these observations indicate a compensatory response, to oppose their mutated mtDNA. However, as the mice age, they eventually succumb to the progerioid phenotype. 



The authors suggest in their discussion that lipids from a HFD are able to function as a preferential metabolic substrate. From this reasoning, does it follow that mice supplemented with a HFD should have a delayed/ameliorated progerioid phenotype? The discussion suggests not, but I wonder why this isn't the case...


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