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Purpose: Both dietary fat and dietary sucrose are major components of Western diets that may differentially affect the risk for body mass gain, diabetes mellitus, and cardiovascular disease., Methods: We have phenotypically analyzed mice with ubiquitously impaired expression of mitochondrial frataxin protein that were challenged with diets differing in macronutrient content, namely high-sucrose/low-fat and high-saturated fat/low-sugar diets., Results: We find here that a high-sucrose/low-fat diet has especially detrimental effects in mice with impaired mitochondrial metabolism promoting several independent cardiovascular risk factors, including impaired glucose metabolism, fasting hyperinsulinemia, reduced glucose-stimulated insulin secretion, increased serum triglycerides, and elevated cholesterol levels due to increased expression of HMG-CoA reductase. In contrast, a high-saturated fat/low-sugar diet protects mice with impaired mitochondrial metabolism from diet-induced obesity by increasing total energy expenditure and increasing expression of ACAA2, a rate-limiting enzyme of mitochondrial beta-oxidation, whereas no concomitant improvement of glucose metabolism was observed., Conclusions: Taken together, our results suggest that mitochondrial dysfunction may cause sucrose to become a multifunctional cardiovascular risk factor, whereas low-sugar diets high in saturated fat may prevent weight gain without improving glucose metabolism.

Increasing cellular glucose uptake is a fundamental concept in treatment of type 2 diabetes, whereas nutritive calorie restriction increases life expectancy. We show here that increased glucose availability decreases Caenorhabditis elegans life span, while impaired glucose metabolism extends life expectancy by inducing mitochondrial respiration. The histone deacetylase Sir2.1 is found here to be dispensable for this phenotype, whereas disruption of aak-2, a homolog of AMP-dependent kinase (AMPK), abolishes extension of life span due to impaired glycolysis. Reduced glucose availability promotes formation of reactive oxygen species (ROS), induces catalase activity, and increases oxidative stress resistance and survival rates, altogether providing direct evidence for a hitherto hypothetical concept named mitochondrial hormesis or "mitohormesis." Accordingly, treatment of nematodes with different antioxidants and vitamins prevents extension of life span. In summary, these data indicate that glucose restriction promotes mitochondrial metabolism, causing increased ROS formation and cumulating in hormetic extension of life span, questioning current treatments of type 2 diabetes as well as the widespread use of antioxidant supplements.