High-fat dietary restriction in mice induces substrate efficiency and improves metabolic health

High energy intake and, specifically, high dietary fat intake challenges the mammalian metabolism and correlates with many metabolic disorders, such as obesity and diabetes. Dietary restriction (DR) is, on the other hand, known to prevent the development of metabolic disorders. The current Western diets are highly enriched in fat and it is as yet unclear whether DR on a certain high-fat (HF) diet elicits similar beneficial effects on health. Here, we report that HF-DR improves metabolic health of mice, compared to mice receiving the same diet on an ad-libitum basis (HF-AL). Already after five weeks of restriction the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, while their glucose sensitivity and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analysed gene expression in white adipose tissue (WAT) with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total 8,643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. This was confirmed by qRT-PCR and substantiated by an increase in mitochondrial density in WAT of HF-DR mice. These results provide new insights in the metabolic flexibility of dietary restricted animals and suggest the development of substrate efficiency. Limiting food intake by decreasing portion sizes, while maintaining energy sufficiency, may similarly benefit metabolic health in humans. Epididymal white adipose tissue (epiWAT) samples were obtained from 36 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a high-fat diet. 12 mice were sacrificed immediately after the adaptation phase (t=0). The other 24 mice remained on the same diet for 12 weeks. Half of the mice, however, received the diet on an ad-libitum basis (HF-AL), while the remaining 12 mice received the high-fat diet on a restricted basis (of 70 en%) (HF-DR). The diet that was used for dietary restriction was in ratio supplemented with a vitamin and mineral premix to guarantee the same level of intake as in the non-restricted group to prevent deficiencies.