Villena 2017 MiP2017
Calorie restriction (CR) exerts multiple beneficial effects on health, including the prevention and amelioration of metabolic pathologies, such as insulin resistance and type 2 diabetes. Owing to its endocrine and lipid-storing functions, white adipose tissue (WAT) plays a central role in the regulation of glucose homeostasis. However, besides the remarkable effects that CR has on adipose mass, little is known about the main cellular processes regulated by CR in WAT.
To uncover the gene networks and cellular processes regulated by CR, we compared the gene expression profiles of WAT from mice subjected to CR (40%) during 16 weeks and mice fed ad libitum. Gene set enrichment analysis revealed that mitochondrial biogenesis was among the most significantly up-regulated processes by CR in WAT. Moreover, to study the role that mitochondrial biogenesis and oxidative function could play on the metabolic effects exerted by CR, we generated a new adipocyte-specific double knockout mouse model in which the expression of PGC-1α and PGC-1β co-activators was simultaneously ablated in adipose tissues (PGC1α/β-FAT-DKO mice).
We found that CR dramatically increased the expression of mitochondrial genes in WAT, as well as the mtDNA content and the oxidative capacity of the tissue. The increase in mitochondrial mass and oxidative function in WAT occurred in parallel with an increase in the expression of the co-activators PGC-1α and PGC-1β, which are recognized as master regulators of mitochondrial biogenesis. To determine if CR-induced mitochondrial biogenesis was mediated by PGC-1s, we used PGC1α/β-FAT-DKO. We found reduced expression of mitochondrial genes, decreased mitochondrial protein content and impaired mitochondrial respiration in WAT of PGC1α/β-FAT-DKO mice fed ad libitum. Moreover, PGC1α/β-FAT-DKO mice failed to increase mitochondrial biogenesis and oxidative function in WAT in response to CR. Enhanced mitochondrial function in response to CR in WAT has been associated with better glucose homeostasis. However, PGC1α/β-FAT-KO mice responded to CR by improving whole body glucose tolerance and insulin sensitivity to the same extent as their wild-type littermates.
In summary, our results demonstrate that PGC-1 co-activators mediate CR-induced mitochondrial biogenesis in WAT. Also, we show that mitochondrial biogenesis and full respiratory capacity in WAT is not required for the beneficial effects of CR on whole body glucose homeostasis, suggesting that other CR-induced pathways could be more relevant in determining insulin sensitivity in response to nutrient deprivation.
Labels: MiParea: mt-Biogenesis;mt-density, mtDNA;mt-genetics, Exercise physiology;nutrition;life style
- Pardo R(1), Vila M(1), Cervela L(1), de Marco M(1), Gama-Perez P(2), Statuto L(1), Gonzalez-Franquesa A(2), Garcia-Roves P(2), Villena J(1)
- Vall d’Hebron-Research Inst
- Inst d’Investigació Biomèdica Bellvitge; Barcelona, Spain. - [email protected]