Calorie restriction prevents diet-induced insulin resistance independently of PGC-1-driven mitochondrial biogenesis in white adipose tissue

Abstract

Calorie restriction (CR) exerts remarkable, beneficial effects on glucose homeostasis bymechanisms that are not fully understood. Given the relevance of white adipose tissue (WAT) in glucose homeostasis, we aimed at identifying the main cellular processes regulated inWAT in response to CR in a pathologic context of obesity. For this, a gene-expression profiling studywas first conducted inmice fed ad libitum or subjected to 40%CR.We found that the genenetwork relatedtomitochondriawas themosthighlyupregulatedinWATbyCR.To study the role that increased mitochondrial biogenesis plays on glucose homeostasis following CR, we generated a mouse model devoid of the coactivators peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1)a and PGC-1b specificallyinadipocytes. Our results showthatmice lackingPGC-1s inadipocytes areunable to increase mitochondrial biogenesis in WAT upon CR. Despite a blunted induction of mitochondrial biogenesis in response to calorie deprivation, mice lacking adipose PGC-1s still respond to CR by improving their glucose homeostasis. Our study demonstrates that PGC-1 coactivators are major regulators of CR-induced mitochondrial biogenesis in WAT and that increased mitochondrial biogenesis and oxidative function in adipose tissue are not required for the improvement of glucose homeostasismediated byCR.