Calorie restriction (CR) exerts remarkable, beneficial effects on glucose homeostasis by mechanisms 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 in WAT in response to CR in a pathologic context of obesity. For this, a gene‐expression profiling study was first conducted in mice fed ad libitum or subjected to 40% CR. We found that the gene network related to mitochondria was the most highly upregulated in WAT by CR. 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 ³ coactivator 1 (PGC‐1)α and PGC‐1β specifically in adipocytes. Our results show that mice lacking PGC‐1s in adipocytes are unable 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 homeostasis mediated by CR.—Pardo, R., Vila, M., Cervela, L., de Marco, M., Gama‐Pérez, P., González‐Franquesa, A., Statuto, L., Vilallonga, R., Simó, R., Garcia‐Roves, P. M., Villena, J. A. Calorie restriction prevents diet‐induced insulin resistance independently of PGC‐1‐driven mitochondrial biogenesis in white adipose tissue. FASEB J. 33, 2343–2358 (2019). http://www.fasebj.org

Introduction Calorie restriction (CR) exerts multiple effects on health, including the amelioration of systemic insulin resistance. Although the precise mechanisms by which CR improves glucose homeostasis remain poorly defined, SIRT1 has been suggested to act as a central mediator of the cellular responses to CR. Here, we aim at identifying the mechanisms by which CR and SIRT1 modulate white adipose tissue (WAT) function, a key tissue in the control of glucose homeostasis. Material and Methods A gene expression profiling study using DNA microarrays is conducted in WAT of control and SIRT1 transgenic mice fed ad libitum (AL) and mice subjected to 40% CR. Results Gene expression profiling reveals a relatively low degree of overlap between the transcriptional programs regulated by SIRT1 and CR. Gene networks related to extracellular matrix appear commonly downregulated by SIRT1/CR, whereas mitochondrial biogenesis is enhanced exclusively by CR. Moreover, WAT inflammation is reduced by CR and SIRT1, although their anti‐inflammatory effects appeared to be achieved by regulating different gene networks related to the immune system. Concluding Remarks In WAT, SIRT1 does not mediate most of the effects of CR on gene expression. Still, gene networks differentially regulated by SIRT1 and CR converge to reduce WAT inflammation.