Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling

• Published in: Cell metabolism 2016-09, Vol.24 (3), p.434-446
• Main Authors: Fabbiano, Salvatore, Suárez-Zamorano, Nicolas, Rigo, Dorothée, Veyrat-Durebex, Christelle, Stevanovic Dokic, Ana, Colin, Didier J., Trajkovski, Mirko
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Beige - metabolism; Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Animals; Caloric Restriction; Diet; Feeding Behavior; Glucose - metabolism; Immunity; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Obese; Signal Transduction - immunology; Subcutaneous Fat - metabolism; Thermogenesis
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.07.023

Caloric restriction (CR) extends lifespan from yeast to mammals, delays onset of age-associated diseases, and improves metabolic health. We show that CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality and in obese leptin-deficient mice. These metabolic changes are mediated by increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage polarization in fat of CR animals. Suppression of the type 2 signaling, using Il4ra−/−, Stat6−/−, or mice transplanted with Stat6−/− bone marrow-derived hematopoietic cells, prevents the CR-induced browning and abrogates the subcutaneous fat loss and the metabolic improvements induced by CR. These results provide insights into the overall energy homeostasis during CR, and they suggest beige fat development as a common feature in conditions of negative energy balance. [Display omitted] •Caloric restriction leads to preferential glucose uptake in white fat•Caloric restriction promotes the development of functional beige fat•Decreased caloric intake enhances type 2 immune response and SIRT1 expression•Type 2 signaling is necessary for the browning and the metabolic improvements during CR Fabbiano et al. demonstrate that caloric restriction promotes functional beige fat development via enhanced type 2 immune response and SIRT1 expression in macrophages. Genetic suppression of type 2 cytokine signaling prevents browning and subcutaneous fat loss, and it abrogates the metabolic improvements elicited by caloric restriction.