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Abstract
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.