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Distinct signaling and transcriptional pathways regulate peri-weaning development and cold-induced recruitment of beige adipocytes

Yixuan Wu,M. Kinnebrew,V. Kutyavin,A. Chawla

Published 2020 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Adipose tissue performs multiple functions in mammals, including insulation, mechanical tissue protection, and energy balance. These functions of adipose tissue are performed by three distinct cell types: white, beige, and brown adipocytes. While white adipocytes store energy, beige and brown adipocytes dissipate energy through mitochondrial respiration. Previous studies have elucidated how environmental cold stimulates recruitment of beige adipocytes in adult animals. However, beige adipogenesis also occurs during the peri-weaning period in mice, a process that is poorly understood. Here, we demonstrate that distinct mechanisms regulate development and recruitment of beige adipocytes. We find that B cell leukemia/lymphoma 6 (BCL6) controls development of beige adipocytes during the peri-weaning period, whereas sympathetic nerves regulate the recruitment of beige adipocytes in cold environments. Adipose tissue provides a defense against starvation and environmental cold. These dichotomous functions are performed by three distinct cell types: energy-storing white adipocytes, and thermogenic beige and brown adipocytes. Previous studies have demonstrated that exposure to environmental cold stimulates the recruitment of beige adipocytes in the white adipose tissue (WAT) of mice and humans, a process that has been extensively investigated. However, beige adipose tissue also develops during the peri-weaning period in mice, a developmental program that remains poorly understood. Here, we address this gap in our knowledge using genetic, imaging, physiologic, and genomic approaches. We find that, unlike cold-induced recruitment in adult animals, peri-weaning development of beige adipocytes occurs in a temperature- and sympathetic nerve-independent manner. Instead, the transcription factor B cell leukemia/lymphoma 6 (BCL6) acts in a cell-autonomous manner to regulate the commitment but not the maintenance phase of beige adipogenesis. Genome-wide RNA-sequencing (seq) studies reveal that BCL6 regulates a core set of genes involved in fatty acid oxidation and mitochondrial uncoupling, which are necessary for development of functional beige adipocytes. Together, our findings demonstrate that distinct transcriptional and signaling mechanisms control peri-weaning development and cold-induced recruitment of beige adipocytes in mammals.

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