| Summary: | Summary: Recruitment of brite/beige cells, known as browning of white adipose tissue (WAT), is an efficient way to turn an energy-storing organ into an energy-dissipating one and may therefore be of therapeutic value in combating obesity. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Here, we exploit the large natural variation in WAT browning propensity between inbred mouse strains to gain an inclusive view of the core regulatory network coordinating this cellular process. Combining comparative transcriptomics, perturbation-based validations, and gene network analyses, we present a comprehensive gene regulatory network of inguinal WAT browning, revealing up to four distinct regulatory modules with key roles for uncovered transcriptional factors, while also providing deep insights into the genetic architecture of brite adipogenesis. The presented findings therefore greatly increase our understanding of the molecular drivers mediating the intriguing cellular heterogeneity and plasticity of adipose tissue. : Browning of white fat, which turns an energy-storing organ into an energy-dissipating one, holds promise for the development of novel therapeutics against obesity. By exploiting intrinsic mouse strain variation and applying a systems-genetics approach, Li et al. reveal a comprehensive gene regulatory network that controls this browning process. Keywords: UCP1, browning, thermogenesis, inbred mouse strains, molecular network, brite/beige adipogenesis, adipose tissue, obesity, transcription factor
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