Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
JMG, Humans, Mice, Animals, Adipose Tissue, Brown, Proteome, Thermogenesis, Adiposity, Obesity, Mice, Inbred C57BL, Proto-Oncogene Proteins
Jonathon O’Brien, Qing Yu, Miljan Kuljanin, Hans-Georg Sprenger, Blythe P. Durbin-Johnson, Raja Ramaswamy, Lin Shao, Talley Lambert, Jennifer Wa- ters, J. Daniel Giardina, Yassir Al-Sayagh, Rachel Hatridge, Matthew Vincent, Nathan Bulloch, John Szpyt, the Harvard Chan Bioinformatics Core, and the Harvard Nikon Imaging Center are acknowledged for technical assistance and helpful discussions. This work was supported by a sponsored research agreement from Calico Life Sciences, LLC (E.T.C.), the Claudia Adams Barr Program (E.T.C.), the Lavine Family Fund (E.T.C.), the Pew Charitable Trust (E.T.C.), NIH DK123095 (E.T.C.), NIH K99AG073461 (H.X.), National Cancer Center (H.X.), NHGRI HG006673 (E.L.H. and S.P.G.) and P30 DK56341 (S.K.), BJC Foundation (S.K.), the USDA-NIFA CA-D-NTR-2618-H (M.C.), American Heart Association 17POST33060003 (M.C.) and 926512 (L.H.M.B.), NIH RC2 DK116691 (E.D.R.), and NIH R01GM070683 (G.A.C.).
Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.
Van Bruggen N,
Architecture of the outbred brown fat proteome defines regulators of metabolic physiology. Cell. 2022;185(24):4654-73.e28