Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis
Felipe Henriques,
Alexander H. Bedard,
Adilson Guilherme,
Mark Kelly,
Jingyi Chi,
Peng Zhang,
Lawrence M. Lifshitz,
Karl Bellvé,
Leslie A. Rowland,
Batuhan Yenilmez,
Shreya Kumar,
Yetao Wang,
Jeremy Luban,
Lee S. Weinstein,
Jiandie D. Lin,
Paul Cohen,
Michael P. Czech
Affiliations
Felipe Henriques
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Alexander H. Bedard
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Adilson Guilherme
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Mark Kelly
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Jingyi Chi
Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
Peng Zhang
Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA
Lawrence M. Lifshitz
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Karl Bellvé
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Leslie A. Rowland
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Batuhan Yenilmez
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Shreya Kumar
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Yetao Wang
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Jeremy Luban
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Lee S. Weinstein
Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Jiandie D. Lin
Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA
Paul Cohen
Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
Michael P. Czech
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA; Corresponding author
Summary: Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes in mouse inguinal white adipose tissues (iWATs). Both cold exposure and iAdFASNKO upregulate the sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, and require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for beige adipocyte appearance, as it is blocked by adipocyte Gsα deficiency. Surprisingly, however, in contrast to cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated adipocyte browning in iAdFASNKO mice. Single-cell transcriptomic analysis of iWAT stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type in iAdFASNKO mice, and their depletion abrogated iWAT beiging. Altogether, these findings reveal that divergent cellular pathways are sufficient to cause adipocyte browning. Importantly, adipocyte signaling to enhance alternatively activated macrophages in iAdFASNKO mice is associated with enhanced adipose thermogenesis independent of the sympathetic neuron involvement this process requires in the cold.
