Program in Molecular Medicine; Graduate School of Biomedical Sciences; Department of Medicine, Diabetes Center of Excellence; Program in Bioinformatics and Integrative Biology; Garber Lab
Amino Acids, Peptides, and Proteins | Bioinformatics | Biological Factors | Biological Phenomena, Cell Phenomena, and Immunity | Cell Biology | Cells | Cellular and Molecular Physiology | Computational Biology | Integrative Biology | Lipids
Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of "brite/beige" thermogenic adipocytes reveals mechanisms for iron accumulation and protection from oxidative stress, necessary for mitochondrial biogenesis and respiration upon activation. Importantly, this signature is enriched in human supraclavicular adipose tissue, confirming that these cells comprise thermogenic depots in vivo, and explain previous findings of a rate-limiting role of iron in adipose tissue browning. The mesenchymal progenitors that give rise to beige/brite adipocytes express a unique set of cytokines and transcriptional regulators involved in immune cell modulation of adipose tissue browning. Unexpectedly, we also find adipocyte subtypes specialized for high-level expression of the adipokines adiponectin or leptin, associated with distinct transcription factors previously implicated in adipocyte differentiation. The finding of a broad adipocyte repertoire derived from a distinct set of mesenchymal progenitors, and of the transcriptional regulators that can control their development, provides a framework for understanding human adipose tissue function and role in metabolic disease.
adipocyte differentiation, brown adipocyte, human adipose tissue, mesenchymal stem cells, progenitor cells
Rights and Permissions
Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DOI of Published Version
Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17970-17979. doi: 10.1073/pnas.1906512116. Epub 2019 Aug 16. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Min, So Yun; Desai, Anand; Yang, Zinger; Sharma, Agastya; DeSouza, Tiffany; Genga, Ryan; Kucukural, Alper; Lifshitz, Lawrence M.; Nielsen, Soren; Scheele, Camilla; Maehr, Rene; Garber, Manuel; and Corvera, Silvia, "Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells" (2019). Open Access Articles. 3967.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Amino Acids, Peptides, and Proteins Commons, Bioinformatics Commons, Biological Factors Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Cell Biology Commons, Cells Commons, Cellular and Molecular Physiology Commons, Computational Biology Commons, Integrative Biology Commons, Lipids Commons