UMMS Affiliation

Program in Molecular Medicine; Graduate School of Biomedical Sciences; Department of Medicine, Diabetes Center of Excellence; Program in Bioinformatics and Integrative Biology; Garber Lab

Publication Date

2019-09-03

Document Type

Article

Disciplines

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

Abstract

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.

Keywords

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

10.1073/pnas.1906512116

Source

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

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

31420514

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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