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Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17970-17979. doi: 10.1073/pnas.1906512116. Epub 2019 Aug 16.

Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells.

Author information

1
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655.
2
Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, MA 01655.
3
Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01655.
4
Program in Bioinformatics, University of Massachusetts Medical School, Worcester, MA 01655.
5
Centre of Inflammation and Metabolism, Rigshospitalet, University of Copenhagen, 1165 Copenhagen Denmark.
6
Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, 1165 Copenhagen Denmark.
7
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, 1165 Copenhagen, Denmark.
8
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655; Silvia.Corvera@umassmed.edu.

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

PMID:
31420514
DOI:
10.1073/pnas.1906512116
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Conflict of interest statement

The authors declare no conflict of interest.

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