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

So Yun Min; Anand Desai; Zinger Yang; Agastya Sharma; Tiffany DeSouza; Ryan M. J. Genga; Alper Kucukural; Lawrence M. Lifshitz; Søren Nielsen; Camilla Scheele; Rene Maehr; Manuel Garber; Silvia Corvera

doi:10.1073/pnas.1906512116

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

So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Tiffany DeSouza, Ryan M. J. Genga, Alper Kucukural, Lawrence M. Lifshitz, Søren Nielsen, Camilla Scheele, Rene Maehr, Manuel Garber, Silvia Corvera

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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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	36
Pages (from-to)	17970-17979
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1906512116
Publication status	Published - 3 Sept 2019

Keywords

human adipose tissue
mesenchymal stem cells
adipocyte differentiation
brown adipocyte
progenitor cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1906512116Licence: CC BY-NC-ND

Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cellsFinal published version, 3.07 MBLicence: CC BY-NC-ND

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Min, S. Y., Desai, A., Yang, Z., Sharma, A., DeSouza, T., Genga, R. M. J., Kucukural, A., Lifshitz, L. M., Nielsen, S., Scheele, C., Maehr, R., Garber, M., & Corvera, S. (2019). Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 116(36), 17970-17979. https://doi.org/10.1073/pnas.1906512116

Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells. / Min, So Yun; Desai, Anand; Yang, Zinger et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 36, 03.09.2019, p. 17970-17979.

Research output: Contribution to journal › Journal article › Research › peer-review

Min, SY, Desai, A, Yang, Z, Sharma, A, DeSouza, T, Genga, RMJ, Kucukural, A, Lifshitz, LM, Nielsen, S, Scheele, C, Maehr, R, Garber, M & Corvera, S 2019, 'Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 36, pp. 17970-17979. https://doi.org/10.1073/pnas.1906512116

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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.",

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AU - Genga, Ryan M. J.

AU - Kucukural, Alper

AU - Lifshitz, Lawrence M.

AU - Nielsen, Søren

AU - Scheele, Camilla

AU - Maehr, Rene

AU - Garber, Manuel

AU - Corvera, Silvia

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AB - 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.

KW - human adipose tissue

KW - mesenchymal stem cells

KW - adipocyte differentiation

KW - brown adipocyte

KW - progenitor cells

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ER -

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

Abstract

Keywords

UN SDGs

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