Brown adipose tissue involution associated with progressive restriction in progenitor competence

Zan Huang; Zengdi Zhang; Zahra Moazzami; Ryan Heck; Ping Hu; Hezkiel Nanda; Kaiqun Ren; Zequn Sun; Alessandro Bartolomucci; Yan Gao; Dongjun Chung; Weiyun Zhu; Steven Shen; Hai Bin Ruan

doi:10.1016/j.celrep.2022.110575

Brown adipose tissue involution associated with progressive restriction in progenitor competence

Zan Huang, Zengdi Zhang, Zahra Moazzami, Ryan Heck, Ping Hu, Hezkiel Nanda, Kaiqun Ren, Zequn Sun, Alessandro Bartolomucci, Yan Gao, Dongjun Chung, Weiyun Zhu, Steven Shen, Hai Bin Ruan^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1⁺ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.

Original language	English (US)
Article number	110575
Journal	Cell reports
Volume	39
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2022.110575
State	Published - Apr 12 2022

Funding

We thank Dr. Maria Razzoli and Dr. Pilar Ariza Guzman for EchoMRI and CLAMS analyses; Dr. Xiang Gao, Dr. Xu Zhang, and Dr. David Broide for providing the Fstl1-floxed mice; Dr. Yu-Hua Tseng for providing immortalized human brown preadipocytes and suggestions; and Dr. Chenbo Ji for providing embryonic human brown preadipocytes. This work was supported by the National Natural Science Foundation of China (32170847), the National Key R&D Program of China (2017YFD0500505), the Natural Science Foundation of Jiangsu Province (BK20150687), and China Scholarship Council postdoctoral fellowship (201606855010) (to Z.H.). This work was also supported by the Natural Science Foundation of Jiangsu Province (BK20170147 to Z.Z.), the NIH/NIDDK (R56 DK118150 to A.B.), and the American Diabetes Association (18-IBS-167) and NIH/NIAID (R01 AI139420 and R21 AI140109 to H.-B.R.). H.N. and S.S. were supported by NIH grants UL1 TR002494 and R01 AI148669. Z.H. and Z.Z. designed and performed experiments, analyzed data, and wrote the manuscript. Z.M. performed Seahorse experiments. R.H. and K.R. assisted with mouse colony management and experiments. P.H. collected human fetal iBAT. Z.S. and D.C. performed longitudinal transcriptomics analyses of bulk RNA-seq of SVF cells. A.B. helped with metabolic phenotyping. Y.G. helped with generation of Fstl1 KO mice. W.Z. supported Z.H. in obtaining funding. H.N. and S.S. analyzed rabbit scRNA-seq data. H.-B.R. conceived the project, designed experiments, analyzed data, and wrote the manuscript. The authors declare no competing interests. We thank Dr. Maria Razzoli and Dr. Pilar Ariza Guzman for EchoMRI and CLAMS analyses; Dr. Xiang Gao, Dr. Xu Zhang, and Dr. David Broide for providing the Fstl1-floxed mice; Dr. Yu-Hua Tseng for providing immortalized human brown preadipocytes and suggestions; and Dr. Chenbo Ji for providing embryonic human brown preadipocytes. This work was supported by the National Natural Science Foundation of China ( 32170847 ), the National Key R&D Program of China ( 2017YFD0500505 ), the Natural Science Foundation of Jiangsu Province ( BK20150687 ), and China Scholarship Council postdoctoral fellowship ( 201606855010 ) (to Z.H.). This work was also supported by the Natural Science Foundation of Jiangsu Province ( BK20170147 to Z.Z.), the NIH / NIDDK ( R56 DK118150 to A.B.), and the American Diabetes Association ( 18-IBS-167 ) and NIH/ NIAID ( R01 AI139420 and R21 AI140109 to H.-B.R.). H.N. and S.S. were supported by NIH grants UL1 TR002494 and R01 AI148669 .

Keywords

Brown adipose tissue
CP: Metabolism
FSTL1
UCP1
Wnt signaling
adipose progenitor cells
aging
involution
single-cell RNA sequencing
thermogenesis
whitening

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110575

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title = "Brown adipose tissue involution associated with progressive restriction in progenitor competence",

abstract = "Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.",

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author = "Zan Huang and Zengdi Zhang and Zahra Moazzami and Ryan Heck and Ping Hu and Hezkiel Nanda and Kaiqun Ren and Zequn Sun and Alessandro Bartolomucci and Yan Gao and Dongjun Chung and Weiyun Zhu and Steven Shen and Ruan, {Hai Bin}",

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AU - Huang, Zan

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AU - Nanda, Hezkiel

AU - Ren, Kaiqun

AU - Sun, Zequn

AU - Bartolomucci, Alessandro

AU - Gao, Yan

AU - Chung, Dongjun

AU - Zhu, Weiyun

AU - Shen, Steven

AU - Ruan, Hai Bin

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AB - Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.

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Brown adipose tissue involution associated with progressive restriction in progenitor competence

Abstract

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Keywords

ASJC Scopus subject areas

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