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

Research output: Contribution to journalArticlepeer-review

13 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 languageEnglish (US)
Article number110575
JournalCell reports
Volume39
Issue number2
DOIs
StatePublished - Apr 12 2022

Bibliographical note

Funding Information:
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.

Funding Information:
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 .

Publisher Copyright:
© 2022 The Author(s)

Keywords

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

PubMed: MeSH publication types

  • Journal Article

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