Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue
Abstract
Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a new brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.
Additional Information
© 2019 American Society for Clinical Investigation. Submitted: March 29, 2019; Accepted: September 25, 2019; Published: November 25, 2019. The authors are grateful to Jiandie Lin, Li Ye, and members of the Diabetes and Metabolism Research Institute for discussions and comments. The authors thank the City of Hope Animal Resource Center, Integrative Genomics Core, Electron Microscopy and Atomic Force Microscopy Core, Light Microscopy Core, Pathology (Solid Tumor) Core (supported by NIH P30CA033572), Analytical Cytometry Core, and City of Hope Comprehensive Cancer Center for guidance and assistance for experiments. This study was supported by NIH grants K01DK107788, R03HD095414, and R56AG063854 (to QAW) and R01DK55758, R01DK099110, P01DK088761, and P01AG051459 (to PES). QAW was also supported by City of Hope Caltech-COH Initiative Award and the American Diabetes Association Junior Faculty Development Award (1-19-JDF-023). PES was also supported by an unrestricted research grant from the Novo Nordisk Foundation and by a grant from the Kristian Gerhard Jebsen Foundation. This work was also supported by the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research for technology development and broad dissemination (http://clover.caltech.edu/) (to VG) and Caltech Divisional Postdoctoral Fellowship (to MJJ). Author Contributions: QAW, PES, and AS designed the experiments. QAW, PES, and LJ wrote the manuscript. AS and QAW handled all the mouse experiments and performed β-gal staining. AL performed histological sectioning. AS performed the mitochondrial membrane potential test and immunofluorescence staining. AS prepared primary brown adipocytes and XW conducted and analyzed scRNA-seq experiments. AS, QAW, LM, TN and WD performed the seahorse and fatty acid intake experiment. AS, MJJ, HZ, and BA performed BAT tissue clearing and 3D imaging. AS, ZL, and MMM performed the transmission electron microscopy. MS, JT, JMH, YL, YZ, LJ, and VG contributed to experimental design and discussion. All authors approved the final manuscript. The authors have declared that no conflict of interest exists.Attached Files
Published - 129167.3-20191218155444-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf
Supplemental Material - JCI129167.sd.pdf
Supplemental Material - JCI129167.sdv1.mp4
Files
129167.3-20191218155444-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf
Additional details
Identifiers
- PMCID
- PMC6934193
- Eprint ID
- 100166
- Resolver ID
- CaltechAUTHORS:20191203-132507070
Funding
- NIH
- P30CA033572
- NIH
- K01DK107788
- NIH
- R03HD095414
- NIH
- R56AG063854
- NIH
- R01DK55758
- NIH
- R01DK099110
- NIH
- P01DK088761
- NIH
- P01AG051459
- Caltech-City of Hope Biomedical Initiative
- American Diabetes Association
- 1-19-JDF-023
- Novo Nordisk Foundation
- Kristian Gerhard Jebsen Foundation
- Caltech Beckman Institute
Dates
- Created
-
2019-12-04Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field