Deconstructing cold-induced brown adipocyte neogenesis in mice
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Evaluation Summary:
Burl and Rondini et al. elucidate the transcriptional profile of the stromal vascular fraction of murine brown adipose tissue in the context of thermogenic stimulation. The authors combined systems and reductionist approaches to show the reliance of mature brown adipocytes on adrenergic activation to indirectly stimulate progenitor proliferation and differentiation and the involvement of dendritic cells in this process. Overall, this is a timely and well-rounded work that will provide beneficial data for public use and further resolve the complexities underlying brown adipose physiology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
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Abstract
Cold exposure triggers neogenesis in classic interscapular brown adipose tissue (iBAT) that involves activation of β1-adrenergic receptors, proliferation of PDGFRA+ adipose tissue stromal cells (ASCs), and recruitment of immune cells whose phenotypes are presently unknown. Single-cell RNA-sequencing (scRNA-seq) in mice identified three ASC subpopulations that occupied distinct tissue locations. Of these, interstitial ASC1 were found to be direct precursors of new brown adipocytes (BAs). Surprisingly, knockout of β1-adrenergic receptors in ASCs did not prevent cold-induced neogenesis, whereas pharmacological activation of the β3-adrenergic receptor on BAs was sufficient, suggesting that signals derived from mature BAs indirectly trigger ASC proliferation and differentiation. In this regard, cold exposure induced the delayed appearance of multiple macrophage and dendritic cell populations whose recruitment strongly correlated with the onset and magnitude of neogenesis across diverse experimental conditions. High-resolution immunofluorescence and single-molecule fluorescence in situ hybridization demonstrated that cold-induced neogenesis involves dynamic interactions between ASC1 and recruited immune cells that occur on the micrometer scale in distinct tissue regions. Our results indicate that neogenesis is not a reflexive response of progenitors to β-adrenergic signaling, but rather is a complex adaptive response to elevated metabolic demand within brown adipocytes.
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Evaluation Summary:
Burl and Rondini et al. elucidate the transcriptional profile of the stromal vascular fraction of murine brown adipose tissue in the context of thermogenic stimulation. The authors combined systems and reductionist approaches to show the reliance of mature brown adipocytes on adrenergic activation to indirectly stimulate progenitor proliferation and differentiation and the involvement of dendritic cells in this process. Overall, this is a timely and well-rounded work that will provide beneficial data for public use and further resolve the complexities underlying brown adipose physiology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their …
Evaluation Summary:
Burl and Rondini et al. elucidate the transcriptional profile of the stromal vascular fraction of murine brown adipose tissue in the context of thermogenic stimulation. The authors combined systems and reductionist approaches to show the reliance of mature brown adipocytes on adrenergic activation to indirectly stimulate progenitor proliferation and differentiation and the involvement of dendritic cells in this process. Overall, this is a timely and well-rounded work that will provide beneficial data for public use and further resolve the complexities underlying brown adipose physiology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This manuscript is a continuation of the impactful work of Lee et al. (2015) [PMID: 25392270], in which the location and identity of brown adipocyte progenitors and their proliferation and differentiation driving brown adipogenesis was significantly refined. In this work, Burl and Rondini et al. attempt to elucidate the transcriptional profile of the stromal vascular fraction of murine brown adipose tissue in the context of thermogenic stimulation and activation of the depot. The authors combined a systems approach that generated detailed information on the dynamics of cellular transcriptomes over a fine time course with a reductionist approach that provides strong causal evidence for the mechanism of brown adipocyte neogenesis, namely showing its reliance on the adrenergic activation of mature brown …
Reviewer #1 (Public Review):
This manuscript is a continuation of the impactful work of Lee et al. (2015) [PMID: 25392270], in which the location and identity of brown adipocyte progenitors and their proliferation and differentiation driving brown adipogenesis was significantly refined. In this work, Burl and Rondini et al. attempt to elucidate the transcriptional profile of the stromal vascular fraction of murine brown adipose tissue in the context of thermogenic stimulation and activation of the depot. The authors combined a systems approach that generated detailed information on the dynamics of cellular transcriptomes over a fine time course with a reductionist approach that provides strong causal evidence for the mechanism of brown adipocyte neogenesis, namely showing its reliance on the adrenergic activation of mature brown adipocytes to indirectly stimulate progenitor proliferation and differentiation and the possible involvement of dendritic cells in this process. Additionally, the manuscript provides strong evidence of a contribution from myeloid cells in the process of progenitor proliferation and differentiation - an often noted but poorly understood process. Overall, this is a timely and well-rounded work that will provide beneficial data for public use and further resolve the complexities underlying brown adipose physiology.
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Reviewer #2 (Public Review):
Thermogenic brown adipocytes can burn energy to make heat, called non-shivering thermogenesis, and their ability to expend energy in this manner makes them an attractive target for anti-obesity therapies. Thus, understanding what controls brown adipose tissue development has both biological and clinical implications. Here, the authors investigate the process of new brown fat formation making two important conceptual advances: first, they identify a population of brown adipocyte precursor cells; and second, they find that the initiation of brown adipogenesis is signaled from the mature cell population through a complex regionalized process involving immune cells, rather than beta-AR signaling directly to the precursor population. This has important implications for understanding brown fat neogenesis. Key …
Reviewer #2 (Public Review):
Thermogenic brown adipocytes can burn energy to make heat, called non-shivering thermogenesis, and their ability to expend energy in this manner makes them an attractive target for anti-obesity therapies. Thus, understanding what controls brown adipose tissue development has both biological and clinical implications. Here, the authors investigate the process of new brown fat formation making two important conceptual advances: first, they identify a population of brown adipocyte precursor cells; and second, they find that the initiation of brown adipogenesis is signaled from the mature cell population through a complex regionalized process involving immune cells, rather than beta-AR signaling directly to the precursor population. This has important implications for understanding brown fat neogenesis. Key strengths include the elegant and rigorous use of RNA-seq, single cell RNA seq, and single molecule FISH to identify key cell populations and their spatial organization. The work establishes new hypothesis as to how brown fat neogenesis occurs; however, it does not go so far into functionally interrogating new mechanisms.
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Reviewer #3 (Public Review):
This study provides a comprehensive analysis of the brown fat adipogenesis process in vivo. The study addresses several outstanding questions in the field regarding the identity of brown fat progenitors, and mechanisms for activation. The extensive scRNAseq studies under basal conditions and during BAT proliferation upon cold exposure, CL316 treatment, and in response to Adrb1 deletion provide a complete view of the adipogenesis process. This analysis leads the authors to identify PDGFRa+ cells (ASC1) as the direct upstream progenitor cell for new brown adipocytes, and identifies Nnat as a novel maker of newly differentiating cells. These findings are reinforced by lineage tracing and in situ hybridization analyses. Additionally, the paper shows that the metabolic activation of mature brown adipocytes …
Reviewer #3 (Public Review):
This study provides a comprehensive analysis of the brown fat adipogenesis process in vivo. The study addresses several outstanding questions in the field regarding the identity of brown fat progenitors, and mechanisms for activation. The extensive scRNAseq studies under basal conditions and during BAT proliferation upon cold exposure, CL316 treatment, and in response to Adrb1 deletion provide a complete view of the adipogenesis process. This analysis leads the authors to identify PDGFRa+ cells (ASC1) as the direct upstream progenitor cell for new brown adipocytes, and identifies Nnat as a novel maker of newly differentiating cells. These findings are reinforced by lineage tracing and in situ hybridization analyses. Additionally, the paper shows that the metabolic activation of mature brown adipocytes provides key signal(s) for progenitor differentiation and that the direct activation of progenitors by norepinephrine is dispensable.
This paper provides an excellent foundation for future work identifying key components of the progenitor niche, and the pathways that regulate progenitor differentiation.
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