A neurogenic signature involving monoamine Oxidase-A controls human thermogenic adipose tissue development
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Curated by eLife
Evaluation Summary:
This manuscript uses a species-hybrid model in which functional human white and thermogenic adipose tissues develop in mice. Interestingly, human adipose tissue is fully able to recruit mouse vascular networks and sympathetic innervation during human adipocyte development. These findings provide novel and valuable information about the development of human thermogenic adipose tissue.
(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. The reviewers remained anonymous to the authors.)
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Abstract
Mechanisms that control ‘beige/brite’ thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin. Thermogenic adipose tissue recruited a denser, qualitatively distinct vascular network, differing in genes mapping to circadian rhythm pathways, and denser sympathetic innervation. The enhanced thermogenic neurovascular network was associated with human adipocyte expression of THBS 4 , TNC , NTRK3, and SPARCL1 , which enhance neurogenesis, and decreased expression of MAOA and ACHE , which control neurotransmitter tone. Systemic inhibition of MAOA, which is present in human but absent in mouse adipocytes, induced browning of human but not mouse adipose tissue, revealing the physiological relevance of this pathway. Our results reveal species-specific cell type dependencies controlling the development of thermogenic adipose tissue and point to human adipocyte MAOA as a potential target for metabolic disease therapy.
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Evaluation Summary:
This manuscript uses a species-hybrid model in which functional human white and thermogenic adipose tissues develop in mice. Interestingly, human adipose tissue is fully able to recruit mouse vascular networks and sympathetic innervation during human adipocyte development. These findings provide novel and valuable information about the development of human thermogenic adipose tissue.
(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. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The authors employed a unique species-hybrid model wherein implanted human cells from white and thermogenic adipose tissues in nude mice. The authors performed molecular analyses of implanted adipose tissues and made several intriguing observations. One of the notable findings is the expression of MAOA in human adipocytes - this is in contrast to previous findings in mice that MAOA is expressed in macrophages. The cell-autonomous role of MAOA in human adipocytes using the species-hybrid system would add additional significance to this work.
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Reviewer #2 (Public Review):
This paper provides important new information that will be of high interest to scientists within the field of thermogenic adipose tissue. The application of xenographic implantation of human adipocytes progenitors provides a powerful approach to analyze the development of human thermogenic adipose tissue in mouse. The key conclusions of the manuscript are fully supported by the data presented.
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