A Neurogenic Signature Involving Monoamine Oxidase-A controls Human Thermogenic Adipose Tissue Development

Abstract

Human beige/brite thermogenic adipose tissue exerts beneficial metabolic effects and may be harnessed to improve metabolic health. To uncover mechanisms by which thermogenic adipose tissue is generated and maintained we developed a species-hybrid model in which human mesenchymal progenitor cells are induced in vitro to differentiate into white or thermogenic adipocytes and are then implanted into immuno-compromised mice. Upon implantation, thermogenic adipocytes form a more densely vascularized and innervated adipose tissue compared to non-thermogenic adipocytes. Mouse endothelial and stem/progenitor cells recruited by implanted human thermogenic adipocytes are also qualitatively different, with differentially expressed genes mapping predominantly to circadian rhythm pathways. We trace the formation of this enhanced neurovascular architecture to higher expression of a distinct set of genes directly associated with neurogenesis (THBS4, TNC, NTRK3 and SPARCL1), and to lower expression of genes associated with neurotransmitter degradation (MAOA, ACHE) by adipocytes in the developed tissue. Further analysis reveals that MAOA is abundant in human adipocytes but absent in mouse adipocytes, revealing species-specific mechanisms of neurotransmitter tone regulation. In summary, our work discovers specific neurogenic genes associated with development and maintenance of human thermogenic adipose tissue, reveals species-specific mechanisms of control of neurotransmitter tone, and suggests that targeting adipocyte MAOA may be a strategy for enhancing thermogenic adipose tissue activity in humans.

Canonical Wnt Signaling Maintains Human Mesenchymal Progenitor Cell Multipotency During Adipose Tissue Development

“…These cells generated a functional human/mouse hybrid adipose depot (Fig. 5b) 28 . Analysis of human transcript-specific reads in the implants 8 weeks after implantation revealed expected expression of human adipocyte genes (ADIPOQ, PLIN1, LPL), but also revealed expression of MGP + cluster markers (MGP, CTHRC1, DCN) (Fig.…”