Morningside Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, United States
Tiffany DeSouza
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Anand Desai
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Sabine Pallat
Morningside Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, United States
Qin Yang
Morningside Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, United States
Raziel Rojas-Rodriguez
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Rachel Ziegler
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Pantos Skritakis
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Shannon Joyce
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Denise Zhong
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Tammy Nguyen
Department of Surgery, University of Massachusetts Medical School, Worcester, United States; Diabetes Center of Excellence, University of Massachusetts Medical Center, Worcester, United States
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Diabetes Center of Excellence, University of Massachusetts Medical Center, Worcester, United States
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 THBS4, 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.
