The transcription factor Osr1 as a novel regulator of adipose tissue development

• Applicant: Professor Dr. Sigmar Stricker
• Subject Area: Developmental Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447381893

Adipose tissue plays a major role in regulating systemic metabolism and whole-body energy homeostasis. White adipose tissue (WAT) stores energy in form of triacylglycerides, whereas brown adipose tissue (BAT) dissipates energy to produce heat in what is called nonshivering thermogenesis. BAT and certain WAT depots that have the capacity of "browning" and are ascribed beneficial roles in metabolic disorders, raising considerable therapeutic hope. To understand the function of adult tissues, elucidation of their developmental history is key. Nevertheless, the emergence of adipose tissue during development, the origin of adult tissue-resident adipogenic stem cells, as well as their molecular regulation are incompletely understood. In preliminary work, using in vivo genetic lineage tracing, we found that the transcription factor Osr1 (odd-skipped related 1) commonly labels dermomyotomal-derived BAT progenitors and lateral plate mesoderm-derived WAT progenitors. Interestingly, in BAT Osr1 labels two temporally and spatially distinct BAT progenitor populations. Osr1 is expressed in the established dermomyotomal lineage, as well as a novel, yet uncharacterized aorta-associated progenitor population. Analysis of a KO mouse mutant shows that Osr1 is necessary for the formation of several BAT and WAT depots. We provide evidence that Osr1 is required for suppression of myogenic cell fate in dermomyotomal progenitors thus enabling adipogenesis, with preliminary data indicating the recruitment of chromatin modulating factors as possible mechanism. Furthermore, we found that developmental Osr1+ cells are also a source of adult adipose tissue-resident progenitors. In adult mice, Osr1 is expressed in bloodvessel associated adipogenic progenitors, but not mature adipocytes. Our preliminary data lead us to hypothesize that Osr1 is a key factor in determining adipogenic cell specification during development and is involved in maintaining undifferentiated adipogenic progenitors in adult adipose depots. In this proposal, we will use Osr1 as a novel lineage marker to revise BAT and BAT-resident progenitor ontogeny, including the definition of a novel progenitor pool. In parallel, contribution of Osr1 progenitors to WAT depots will be characterized. Combined in vivo and in vitro analysis will dissect the functional role of Osr1 in adipose tissue development as well as adult homeostasis. We will elucidate the transcriptional / epigenetic mechanism used by this transcription factor to drive adipogenic gene expression while suppressing genes for alternative cell fates (e.g. myogenic) as a prime example of transcriptional lineage switching. This project will shed new light on the developmental origin of adipose tissue and greatly add to our understanding of adipose tissue differentiation in development and adulthood.

• DFG Programme: Research Grants