Identification and enrichment of beige/brown adipocyte progenitors from white adipose tissue for the generation of functional brown fat in humans

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The existence of functional relevant brown adipose tissue (BAT) in human adults has been accepted in the scientific community since 2009. In contrast to the energy storing white adipose tissue (WAT), BAT utilizes energy to generate heat. Recent data demonstrated that BAT activity is reduced in obese patients. Therefore it became an attractive pharmacological target for the treatment of overweight and obesity. Besides white and brown adipocytes a third adipocyte type has been recently described, the so-called beige adipocyte. In mice, this cell type emerges under certain circumstances within the WAT depot. The cellular and molecular basis for the recruitment of beige adipocytes in humans is only poorly understood. However, both brown and beige adipocytes are thermogenic and can contribute to an increase in energy expenditure. Our group demonstrated recently that human progenitor cells of white and brown adipocytes have distinct gene expression signatures. Among the differentially expressed genes were many surface proteins, which could potentially be used to enrich brown adipocytes. The fundamental hypothesis of this proposal is that specific progenitor cells, which are able to differentiate into functional brown or beige adipocytes reside in the stromal-vascular fraction of white adipose tissue depots. Specific aims are: 1. We want to identify surface markers of human white and beige/brown adipocyte progenitors. 2. We want to use these markers to enrich beige/brown adipocyte progenitor cells from white adipose tissue. 3. We will investigat if the identified markers play a causal role for the generation of beige/brown adipocytes. 4. Taking advantage of transplantation experiments, we want to test if progenitor cells enriched from WAT which display a beige/brown gene signature in vitro can give rise to functional beige/brown adipocyte tissue in vivo. In mice, transplantation of BAT can prevent or revert diet-induced obesity and its associated comorbidities. Our vision is to develop such a strategy for humans. The planned experiments provide a scientific basis for this approach.