DISSECTING THE ORIGIN OF INDUCIBLE BROWN FAT IN ADULT HUMANS THROUGH A NOVEL ADIPOSE STEM CELL MODEL FROM ADIPOSE TISSUE SURROUNDING PHEOCHROMOCYTOMA

Context: The recent discovery of inducible-brown adipose tissue (BAT) in adult humans, where it is involved in controlling adiposity, is pivotal in the development of treatment strategies for obesity. However, the origin of these adipocytes in white adipose tissue (WAT) is still unclear and no human brown-adipose-cell-models are currently available. Objective: To define the origin of inducible-BAT (iBAT) by isolating brown adipose stem cells (B-ASC) from periadrenal fat in adult patients with catecholamine-secreting pheochromocytoma. Design:1-year-study to enroll adrenal tumor patients undergoing surgery. Setting: University Hospital Patients and Intervention: 8 patients operated for pheochromocytoma and 3 for adrenocortical adenoma. Main Outcome Measures: Isolation of iB-ASC from fat surrounding the pheochromocytoma. Results: We demonstrated the presence of iBAT islets dispersed in periadrenal WAT in patients operated for pheochromocytoma. From this fat depot, which expresses brite/classical BAT markers and high levels of uncoupling-protein-1 (UCP-1), we isolated B-ASC and compared their properties with precursors from subcutaneous WAT (S-ASC) of the same patients. B-ASC showed mesenchymal, stem and multipotency features and expression of brite/classical BAT markers. When differentiated toward white phenotype, B-ASC accumulated lipid droplets smaller than S-ASC and expressed adiponectin. Upon induction of brown differentiation, brown commitment was only found in B-ASC and not in S-ASC, with no mature brown adipocytes. Conclusions: Our findings demonstrate that iBAT developed in periadrenalWATderives from adult stem cells unalike WAT precursors, confirming an independent origin of the two fat depots. These stem cells represent a unique in vitro stem cell model to study brown adipogenesis and develop novel anti-obesity therapies targeting WAT-BAT conversion.