Dissecting the Origin of Inducible Brown Fat in Adult Humans Through a Novel Adipose Stem Cell Model from Adipose Tissue Surrounding Pheochromocytoma

The recent discovery of inducible brown adipose tissue (BAT) in adult humans, in which 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.The objective of the study was to define the origin of inducible BAT (iBAT) by isolating brown adipose stem cells (B-ASCs) from periadrenal fat in adult patients with catecholamine-secreting pheochromocytoma.This was a 1-year study to enroll adrenal tumor patients undergoing surgery.The study was conducted at a university hospital.Eight patients operated for pheochromocytoma and three for adrenocortical adenoma participated in the study.Isolation of inducible B-ASCs from fat surrounding the pheochromocytoma was measured.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, we isolated B-ASCs and compared their properties with precursors from sc WAT (S-ASC) of the same patients. B-ASCs showed mesenchymal, stem, and multipotency features and expression of brite/classical BAT markers. When differentiated toward white phenotype, B-ASCs accumulated lipid droplets smaller than S-ASCs and expressed adiponectin. Upon induction of brown differentiation, brown commitment was found only in B-ASCs and not in S-ASCs, with no mature brown adipocytes.Our findings demonstrate that iBAT developed in periadrenal WAT derives from adult stem cells, unlike 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 antiobesity therapies targeting WAT-BAT conversion.