Endocrine Abstracts

Adipocytes have a key role in obesity and precursor cells can differentiate into white or brown adipocytes, with different metabolic functions. However the process by which stem cells commit to these lineages, and the factors that distinguish white adipogenesis from brown, are poorly understood.

Fetal mesenchymal stem cells (fMSCs) can differentiate into adipocytes, but neither the regulation of this process, nor the phenotype differentiated cells has been examined.

We have shown that the expression of key adipocyte regulators and markers during differentiation broadly reflects patterns seen in other human and murine adipocyte models, including inductions of PPARγ2 and FABP4. Notably we have observed a biphasic pattern of expression of the pre-adipocyte marker Pref-1 in which its expression is induced early in differentiation and then declines markedly as the process continues. This suggests MSCs acquire pre-adipocyte characteristics as they commit to the adipogenic line, prior to then differentiating into mature adipocytes.

There is also heterogeneity of the phenotype of the differentiated fat cells, with some isolates of stem cells differentiating into cells resembling brown adipocytes, expressing the brown fat specific marker UCP-1. One such isolate was examined in more detail and expresses the novel brown fat determining factor PRDM16 both before and after differentiation, suggesting intrinsic differences in the stem cells that determine adipocyte fate. These cells also exhibit elevated basal UCP-1 expression, even in the absence of β-adrenergic signalling, which is dependant on the activity of the orphan nuclear receptor ERRα. This highlights a novel role for ERRα in human brown fat.

Fetal MSCs represent a useful in vitro model for human adipogenesis, and provide opportunities to study the stages prior to commitment to the adipocyte lineage. They also offer invaluable insights into the previously difficult to study characteristics of human brown fat.