CNRS, IBDC, Nice, France.
Stem Cells. 2011 Nov;29(11):1837-48. doi: 10.1002/stem.737.
Although adipocyte terminal differentiation has been extensively studied, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown. Here we describe a novel role for the pre-B-cell leukemia transcription factor one (PBX1) in adipocyte development using both mouse embryonic stem cells (mESCs) and human multipotent adipose-derived stem (hMADS) cells. We show that Pbx1(-/-) mESCs are unable to generate adipocytes, despite normal expression of neuroectoderm and neural crest (NC) markers. Early adipocyte lineage markers are not induced in Pbx1(-/-) mESCs, suggesting that Pbx1 controls the generation and/or the maintenance of adipocyte progenitors (APs) from the NC. We further characterize the function of PBX1 in postnatal adipogenesis and show that silencing of PBX1 expression in hMADS cells reduces their proliferation by preventing their entry in the S phase of the cell cycle. Furthermore, it promotes differentiation of hMADS cells into adipocytes and partially substitutes for glucocorticoids and rosiglitazone, two key proadipogenic agents. These effects involve direct modulation of PPARγ activity, most likely through regulation of the biosynthesis of PPARγ natural endogenous ligand(s). Together, our data suggest that PBX1 regulates adipocyte development at multiple levels, promoting the generation of NC-derived APs during embryogenesis, while favoring APs proliferation and preventing their commitment to the adipocyte lineage in postnatal life.
尽管脂肪细胞终末分化已得到广泛研究，但脂肪细胞发育的早期步骤及其谱系的胚胎起源在很大程度上仍不清楚。在这里，我们使用小鼠胚胎干细胞（mESCs）和人多能脂肪来源干细胞（hMADS）描述了前 B 细胞白血病转录因子 1（PBX1）在脂肪细胞发育中的新作用。我们表明，尽管神经外胚层和神经嵴（NC）标志物的正常表达，Pbx1(-/-) mESCs 无法生成脂肪细胞。早期脂肪细胞谱系标志物在 Pbx1(-/-) mESCs 中未被诱导，这表明 Pbx1 控制来自 NC 的脂肪细胞祖细胞（APs）的生成和/或维持。我们进一步表征了 PBX1 在出生后脂肪生成中的功能，并表明在 hMADS 细胞中沉默 PBX1 表达可通过阻止其进入细胞周期的 S 期来减少其增殖。此外，它促进 hMADS 细胞分化为脂肪细胞，并部分替代糖皮质激素和罗格列酮，这两种关键的促脂肪生成剂。这些作用涉及对 PPARγ 活性的直接调节，最有可能通过调节 PPARγ 天然内源性配体的生物合成来实现。总之，我们的数据表明 PBX1 在多个水平上调节脂肪细胞发育，在胚胎发生过程中促进 NC 来源的 APs 的生成，同时促进 APs 的增殖并防止它们在出生后生活中向脂肪细胞谱系分化。
