C/EBPα induces adipogenesis through PPARγ: a unified pathway

Abstract

PPAR␥ and C/EBP␣ are critical transcription factors in adipogenesis, but the precise role of these proteins has been difficult to ascertain because they positively regulate each other's expression. Questions remain about whether these factors operate independently in separate, parallel pathways of differentiation, or whether a single pathway exists. PPAR␥ can promote adipogenesis in C/EBP␣-deficient cells, but the converse has not been tested. We have created an immortalized line of fibroblasts lacking PPAR␥, which we use to show that C/EBP␣ has no ability to promote adipogenesis in the absence of PPAR␥. These results indicate that C/EBP␣ and PPAR␥ participate in a single pathway of fat cell development with PPAR␥ being the proximal effector of adipogenesis. Received September 27, 2001; revised version accepted November 9, 2001. Adipogenesis is the process by which undifferentiated precursor cells differentiate into fat cells. This has become one of the most intensively studied developmental processes for at least two reasons: the increasing prevalence of obesity in our society has focused attention on many aspects of fat cell biology, and the availability of good cell culture models of adipocyte differentiation has permitted detailed studies not possible in other systems. Experiments using these in vitro models of adipogenesis, which include the 3T3-L1 and 3T3-F442A lines, have illustrated the transcriptional cascade that promotes fat cell differentiation (Rosen et al. 2000). Representatives of several transcription factor families have been implicated in this process, including the CCAAT/enhancer binding proteins C/EBP␣, C/EBP␤, and C/EBP␦; the nuclear hormone receptor peroxisome proliferator-activated receptor ␥ (PPAR␥); and the basic helix-loop-helix protein ADD1/SREBP1c. Studies in adipogenic cell lines have shown that hormonal induction of differentiation is rapidly followed by expression of C/EBP␤ and C/EBP␦ (Cao et al. 1991;Yeh et al. 1995). Within the next day or so, levels of these proteins peak and then begin to drift downward, coincident with a rise in C/EBP␣ and PPAR␥. These latter factors induce gene expression changes characteristic of mature adipocytes and remain elevated for the life of the cell. In the present model of the transcriptional cascade leading to adipogenesis, C/EBP␤ and C/EBP␦ induce low levels of PPAR␥ and C/EBP␣, which are then able to induce each other's expression in a positive feedback loop that promotes and maintains the differentiated state. This model is consistent with gain-offunction data showing that the addition of either PPAR␥ or C/EBP␣ can promote adipogenesis in fibroblast cell lines (Lin and Lane 1994;Tontonoz et al. 1994).Loss-of-function studies have shown convincingly that PPAR␥ is required for adipogenesis in vivo and in vitro, and cells lacking PPAR␥ express greatly reduced levels of C/EBP␣ (Barak et al. 1999;Kubota et al. 1999;Rosen et al. 1999). Similarly, fibroblasts lacking C/EBP␣ have reduced adipogenic potential, and express reduced levels of PPAR␥ (Wu...

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