Role of cyclin-dependent kinase inhibitors in estrogen regulation of adipogenesis

Adipose tissue is responsive to steroid hormones like estrogen. Loss of estrogen receptor a (ERalpha) caused a 100% increase in adipose tissue, indicating the importance of ERalpha signaling. ERalpha knockout mice (alphaERKO) mice have intact ERbeta signaling. Removal of ERbeta/estrogen signaling in the absence of ERalpha/E2 signaling decreased adipose tissue indicating that ERalpha and ERbeta might have an opposite effect in adipose tissue. The obese phenotype in alphaERKO mice is due to both hypertrophy and hyperplasia of adipocytes. Since estrogen has an effect on the levels of cell cycle inhibitors like p27 Kip1 (p27) and p21 Cip1 (p21) in breast cancer cell lines, estrogen might have an effect on the number of adipocytes by its effect on these proteins. Lack of p27 and p21 caused obesity due to hyperplasia in mice, which led to metabolic disorders. This increase in obesity was due to increase in transcriptional factors like C/EBPbeta, C/EBPalpha, PPARgamma and Glut4. Wild-type (WT) mouse embryonic fibroblast (MEFs) had increased mitotic clonal expansion (MCE) due to lack of estrogen but this was not seen in p27KO MEFs, that showed that the effects due to these two pathways were not additive and a possibility that they might be acting through the same pathway. ERalpha signaling was increased in p27KO MEFs during adipogenesis indicating that the pathways of ERalpha/E2 signaling and p27 activity during adipogenesis might be connected. In conclusion these studies have shown that though ERalpha is the major receptor involved in ER/E2 signaling in adipose tissue, ERbeta might also have a role which is opposite of ERalpha. The hyperplasia in adipocytes caused by lack of estrogen might be due to its effect on the signaling pathways of cell cycle inhibitors like p27. Increase in the number of adult adipocytes due to the activities of these pathways would ultimately lead to obesity and metabolic disorders associated with obesity in the animal.