Regulation by PPARγ: Expanding its Biological Functions

Abstract

The peroxisome proliferator-activated receptor (PPAR) family is comprised of ligand-regulated transcription factors that have been implicated in controlling lipid metabolism. When stimulated, PPARγ induces the expression of genes that mediate fatty acid uptake, metabolism, and storage. PPARγ activation also induces adipocyte differentiation and sensitivity to insulin. Barrak et al. and Kubota et al. have now generated PPARγ-deficient mice. Both groups show that PPARγ-deficient mice die during prenatal development due to a defect in placenta vacularization and heart development. Those mutant mice that survived following a placental reconstitution procedure displayed no adipose tissue and died shortly after birth. Heterozygote mutant mice did not exhibit adipocyte hypertrophy from a high fat diet nor did they show insulin resistance, indicating that both PPARγ alleles are required for obesity and insulin resistance to occur as the result of such a diet. Rosen et al. generated chimeric mice by injecting ES cells homozygous for PPARγ deficiency into wild type blastocysts, and also found that the gene was necessary for normal development of adipocytes. The expanse in PPARγ function revealed in these studies and the proposed and molecular control of these various processes by PPARγ are further discussed by Lowell. Lowell, B.B. (1999) PPARγ: An essential regulator of adipogenesis and modulator of fat cell function. Cell 99 : 239-242. [Online Journal] Barak,Y., Nelson, M.C., Ong, E.S., Jones,Y.Z.,Ruiz-Lozano, P., Chien, K.R., Koder, A., and Evans, R.A. (1999) PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4 : 585-595. [Online Journal] Kubota, N., Terauchi,Y., Miki, H., Tamemoto, H., Yamauchi, T., Komeda, K., Satoh, S., Nakano, R., Ishii, C., Sugiyama, T., Eto, K., Tsubamoto, Y., Okuno, A., Murakami, K., Sekihara, H., Hasegawa, G., Naito, M., Toyoshima, Y., Tanaka, S., Shiota, K., Kitamura, T., Fujita, T., Ezaki, O., Aizawa, S., Nagai, R., Tobe, K., Kimura, S., and Kadowaki, T. (1999) PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 4 : 597-609. [Online Journal] Rosen, E.D., Sarraf, P., Troy, A.E., Bradwin, G., Moore, K., Milstone, D.S., Spiegelman, B.M., and Mortensen, R.M. (1999) PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4 : 611-617. [Online Journal]