The relationship between obesity and type 2 diabetes has been known for decades and the recent increase in such diseases represents a major medical problem worldwide. Type 2 diabetes is preceded by insulin resistance, a condition in which insulin is less able to drive glucose into muscle and adipose tissue. Adipose tissue is not only an important storage organ but plays a much more active role in metabolism control than originally suspected. Mature adipocytes regulate metabolism mainly through secreted proteins (e.g. leptin, adiponectin), which function in an endocrine or paracrine fashion. The amount of mature adipocytes is largely determined by the differentiation of fibroblasts, a process called adipogenesis (Figure 1).
A huge amount of data indicates that the transcription factor PPARgamma is one of the key players in adipogenesis (Figure 1). For example, PPARgamma -/- mice lack adipose tissue, while in vitro differentiation of fibroblasts into mature adipocytes can be induced by introduction of PPARgamma. PPARgamma is a member of the nuclear receptor superfamily of transcription factors. Upon binding of ligand these proteins undergo a conformational change, which allows the interaction with co-regulator proteins, starting a cascade of protein interactions and modifications that finally results in the induction of specific target genes (Figure 2).
We aim to understand how the activity of the transcription factor PPARgamma is regulated. Within this program we have recently characterized two mutated forms of PPARgamma, as found in a patients with familial partial lipodystrophy (FPL). The first extensive ligand-induced PPAR-coregulator interaction profiles were recently generated using a novel peptide-based array technology, which is operational in the lab of Dr. Kalkhoven through collaboration with Pamgene International B.V. To study the role of post-translational modifications and protein-protein interactions in the regulation of PPARgamma activity, we have used state-of-the-art molecular biology approaches combined with in vitro cell differentiation assays. One of the novel coregulators we found in these studies is the acetyltransferase Tip60. In addition, we have recently identified a number of novel PPARgamma target genes by microarray analysis.
We have recently started to study the endocrine function of adipocytes and adipose tissue by defining the adipocyte “secretome”, i.e. the complete set of bioactive molecules secreted by mature adipocytes, under different conditions. In this project, which is performed in collaboration with Prof. Dr. B. Prakken (Pediatric Immunology), we use a combination of Luminex bead-array analysis and advanced mass spectrometry methods.
The following people are working on this project:
Olivier van Beekum - Novel mechanisms in PPARg-mediated adipogenesis. 10 April 2008.
Ellen Jeninga - The role of PPAR-gamma in lipid metabolism. 19 May 2009
Van Beekum O., Fleskens, V. and Kalkhoven, E. (2008). Posttranslational modifications of PPAR: fine-tuning the metabolic master regulator. Obesity, in press.
Sanderson, L.M., de Groot, P.J., Hooiveld, G.J.E.J., Koppen, A., Kalkhoven, E., Müller, M. and Kersten, S. (2008) Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics. PlosOne 3, e1681.
Van Beekum O., Brenkman A.B., Grøntved, L., Hamers N., van den Broek N., Berger R., Mandrup, S. and Kalkhoven E. (2008). The adipogenic acetyltransferase Tip60 targets activation function 1 of PPARgamma. Endocrinology 149, 1840-1849.
Van Beekum, O. and Kalkhoven, E. (2007) Aberrant forms of histone acetyltransferases in human disease. Subcell Biochem., 41:233-62.
Jeninga, E.H., van Beekum, O., van Dijk, A.D.J., Hamers, N., Hendriks-Stegeman, B.I., Bonvin, A.M.J.J., Berger, R. and Kalkhoven, E. (2007) Impaired PPAR function through mutation of a conserved salt bridge (R425C) in Familial Partial Lipodystrophy. Mol Endocrinol. 21, 1049-1065.
Monajemi, H., Zhang, L., Li, G., Jeninga, E.H., Cao, H., Maas, M., Brouwer, C.B., Kalkhoven, E., Stroes, E., Hegele, R.A. and Leff, T. (2007) Familial partial lipodystrophy phenotype resulting from a single-base mutation in DNA binding domain of peroxisome proliferator-activated receptor gamma. J. Clin. Endocrinol. Metab. 92, 1606-1612
Winkler, G.S., Mulder, K.W., Bardwell, V.J., Kalkhoven, E. and Timmers, H.Th.M. (2006) Human Ccr4-Not complex is a ligand-dependent repressor of nuclear receptor-mediated transcription. EMBO J. 25, 3089-3099.
Last update: March 2, 2011