Assistant Professor of Biochemistry
B.S. California State University, San Bernardino
Ph.D. University of California, San Francisco
Claudio Villanueva's Lab Page
Claudio Villanueva's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Transcriptional Regulation and Energy Metabolism
We are interested in the transcriptional regulation of metabolism and how adipocytes establish their metabolic programs. Adipocytes are specialized cells with a tremendous capacity to store energy in the form of triglycerides. Obesity results from the imbalance between energy intake and energy expenditure where excess energy is stored in adipose tissue depots. Obesity increases the risk for chronic diseases such as type 2 diabetes, cardiovascular disease, and certain forms of cancer. Estimates from the world health organization (WHO) indicate that there are 364 million diabetics in the world. In 2004, it was estimated that 3.4 million people in the world died from complications related to diabetes (WHO estimates). Because of the continued rise in rates of obesity and diabetes in industrialized countries, there is an urgent need to investigate the molecular pathways involved in the development and maintenance of adipose tissue function. Our laboratory will use imaging, biochemical, genetic, genomic, proteomic, and lipidomic approaches to study transcriptional regulators of adipocyte biology.
Transcriptional Regulation of Adipogenesis
The central regulator of adipogenesis is PPARγ, a ligand activated transcription factor that belongs to the nuclear receptor family. PPARγ is also the molecular target of thiazolidinediones (TZDs), a class of potent antidiabetic drugs. PPARγ has a major role in driving adipocyte development and establishing the metabolic program of adipocytes. We recently identified TLE3 (transducin-like enhancer of split) as a transcriptional coregulator that works in concert with PPARγ to drive adipocyte specific gene expression. We discovered that TLE3 and PPARγ are involved in a feedforward loop and work synergistically to drive expression of genes involved in lipid handling and storage (Figure 1). Like TZD administration, overexpression of TLE3 in adipose tissue activates PPARγ signaling and improves glucose handling and insulin sensitivity. Future investigations will examine the molecular crosstalk between TLE3 and PPARγ signaling in adipocyte biology.
TLE3 and Wnt Signaling
PPARγ and Wnt signaling are opposing forces in adipogenesis (Figure 1). While PPARγ drives adipogenesis, components of the Wnt signaling pathway oppose it. Genomewide association studies have identified polymorphisms in PPARγ and TCF7L2 that strongly associate with type 2 diabetes. Although a wealth of data exists on how PPARγ affects adipocyte biology and improves insulin sensitivity, little is known about the role of TCF7L2 in adipocyte development, endocrine function and energy metabolism. We discovered that during the course of adipogenesis expression of Wnt responsive genes inversely correlates with PPARγ and TLE3 expression. We found that forced expression of TLE3 blocks Wnt-dependent gene expression and β-catenin-dependent reporter activity. Through a direct interaction TLE3 prevents the downregulation of adipogenic genes by Wnt3a. Notably, through TLE3 we identified a new mechanism that links PPARγ to the inhibition of β-catenin-dependent Wnt signaling during the course of adipogenesis. Our lab will explore how transcriptional regulators of the Wnt signaling pathway modulate adipocyte biology.
Role of TLE3 in White and Brown Fat Cell Determination
There are two types of adipocytes, white and brown. White adipocytes play a major role in storing lipid in the form of triglycerides, and mobilizing lipids as free fatty acids to provide an energy source for peripheral tissues such as heart, liver, and muscle. In contrast, brown adipocytes are thermogenic cells that express high levels of UCP1, a mitochondrial uncoupling protein that uncouples the proton gradient to generate heat. During cold exposure brown adipocytes catabolize lipids as an energy source for heat production. The molecular determinants that drive white versus brown fat gene expression are incompletely understood. Recently Prdm16 was identified as a critical determinant of brown adipocyte development. We are interested in investigating the crosstalk between TLE3 and Prdm16 in driving brown fat cell specification.
Our goal is to study transcriptional regulators of metabolism and adipocyte development, and how they relate to physiology and disease. Ultimately we hope to that our investigations will lead to novel therapeutics for the treatment of metabolic disorders such as obesity and type 2 diabetes.
- Villanueva CJ, Vergnes L, Wang J, Drew BG, Hong C, Tu Y, Hu Y, Peng X, Xu F, Saez E, Wroblewski K, Hevener A, Reue K, Fong LG, Young SG, Tontonoz P (2013) Adipose subtype–selective recruitment of TLE3 or Prdm16 by PPARγ specifies lipid-storage versus thermogenic gene programs. Cell Metabolism 17:423-45
- Zhang Q, Ramlee MK, Brunmeir R, Villanueva CJ, Halperin D, Xu F (2012)Dynamic and distinct histone modifications modulate the expression of key adipogenesis regulatory genes.Cell Cycle 11(23):4310-22
- Villanueva CJ, Waki H, Godio C, Nielsen R, Chou W, Vargas L, Wroblewski K, Schmedt C, Boyadjian R, Chao LC, Mandrup S, Hevener A, Saez E, Tontonoz P (2011) TLE3 is a dual function transcriptional coregulator of adipogenesis. Cell Metabolism 13(4):413-27
- Villanueva CJ and Tontonoz P (2010) Licensing PPARγ to work in macrophages. Immunity 33(5):647-9
- Villanueva CJ, Monetti M, Shih M, Zhou P, Watkins SM, Bhanot S, Farese RV Jr (2009) A Specific Role for Dgat1 in Hepatic Steatosis Due to Exogenous Fatty Acids. Hepatology 50(2):434-42
- Chao LC, Bensinger SJ, Villanueva CJ, Wroblewski K, and Tontonoz P (2008) Inhibition of adipocyte differentiation by Nur77, Nurr1 and Nor1. Molecular Endocrinology 22(12):2596-608
- Park KW, Waki H, Villanueva CJ, Monticelli LA, Hong C, Kang S, Macdougald O, Goldrath AW, Tontonoz P (2008) Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferators-activated receptor-gamma expression and adipocyte differentiation. Molecular Endocrinology 22(9):2038-48
- Minehira K, Young SG, Villanueva CJ, Yetukuri L, Oresic M, Hellerstein MK, Farese, RV Jr, Horton JD, Preitner F, Thorens B, Tappy L (2008) Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. Journal of Lipid Research 49(9):2038-44
- Streeper RS, Koliwad SK, Villanueva CJ, Farese RV Jr (2006) Effects of DGAT1 deficiency on energy and glucose metabolism are independent of Adiponectin. American Journal of Physiology: Endocrinology and Metabolism 291(2):E388-94