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.
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.
Cold Adaptation and Cellular Energetics
Throughout evolution there has been selective pressure for mammals to adapt to changes in ambient temperature. In response to cooling, mammals increase energy expenditure to enhance heat production, a process that could be targeted to treat obesity. The metabolic adaptations that are required to switch towards fuel utilization are not well understood. Our lab has used untargeted LC-MS to uncover the changes in lipid metabolism that are required to promote energy expenditure. Using this strategy, we identified long chain acylcarnitines, a mitochondrial-derived lipid, that circulates in the blood in response to the cold. Our studies suggest that acylcarnitines are synthesized by the liver and are actively transported into brown fat to promote thermogenesis. Future studies in our lab will focus on understanding how the liver changes its metabolic program to promote adaptive thermogenesis.
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.
- Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M, Miao R, Lee S, Jian L, Huck I, Kershaw EE, Donato AJ, Apte U, Longo N, Rutter J, Schreiber R, Zechner R, Cox J, Villanueva CJ. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metabolism. 2017 In Press.
- Song NJ, Chang SH, Li DY, Villanueva CJ, Park KW. Induction of thermogenic adipocytes: molecular targets and thermogenic small molecules. Exp Mol Med. 2017 Jul 7;49(7):e353.
- Wang J, Rajbhandari P, Damianov A, Han A, Sallam T, Waki H, Villanueva CJ, Lee SD, Nielsen R, Mandrup S, Reue K, Young SG, Whitelegge J, Saez E, Black DL, Tontonoz P. RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs. J Clin Invest. 2017 Mar 1;127(3):987-1004.
- Kikani CK, Wu X, Paul L, Sabic H, Shen Z, Shakya A, Keefe A, Villanueva C, Kardon G, Graves B, Tantin D, Rutter J. Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis. Elife. 2016 Sep 23;5.
- Drew BG, Hamidi H, Zhou Z, Villanueva CJ, Krum SA, Calkin AC, Parks BW, Ribas V, Kalajian NY, Phun J, Daraei P, Christofk HR, Hewitt SC, Korach KS, Tontonoz P, Lusis AJ, Slamon DJ, Hurvitz SA, Hevener AL. Estrogen receptor (ER)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. J Biol Chem. 2015 Feb 27;290(9):5566-81.
- 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