Paul F. Pilch
Lab Phone: 617-638-4045
Joint Appointment: Department of Medicine
BA, Temple University, Philadelphia, PA
PhD, Purdue University, W. Lafayette, IN
Cell biology of adipocytes and muscle
Fat cells or adipocytes play a key role in the regulation of metabolism by insulin and other hormones, and the study of this role at many levels constitutes a major activity of modern cellular and molecular biology. Adipocytes have an unusually high number of plasma membrane micro-domains called caveolae, invaginations resembling little caves, which comprise 50% of their cell surface. We have engineered mice to lack a protein component of caveolae, cavin-1, which leads to a total loss of caveolae in in all tissues and results in profound insulin resistance, lipo- and muscular dystrophy, pathologies identical to those resulting from functional loss of caveolae in humans. We are studying this physiologically relevant mouse model of multiple pathologies to understand the functions of caveolae and their roles in cellular functions in three organs, adipose, skeletal muscle and heart, all of which are dysfunctional. The broader functions affected by caveolae in a variety of cells include motility, cell surface dynamics/mechano-transduction and membrane repair, and we study these roles of caveolae as well.
Adipose tissue is a robust endocrine organ that makes and secretes hormone-like proteins called adipokines, e.g., leptin and adiponectin, which in turn have profound affects on overall metabolism and energy balance. We have identified in the adipocyte endoplasmic reticulum (E.R.), a resident protein we call adiporedoxin (see the Figure) that is most highly expressed in fat cells. In vitro, adiporedoxin loss and over expression cause decreases and increases in secretion of adiponectin, respectively, and its manipulation affects many other secreted proteins in a similar manner. We created mice null for adiporedoxin, and they have a reduced level of circulating adiponectin, a marker for insulin sensitivity, and they develop glucose intolerance/insulin resistance on a high fat diet. Data from human adipocytes show adiporedoxin expression also correlates positively with insulin sensitivity. We are exploiting our mouse model, cultured murine and human fat cells to further understand the mechanism of adiporedoxin’s actions and its affects on metabolic regulation.
- Jedrychowski MP, Liu L, Laflamme CJ, Karastergiou K, Meshulam T, Ding SY, Wu Y, Lee MJ, Gygi SP, Fried SK, Pilch PF. Adiporedoxin, an upstream regulator of ER oxidative folding and protein secretion in adipocytes. Mol Metab. 2015 Nov; 4(11):758-70. PubMed
- Lo HP, Nixon SJ, Hall TE, Cowling BS, Ferguson C, Morgan GP, Schieber NL, Fernandez-Rojo MA, Bastiani M, Floetenmeyer M, Martel N, Laporte J, Pilch PF, Parton RG. The caveolin-cavin system plays a conserved and critical role in mechanoprotection of skeletal muscle. J Cell Biol. 2015 Aug 31; 210(5):833-49. PubMed
- Scheller EL, Doucette CR, Learman BS, Cawthorn WP, Khandaker S, Schell B, Wu B, Ding SY, Bredella MA, Fazeli PK, Khoury B, Jepsen KJ, Pilch PF, Klibanski A, Rosen CJ, MacDougald OA. Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat Commun. 2015; 6:7808. PubMed
- Liu L, Hansen CG, Honeyman BJ, Nichols BJ, Pilch PF. Cavin-3 knockout mice show that cavin-3 is not essential for caveolae formation, for maintenance of body composition, or for glucose tolerance. PLoS One. 2014; 9(7):e102935. PubMed
- Pleiotropic effects of cavin-1 deficiency on lipid metabolism. Ding SY, Lee MJ, Summer R, Liu L, Fried SK, Pilch PF. J Biol Chem. 2014 Mar 21;289(12):8473-83.
- Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling. Fernández-Rojo MA, Gongora M, Fitzsimmons RL, Martel N, Martin SD, Nixon SJ, Brooks AJ, Ikonomopoulou MP, Martin S, Lo HP, Myers SA, Restall C, Ferguson C, Pilch PF, McGee SL, Anderson RL, Waters MJ, Hancock JF, Grimmond SM, Muscat GE, Parton RG. Cell Rep. 2013 Jul 25;4(2):238-47. doi: 10.1016/j.celrep.2013.06.017. Epub 2013 Jul 11.
- IDOL Stimulates Clathrin-Independent Endocytosis and Multivesicular Body-Mediated Lysosomal Degradation of the Low-Density Lipoprotein Receptor. Scotti E, Calamai M, Goulbourne CN, Zhang L, Hong C, Lin RR, Choi J, Pilch PF, Fong LG, Zou P, Ting AY, Pavone FS, Young SG, Tontonoz P. Mol Cell Biol. 2013 Apr;33(8):1503-14. doi: 10.1128/MCB.01716-12. Epub 2013 Feb 4.
- Co-regulation of cell polarization and migration by caveolar proteins PTRF/Cavin-1 and caveolin-1. Hill MM, Daud NH, Aung CS, Loo D, Martin S, Murphy S, Black DM, Barry R, Simpson F, Liu L, Pilch PF, Hancock JF, Parat MO, Parton RG. PLoS One. 2012;7(8):e43041. doi: 10.1371/journal.pone.0043041.
- Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin-2 in a switch-like fashion. Breen MR, Camps M, Carvalho-Simoes F, Zorzano A, Pilch PF. PLoS One. 2012;7(4):e34516. Epub 2012 Apr 6.
- Caveolae, fenestrae and transendothelial channels retain PV1 on the surface of endothelial cells. Tkachenko E, Tse D, Sideleva O, Deharvengt SJ, Luciano MR, Xu Y, McGarry CL, Chidlow J, Pilch PF, Sessa WC, Toomre DK, Stan RV. PLoS One. 2012;7(3):e32655.
- Caveolins/caveolae protect adipocytes from fatty acid-mediated lipotoxicity. Meshulam T, Breen MR, Liu L, Parton RG, Pilch PF. J Lipid Res. 2011 Aug;52(8):1526-32. Epub 2011 Jun 7.
- Caveolae and lipid trafficking in adipocytes. Pilch PF, Meshulam T, Ding S, Liu L. Clin Lipidol. 2011;6(1):49-58.
- Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes. Pilch PF, Liu L. Trends Endocrinol Metab. 2011 Aug;22(8):318-24. Epub 2011 May 17. Review.
- The sugar is sIRVed: sorting Glut4 and its fellow travelers. Kandror KV, Pilch PF. Traffic. 2011 Jun;12(6):665-71. doi: 10.1111/j.1600-0854.2011.01175.x.
- Jedrychowski MP, Gartner CA, Gygi SP, Zhou L, Herz J, Kandror KV, Pilch PF. (2010) Proteomic analysis of GLUT4 storage vesicles reveals LRP1 to be an important vesicle component and target of insulin signaling. J Biol Chem. 285:104-14.
- Simard JR, Meshulam T, Pillai BK, Kirber MT, Brunaldi K, Xu S, Pilch PF, Hamilton JA. (2010) Caveolins sequester fatty acids on the cytoplasmic leaflet of the plasma membrane, augment triglyceride formation and protect cells from lipotoxicity. J Lipid Res. 51: 914-922.
- Bastiani M, Liu L, Hill MM, Jedrychowski MP, Nixon SJ, Lo HP, Abankwa D, Luetterforst R, Fernandez-Rojo M, Breen MR, Gygi SP, Vinten J, Walser PJ, North KN, Hancock JF, Pilch PF, Parton RG. (2009) MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes. J Cell Biol. 185:1259-73
- Chao LC, Wroblewski K, Zhang Z, Pei L, Vergnes L, Ilkayeva OR, Ding S, Reue K, Watt MJ, Newgard CB, Pilch PF, Hevener AL, Tontonoz P. (2009) Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77. Diabetes. 58:2788-96.
- Liu L, Brown D, McKee M, Lebrasseur NK, Yang D, Albrecht KH, Ravid K, Pilch PF. (2008). Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab. 8:310-7
- Liu L and Pilch P.F.( 2008) A critical role of cavin (PTRF) in caveolae formation and organization. J Biol Chem. 283, 4314-4322.
- Saito, T., Jones, C.C., Huang, S., Czech, M.P. and Pilch, P.F. (2007) The interaction of AKT with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 2007 Sep 11; [Epub ahead of print].
- Chao LC, Zhang Z, Pei L, Saito T, Tontonoz P, Pilch PF. (2007) Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle. Mol Endocrinol. 21, 2152-2163.
- Pilch PF, Souto RP, Liu L, Jedrychowski MP, Berg EA, Costello CE, Gygi SP. (2007) Cellular spelunking: exploring adipocyte caveolae. J Lipid Res. 48, 2103-2111