Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Genes & Dev. 21 (7): 756-769

Copyright © 2007 by Cold Spring Harbor Laboratory Press.

Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4{alpha}

Rana K. Gupta1,3, Nan Gao1,3, Regina K. Gorski1,2, Peter White1, Olga T. Hardy1, Kiran Rafiq1, John E. Brestelli1, Guang Chen2, Christian J. Stoeckert, Jr.1,2,, and Klaus H. Kaestner1,4

1 Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
2 Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Abstract: The failure to expand functional pancreatic beta-cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is the principle mechanism for beta-cell expansion in adult mice. Here we demonstrate that the proliferative response of beta-cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4{alpha} (HNF-4{alpha}), the gene that is mutated in Maturity-Onset Diabetes of the Young 1 (MODY1). Computational analysis of microarray expression profiles from isolated islets of mice lacking HNF-4{alpha} in pancreatic beta-cells reveals that HNF-4{alpha} regulates selected genes in the beta-cell, many of which are involved in proliferation. Using a physiological model of beta-cell expansion, we show that HNF-4{alpha} is required for beta-cell replication and the activation of the Ras/ERK signaling cascade in islets. This phenotype correlates with the down-regulation of suppression of tumorigenicity 5 (ST5) in HNF-4{alpha} mutants, which we identify as a novel regulator of ERK phosphorylation in beta-cells and a direct transcriptional target of HNF-4{alpha} in vivo. Together, these results indicate that HNF-4{alpha} is essential for the physiological expansion of adult beta-cell mass in response to increased metabolic demand.

Key Words: Ras • extracellular regulated kinase • mitogen activated protein kinase • beta-cells • HNF-4{alpha} • type 2 diabetes • gestational diabetes

Received for publication January 26, 2007. Accepted for publication February 9, 2007.

3 These authors contributed equally to this work.

4 Corresponding author.

E-MAIL kaestner{at}; FAX (215) 573-5892.

Supplemental material is available at

Article is online at

Elevated Mouse Hepatic Betatrophin Expression Does Not Increase Human {beta}-Cell Replication in the Transplant Setting.
Y. Jiao, J. Le Lay, M. Yu, A. Naji, and K. H. Kaestner (2014)
Diabetes 63, 1283-1288
   Abstract »    Full Text »    PDF »
DNA methylation is required for the control of stem cell differentiation in the small intestine.
K. L. Sheaffer, R. Kim, R. Aoki, E. N. Elliott, J. Schug, L. Burger, D. Schubeler, and K. H. Kaestner (2014)
Genes & Dev. 28, 652-664
   Abstract »    Full Text »    PDF »
The orphan nuclear receptors at their 25-year reunion.
S. E. Mullican, J. R. DiSpirito, and M. A. Lazar (2013)
J. Mol. Endocrinol. 51, T115-T140
   Abstract »    Full Text »    PDF »
Advancements and challenges in generating accurate animal models of gestational diabetes mellitus.
R. C. Pasek and M. Gannon (2013)
Am J Physiol Endocrinol Metab 305, E1327-E1338
   Abstract »    Full Text »    PDF »
Pdx-1 Activates Islet {alpha}- and {beta}-Cell Proliferation via a Mechanism Regulated by Transient Receptor Potential Cation Channels 3 and 6 and Extracellular Signal-Regulated Kinases 1 and 2.
H. L. Hayes, L. G. Moss, J. C. Schisler, J. M. Haldeman, Z. Zhang, P. B. Rosenberg, C. B. Newgard, and H. E. Hohmeier (2013)
Mol. Cell. Biol. 33, 4017-4029
   Abstract »    Full Text »    PDF »
Anks4b, a Novel Target of HNF4{alpha} Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic {beta}-Cells.
Y. Sato, M. Hatta, M. F. Karim, T. Sawa, F.-Y. Wei, S. Sato, M. A. Magnuson, F. J. Gonzalez, K. Tomizawa, T. Akaike, et al. (2012)
J. Biol. Chem. 287, 23236-23245
   Abstract »    Full Text »    PDF »
Loss of HGF/c-Met Signaling in Pancreatic {beta}-Cells Leads to Incomplete Maternal {beta}-Cell Adaptation and Gestational Diabetes Mellitus.
C. Demirci, S. Ernst, J. C. Alvarez-Perez, T. Rosa, S. Valle, V. Shridhar, G. P. Casinelli, L. C. Alonso, R. C. Vasavada, and A. Garcia-Ocana (2012)
Diabetes 61, 1143-1152
   Abstract »    Full Text »    PDF »
Islet-1 Regulates Arx Transcription during Pancreatic Islet {alpha}-Cell Development.
J. Liu, C. S. Hunter, A. Du, B. Ediger, E. Walp, J. Murray, R. Stein, and C. L. May (2011)
J. Biol. Chem. 286, 15352-15360
   Abstract »    Full Text »    PDF »
Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.
I. Sandovici, N. H. Smith, M. D. Nitert, M. Ackers-Johnson, S. Uribe-Lewis, Y. Ito, R. H. Jones, V. E. Marquez, W. Cairns, M. Tadayyon, et al. (2011)
PNAS 108, 5449-5454
   Abstract »    Full Text »    PDF »
Proteomic Analysis of Native Hepatocyte Nuclear Factor-4{alpha} (HNF4{alpha}) Isoforms, Phosphorylation Status, and Interactive Cofactors.
K. Daigo, T. Kawamura, Y. Ohta, R. Ohashi, S. Katayose, T. Tanaka, H. Aburatani, M. Naito, T. Kodama, S. Ihara, et al. (2011)
J. Biol. Chem. 286, 674-686
   Abstract »    Full Text »    PDF »
Hepatocyte Nuclear Factor-4{alpha} Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species.
M. Darsigny, J.-P. Babeu, E. G. Seidman, F.-P. Gendron, E. Levy, J. Carrier, N. Perreault, and F. Boudreau (2010)
Cancer Res. 70, 9423-9433
   Abstract »    Full Text »    PDF »
Glucose and aging control the quiescence period that follows pancreatic beta cell replication.
S. J. Salpeter, A. M. Klein, D. Huangfu, J. Grimsby, and Y. Dor (2010)
Development 137, 3205-3213
   Abstract »    Full Text »    PDF »
Rgs16 and Rgs8 in embryonic endocrine pancreas and mouse models of diabetes.
A. Villasenor, Z. V. Wang, L. B. Rivera, O. Ocal, I. W. Asterholm, P. E. Scherer, R. A. Brekken, O. Cleaver, and T. M. Wilkie (2010)
Dis. Model. Mech. 3, 567-580
   Abstract »    Full Text »    PDF »
Gestational Diabetes Mellitus Resulting From Impaired {beta}-Cell Compensation in the Absence of FoxM1, a Novel Downstream Effector of Placental Lactogen.
H. Zhang, J. Zhang, C. F. Pope, L. A. Crawford, R. C. Vasavada, S. M. Jagasia, and M. Gannon (2010)
Diabetes 59, 143-152
   Abstract »    Full Text »    PDF »
Hepatocyte nuclear factor 4{alpha} contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation.
J.-P. Babeu, M. Darsigny, C. R. Lussier, and F. Boudreau (2009)
Am J Physiol Gastrointest Liver Physiol 297, G124-G134
   Abstract »    Full Text »    PDF »
FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine.
B. B. Madison, L. B. McKenna, D. Dolson, D. J. Epstein, and K. H. Kaestner (2009)
J. Biol. Chem. 284, 5936-5944
   Abstract »    Full Text »    PDF »
Regulation of Pancreatic {beta} Cell Mass by Neuronal Signals from the Liver.
J. Imai, H. Katagiri, T. Yamada, Y. Ishigaki, T. Suzuki, H. Kudo, K. Uno, Y. Hasegawa, J. Gao, K. Kaneko, et al. (2008)
Science 322, 1250-1254
   Abstract »    Full Text »    PDF »
On the origin of the {beta} cell.
J. M. Oliver-Krasinski and D. A. Stoffers (2008)
Genes & Dev. 22, 1998-2021
   Abstract »    Full Text »    PDF »
HNF4A and Diabetes: Injury Before Insult?.
B. Z. Stanger (2008)
Diabetes 57, 1461-1462
   Full Text »    PDF »
ICA512 signaling enhances pancreatic -cell proliferation by regulating cyclins D through STATs.
H. Mziaut, S. Kersting, K.-P. Knoch, W.-H. Fan, M. Trajkovski, K. Erdmann, H. Bergert, F. Ehehalt, H.-D. Saeger, and M. Solimena (2008)
PNAS 105, 674-679
   Abstract »    Full Text »    PDF »
Regeneration in Liver and Pancreas: Time to Cut the Umbilical Cord?.
Y. Dor and B. Z. Stanger (2007)
Sci. STKE 2007, pe66
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882