Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and β-cell mass.
Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic β-cells of adult mice. atRA signaling was ablated in β-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-α mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in β-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in β-cell mass and insulin per β-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both β-cell function and mass, and provide insights into molecular mechanisms underlying these actions.
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Pierre-Jacques
PJ
Brun
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Ambar
A
Grijalva
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Richard
R
Rausch
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Elizabeth
E
Watson
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Jason J
JJ
Yuen
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Bhaskar C
BC
Das
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Koichi
K
Shudo
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Hiroyuki
H
Kagechika
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Rudolph L
RL
Leibel
Departments of *Medicine and Pediatrics and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY USA; Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; Research Foundation Itsuu Laboratory, Tokyo, Japan; and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan wsb2@columbia.edu.
William S
WS
Blaner
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005838:Genotype; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C045073:Cre recombinase; D019426:Integrases
Cre recombinase; dominant-negative RAR; glucagon; pancreatic islet; retinoid