Regulation of wingless-type MMTV integration site family (WNT) signalling in pancreatic islets from wild-type and obese mice.
OBJECTIVE
TCF7L2 is a type 2 diabetes susceptibility gene and downstream effector of canonical wingless-type MMTV integration site family (WNT) signalling. However, it is unknown whether this pathway is active in adult pancreatic islets in vivo, and whether it is regulated in obesity.


METHODS
We analysed activation of endogenous WNT signalling in the endocrine pancreas from wild-type and obese mice (ob/ob) using a reporter transgene (Topgal). Regulation of WNT signalling was compared using gene chip experiments from isolated pancreatic islets. Activation of canonical WNT signalling in pancreatic islets and the mouse beta cell line MIN6 was measured using immunoblotting for cytosolic beta-catenin.


RESULTS
Endogenous canonical WNT signalling was absent in the adult endocrine pancreas in both wild-type and obese mice. We identified WNT4 as an abundant WNT signalling molecule in adult pancreatic islets that is induced in two different insulin-resistant mouse models. Increased expression of WNT4 inhibited canonical WNT signalling in pancreatic islets and MIN6 cells.


CONCLUSIONS
Canonical WNT signalling is not active in adult beta cells in vivo. WNT4 provides a potential mechanism for suppression of canonical WNT signalling in obese mice.
Krützfeldt
J
J
Laboratory of Metabolic Diseases, The Rockefeller University, New York, NY, USA.
Stoffel
M
M
D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006946:Hyperinsulinism / Q000503:physiopathology; D007515:Islets of Langerhans / Q000502:physiology / Q000821:virology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D016662:Virus Integration; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000502:physiology
D001786:Blood Glucose; D051820:TCF Transcription Factors; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin; D012313:RNA