Liver-specific overexpression of pancreatic-derived factor (PANDER) induces fasting hyperglycemia in mice.
The pancreas-derived hormones, insulin and glucagon, are the two main regulators of glucose homeostasis. However, their actions can be modulated by the presence of other circulating factors including cytokines. Pancreatic-derived factor (PANDER) is a novel cytokine-like molecule secreted from the endocrine pancreas, but its biological function is currently unknown. To address this, we employed adenoviral gene delivery to develop a novel murine model of PANDER overexpression, which we used to study PANDER's effect on glucose homeostasis. Although serum metabolites in fed mice were unaffected by PANDER overexpression, fasting glucose, insulin, and corticosterone levels were significantly elevated. Additionally, PANDER-overexpressing mice displayed elevated glucose and insulin levels during a glucose tolerance test, indicating that glucose tolerance was impaired. However, there were no defects in glucose-stimulated insulin secretion or peripheral insulin sensitivity. Elevated transcription of hepatic gluconeogenic genes, PEPCK and G6Pase accompanied the fasting hyperglycemia observed in PANDER-overexpressing animals. Similarly, treatment of primary hepatocytes with PANDER-expressing adenovirus or PANDER-enriched conditioned medium elevated gluconeogenic gene expression and glucose output. PANDER treatment also resulted in higher levels of Ser133-phosphorylated cAMP-response element-binding protein in hepatocytes stimulated with 8-bromo-cAMP and dexamethasone and higher levels of intracellular cAMP upon stimulation with forskolin. In summary, we provide the first report that identifies PANDER as a regulator of hepatic glucose metabolism, where it serves as a novel factor that amplifies hepatic cAMP and cAMP-response element-binding protein signaling to induce gluconeogenic gene expression and glucose output.
Wilson
Camella G
CG
University of Pennsylvania School of Medicine, 803B Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4399, USA. cgwilson@mail.med.upenn.edu
Schupp
Michael
M
Burkhardt
Brant R
BR
Wu
Jianmei
J
Young
Robert A
RA
Wolf
Bryan A
BA
D000256:Adenoviridae; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D017077:Culture Media, Conditioned; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism*; D015870:Gene Expression; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
D001786:Blood Glucose; D017077:Culture Media, Conditioned; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D007328:Insulin; C504749:PANDER protein, mouse; D000242:Cyclic AMP