Liver-Specific Overexpression of Pancreatic-Derived Factor (PANDER) Induces Fasting Hyperglycemia in Mice

Abstract

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.

Quantitative proteomic profiling reveals hepatic lipogenesis and liver X receptor activation in the PANDER transgenic model

“…Evidence to date has demonstrated that PANDER can promote a selective hepatic insulin resistant (SHIR) phenotype whereby insulin signaling is partially inhibited and therefore hepatic glucose production and lipogenesis is increased (Robert-Cooperman et al, 2014), phenomena observed in T2D animal models and clinical human observations (Brown and Goldstein, 2008). Earlier studies demonstrated that PANDER overexpression induces fasting hyperglycemia by upregulating gluconeogenic gene pathways and subsequently increasing hepatic glucose output in mice (Robert-Cooperman et al, 2014, Li et al, 2011, Wilson, Schupp, Burkhardt et al, 2010). These effects were attributed to the presence of increased transcript levels of PEPCK and Glucose 6-phosphatase (G6Pase) due to inhibited phosphorylation of critical insulin signaling molecules such as Akt and AMPK.…”

PANDER transgenic mice display fasting hyperglycemia and hepatic insulin resistance

“…PEPCK controls the rate limiting step in gluconeogenesis and suppression is expected under conditions of hyperglycemia and insulin secretion (Hanson & Reshef 1997). ACSL1 is an isozyme of the longchain fatty-acid-coenzyme A ligase family that convert Wilson et al (2010) and Li et al (2011), respectively. PANTG describes summary of results from currently described study free long-chain fatty acids into fatty acyl-CoA esters, and serve a central role in lipid biosynthesis (Ning et al 2011).…”

“…Wilson et al (2010) evaluated hepatic PANDER overexpression achieved through adenoviral delivery. This model revealed fasting hyperglycemia, hyperinsulinemia, and elevated corticosterone levels.…”

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…Isolation of hepatocytes was performed essentially as previously described 56 . In brief, livers of anesthetized 6-to 12-week-old male WT C57BL/6J or Ho-1 −/− mice were perfused with digestion buffer containing 5,000 U collagenase (Worthington Biochemical).…”