Abstract
Pancreatic-derived factor (PANDER; also known as FAM3B) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and to serve a potential role in the onset or progression of type 2 diabetes (T2D). Despite having potentially pivotal pleiotropic roles in glycemic regulation and T2D, there has been limited generation of stable animal models for the investigation of PANDER function, and there are no models on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure-bred PANDER knockout C57BL/6 (PANKO-C57) model was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 model exhibited an enhanced metabolic phenotype, particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and C-peptide levels, whereas leptin levels were increased as compared with matched C57BL/6J wild-type mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic PKB/Akt and AMPK, along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared with wild-type C57BL/6 mice. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D.
Highlights
Pancreatic-derived factor (PANDER; known as FAM3B), discovered in 2002, is a 235-amino-acid protein that belongs to the family with sequence similarity 3 (FAM3) gene family (Zhu et al, 2002)
Hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic protein kinase B (PKB/Akt) and adenosine monophosphate-activated protein kinase (AMPK), along with mature sterol regulatory element-binding protein 1 (SREBP-1) expression in the PANDER knockout (PANKO)-C57 model
Distinct metabolic differences observed in the PANKO-C57 model as compared to those on a mixed genetic background In contrast to the previous mixed PANKO model, the PANKO-C57 mice demonstrated (1) enhanced glucose tolerance during glucose tolerance tests (GTTs) and fasting conditions, (2) decreased fasting insulin and C-peptide levels, (3) increased fasting leptin levels, (4) increased body weight and (5) increased phosphorylated Akt, phosphorylated AMPK and mature sterol-regulatory elementbinding proteins (SREBPs)-1 levels
Summary
Pancreatic-derived factor (PANDER; known as FAM3B), discovered in 2002, is a 235-amino-acid protein that belongs to the family with sequence similarity 3 (FAM3) gene family (Zhu et al, 2002). PANDER comprises two anti-parallel β sheets lined by three short helices arranged to form a highly conserved water-filled cavity that does not resemble any currently known cytokine, thereby contradicting the earlier predictive models (Johansson et al, 2013) This structure is conserved among other members of the FAM3 family. There is a strong need for novel animal models on congenic backgrounds with discernible phenotypes for the investigation of PANDER function
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