Abstract
Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1). Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin.
Highlights
Insulin resistance or Type 2 Diabetes mellitus (T2DM) are often associated with impaired insulin signaling [1,2,3]
Ad36, a human adenovirus increases cellular glucose uptake and improves hyperglycemia in mice fed a high fat (HF) diet[4] and this action of Ad36 appears to be independent of proximal insulin signaling[5]
To establish a Tet-regulated inducible cell line, the pTet-On vector was first transfected into 3T3-L1 cells
Summary
Insulin resistance or Type 2 Diabetes mellitus (T2DM) are often associated with impaired insulin signaling [1,2,3]. Most of the currently available anti-diabetic drugs depend on insulin signaling, which may be impaired. Anti-diabetic drugs that act partially or completely independent of insulin signaling may be more effective and desirable. Ad36, a human adenovirus increases cellular glucose uptake and improves hyperglycemia in mice fed a high fat (HF) diet[4] and this action of Ad36 appears to be independent of proximal insulin signaling[5]. E4orf may offer a novel template to develop better anti-diabetic drugs and is currently under investigation to help understand the underlying cellular signaling it modulates
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