E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte

Abstract

Background/PurposeType 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism.MethodsWe have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes.ResultsUsing the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events.ConclusionWe conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

Adenovirus Protein E4-ORF1 Activation of PI3 Kinase Reveals Differential Regulation of Downstream Effector Pathways in Adipocytes

“…However, E4-ORF1-induced alterations in PI3K and Glut4 trafficking are not accounted for by changes in gene expression, demonstrating these are acute effects. Our findings do not agree with the results of a recent study where in adipose-Ad36 E4-ORF1 expressing mouse Ras/ERK/MAPK pathway was shown enriched in adipose tissue (Kusminski et al, 2015). These different results could reflect differences in activities of Ad36 and Ad5 E4-ORF1 proteins or difference in cell system versus tissue.…”

Hepatic Expression of Adenovirus 36 E4ORF1 Improves Glycemic Control and Promotes Glucose Metabolism Through AKT Activation

“…Collectively, these data indicate that Ad36E4ORF1 is not a typical sensitizer, mimetic, or secretagogue of insulin. Instead, it appears to have an insulin-sparing action (9), which reduces the need for insulin and, hence, reduces insulin levels.…”

“…Although Ad36E4ORF1 interacts with adipose tissue, skeletal muscle, and liver to modulate glucose disposal, the interaction of Ad36E4ORF1 with individual tissues involved in systemic glycemic control is unclear. A recent study showed that fat-specific inducible expression of Ad36E4ORF1 improves glycemic control in DIO mice (9). …”

An adenovirus-derived protein: A novel candidate for anti-diabetic drug development

“…This mouse model improved glycemic control transiently but predictably and reproducibly, in response to E4orf1 booster doses. Recently, Kusminski et al [29] also inducibly expressed E4orf1 in adipose tissue of high fat fed mice to improve glycemic control, indicating suitability of the model to further study the phenomenon.…”