Background

Ameliorating hyperinsulinemia is a goal of comprehensive obesity management.Transgenic expression of E4orf1 (E4), a virus-derived protein, directly improves glycemic control and thus reduces endogenous insulin response to glucose load in mice, without altering insulin sensitivity.This model allowed a unique opportunity to determine the effect of reduction in insulin on its role beyond glycemic control. Accordingly, we observed that E4-induced reduction in endogenous insulin reduces the gene expression of hepatic lipogenesis.Here we investigated key metabolic functions that could be potentially affected due to reduced endogenous insulin levels.

Methods

About 29wk old C57Bl/6J wild type (WT; n=14) or transgenic mice that expressed E4orf1 in adipose tissue upon doxycycline (Dox) ingestion (E4; n=6) started chow diet with Dox for 6wk, followed by 10wk of a 60% high-fat diet (HFD) with Dox.Body fat %, and serum glucose and insulin for 2 h upon oral glucose load, were measured at weeks 0, 6, and 16.

Results

After 6wk of the chow-Dox diet, E4 mice reduced whereas WT mice increased % body fat, weight, and 2h area under the curve (AUC) for insulin in response to glucose load (all p<.05).On HFD, the increase in % body fat, body weight and the insulin AUC in response to glucose load were significantly lower for the E4 group. Upon sacrifice, E4 mice significantly lowered adipose tissue weight, hepatic triglycerides (TG), serum Free Fatty Acid, but increased serum TG.Combined mRNA and western blot data suggested that E4 decreased lipogenesis and increased lipolysis in adipose tissue, and reduced hepatic de novo lipogenesis and increased lipid export.

Conclusions

E4 expression in adipose tissue lowers hepatic TG accumulation, body fat, improves glycemic control and lowers endogenous insulin response.Importantly, this study highlights the concept that reduced requirement of endogenous insulin may also influence key functions related to lipid metabolism.