MAPK/ERK signaling regulates insulin sensitivity to control glucose metabolism in Drosophila

Abstract

Insulin-like signaling is an important and conserved physiological regulator of growth and metabolism in multicellular animals. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, due to less glucose uptake by liver and fat and other tissues, which is a hallmark of diabetes.

While the core components of insulin-like pathway have been well established, the mechanisms that adjust insulin responsiveness are only known to a limited extent. A genetic screen in Drosophila that was designed to identify regulators of cellular insulin sensitivity in an in vivo context was done in our lab. This screen identified kinase suppressor of ras (ksr), an essential scaffold protein involved in MAPK/ERK signaling, as an enhancer of FoxO overexpression phenotype. Based on this screen, surprisingly, I discovered cross-talk between the epidermal growth factor receptor (EGFR)-activated MAPK/ERK and insulin-like signaling pathways. Cellular insulin resistance observed was due to downregulation of insulin-like receptor (inr) gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway regulates inr expression via the ETS-1 transcription factor Pointed. This regulation permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels, as failure of this regulation in the fat body leads to elevated circulating glucose levels, likely reflecting impaired clearance of dietary glucose from the circulation by the fat body.

Overall, I provide evidence for a regulatory feed-forward mechanism through PI3K and InR that allows for dynamic transient responsiveness as well as more stable, long lasting modulation of insulin responsiveness by growth factor receptor signaling. The combination of MAPK/ERK and insulin-like signaling pathways may contribute to robustness, allowing metabolism to be appropriately responsive to physiological inputs, while mitigating the effects of biological noise.