Lrtm1 - A Novel Sensor of Insulin Signaling and Regulator of Metabolism and Activity

Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here we show that Lrtm1 (Leucine Rich Repeats and Transmembrane Domains 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1 deficient mice exhibit reduced fat mass, increased lean mass, and enhanced glucose tolerance and insulin sensitivity compared to control mice, under both chow and high fat diet conditions. Lrtm1 whole-body deficiency also affects dopamine signaling in the brain leading to hyperactivity. The improvements in glucose and insulin tolerance, but not the behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. The effects are independent of the classical insulin receptor-Akt signaling. Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel post-receptor regulator of metabolic and behavioral activity.