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 repeat and transmembrane domain 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 a reduced percentage of fat mass, an increased percentage of lean mass, and an enhanced glucose tolerance and insulin sensitivity compared with 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 behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. These effects occur with no change in classical insulin receptor-Akt signaling. Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel postreceptor regulator of metabolic and behavioral activity.