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.
Article Highlights
- Insulin resistance is due to a combination of alteration in insulin signaling in both the classical insulin signaling pathway and changes at the postreceptor level, the majority of which remain unknown.
- In this study, we show that a molecule of previously unknown function, Lrtm1, is enriched in metabolic tissues, senses changes in insulin signaling in muscle, and serves as a regulator of metabolic homeostasis.
- Both whole-body and muscle-specific Lrtm1-deficient mice exhibited improved glucose and insulin tolerance without changing classical insulin receptor-Akt signaling. In addition, the whole-body Lrtm1 knockout mice exhibited altered dopamine signaling in the brain, leading to hyperactivity.
- Lrtm1 serves as a novel postreceptor regulator of metabolic and behavioral activity.
