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. Overall design: The tibialis anterior muscle from 6-month-old Lrtm1 flox control and Lrtm1 ko mice that had a C57BL/6 background after a 3-h fast were studied by RNA-sequencing, n=4 per group.

胰岛素通过胰岛素受体（insulin receptor）调控肌肉组织中的葡萄糖摄取与代谢。本研究表明，功能尚未阐明且富集于胰岛素应答代谢组织的蛋白Lrtm1（Leucine Rich Repeats and Transmembrane Domains 1，亮氨酸重复序列与跨膜结构域1），可感知肌肉组织中胰岛素信号通路的变化，并作为代谢应答的调控因子发挥作用。因此，在普通饲料与高脂饲料喂养条件下，全身Lrtm1敲除小鼠与对照组小鼠相比，体脂量降低、瘦体重增加，葡萄糖耐受与胰岛素敏感性均得到改善。全身Lrtm1敲除还会影响大脑中的多巴胺信号通路，进而导致运动亢进。在骨骼肌特异性Lrtm1敲除（ko）小鼠中，同样可观察到葡萄糖耐受与胰岛素敏感性的改善，但未出现行为学或体成分的变化。上述效应不依赖于经典的胰岛素受体-Akt信号通路。综上，Lrtm1可感知胰岛素受体信号通路的变化，是一类新型的受体后代谢与行为活动调控因子。实验整体设计：对禁食3小时后、背景品系为C57BL/6的6月龄Lrtm1 flox对照小鼠与Lrtm1敲除（ko）小鼠的胫骨前肌进行RNA测序（RNA-sequencing）分析，每组n=4。