LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes

Abstract Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, LRIG3 has hindered detailed elucidation their physiological functions. Here, we show that Lrig -null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis bone morphogenetic protein (BMP) signaling. In contrast, transforming factor-beta (TGF-?) receptor tyrosine kinase (RTK) signaling appeared unaltered cells. The BMP defect was rescued by ectopic expression LRIG1 or but not LRIG2. Caenorhabditis elegans with mutant LRIG / sma-10 variants also exhibited a lipid storage defect. Human were strongly associated increased body mass index (BMI) yet protected against type 2 diabetes; these effects likely mediated altered adipocyte morphology. These results demonstrate function evolutionarily conserved metabolism implications for human disease.