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

Carl Herdenberg,Peter Arner,Rona J Strawbridge,Camilla Holmlund,Ola Billing,Paul W Franks,Pascal M Mutie,Roger Henriksson,Simon Tuck,Håkan Hedman,Ahmad Abdullah,Ingrid Dahlman

doi:10.1038/s42003-020-01613-w

Carl Herdenberg, Peter Arner + Show 10 more

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https://doi.org/10.1038/s42003-020-01613-w

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

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Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions
The proliferation rates were similar between the wild-type and Lrig-null mouse embryonic fibroblasts (MEFs), both under standard cell culture conditions in 10% fetal bovine serum (FBS) (Supplementary Fig. 1c) and under proliferation-limiting FBS concentrations, the Lrig-null MEFs showed a higher apparent proliferation rate than the wild-type MEFs with 5% FBS (Supplementary Fig. 1d)
We analyzed basic metabolic functions on a Seahorse XF analysis platform. These analyses did not reveal any significant difference between the wild-type and Lrig-null MEF lines with regard to their aerobic or anaerobic responses, as measured by the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively (Supplementary Fig. 1f, g)

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Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease. Numerous reports have indicated that LRIG proteins are important etiological and prognostic factors in cancer[3,4] In most cases, these roles have been attributed to the ability of LRIG1 to negatively regulate various receptor tyrosine kinases (RTKs)[5,6,7,8,9,10,11]. The phosphorylated SMAD1/5/8 complex recruits the co-SMAD

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