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

Herdenberg, Carl ; Mutie, Pascal M LU ; Billing, Ola ; Abdullah, Ahmad ; Strawbridge, Rona J ; Dahlman, Ingrid ; Tuck, Simon ; Holmlund, Camilla ; Arner, Peter and Henriksson, Roger , et al. (2021) In Communications Biology 4.
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, 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... (More)

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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publication status
published
subject
keywords
Adipogenesis/physiology, Adult, Aged, Animals, Body Mass Index, Bone Morphogenetic Proteins/metabolism, Caenorhabditis elegans, Diabetes Mellitus, Type 2/metabolism, Female, Fibroblasts/metabolism, Humans, Lipid Metabolism/physiology, Male, Membrane Glycoproteins/metabolism, Membrane Proteins/metabolism, Mice, Middle Aged, Prognosis, Risk Factors, Signal Transduction/physiology
in
Communications Biology
volume
4
article number
90
publisher
Nature Publishing Group
external identifiers
  • pmid:33469151
  • scopus:85099541477
ISSN
2399-3642
DOI
10.1038/s42003-020-01613-w
language
English
LU publication?
yes
id
534e05d3-b144-4c7e-80db-acc6d05e9487
date added to LUP
2022-05-24 12:33:09
date last changed
2024-06-13 15:30:47
@article{534e05d3-b144-4c7e-80db-acc6d05e9487,
  abstract     = {{<p>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.</p>}},
  author       = {{Herdenberg, Carl and Mutie, Pascal M and Billing, Ola and Abdullah, Ahmad and Strawbridge, Rona J and Dahlman, Ingrid and Tuck, Simon and Holmlund, Camilla and Arner, Peter and Henriksson, Roger and Franks, Paul W and Hedman, Håkan}},
  issn         = {{2399-3642}},
  keywords     = {{Adipogenesis/physiology; Adult; Aged; Animals; Body Mass Index; Bone Morphogenetic Proteins/metabolism; Caenorhabditis elegans; Diabetes Mellitus, Type 2/metabolism; Female; Fibroblasts/metabolism; Humans; Lipid Metabolism/physiology; Male; Membrane Glycoproteins/metabolism; Membrane Proteins/metabolism; Mice; Middle Aged; Prognosis; Risk Factors; Signal Transduction/physiology}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Communications Biology}},
  title        = {{LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1038/s42003-020-01613-w}},
  doi          = {{10.1038/s42003-020-01613-w}},
  volume       = {{4}},
  year         = {{2021}},
}