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

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.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
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

Mutie, Pascal MLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)pa4264mu (author)
Billing, Ola,1981-Umeå universitet,Umeå University,Kirurgi(Swepub:umu)olabig00 (author)
Abdullah, AhmadUmeå universitet,Umeå University,Onkologi(Swepub:umu)ahab0021 (author)
Strawbridge, Rona JKarolinska Institutet,Karolinska Institute,University of Glasgow (author)
Dahlman, IngridKarolinska Institutet,Karolinska Institute (author)
Tuck, SimonUmeå universitet,Umeå University,Umeå centrum för molekylär medicin (UCMM)(Swepub:umu)situ0001 (author)
Holmlund, CamillaUmeå universitet,Umeå University,Onkologi(Swepub:umu)caho0001 (author)
Arner, PeterKarolinska Institutet (author)
Henriksson, RogerUmeå universitet,Umeå University,Onkologi(Swepub:umu)rohe0003 (author)
Franks, Paul WLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-plf (author)
Hedman, HåkanUmeå universitet,Umeå University,Onkologi(Swepub:umu)hahe0001 (author)
Umeå UniversityOnkologi (creator_code:org_t)

By the author/editor: Herdenberg, Carl; Mutie, Pascal M; Billing, Ola, 19 ...; Abdullah, Ahmad; Strawbridge, Ron ...; Dahlman, Ingrid; show more...; Tuck, Simon; Holmlund, Camill ...; Arner, Peter; Henriksson, Roge ...; Franks, Paul W; Hedman, Håkan; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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