The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner
Ashbeck, Erin L
Roche, Paul A
Truong, Sarah Mai
Wertheim, Betsy C
Klimentidis, Yann C
Renquist, Benjamin J
AffiliationUniv Arizona, Cellular & Mol Med
Univ Arizona, Canc Ctr
Univ Arizona, Mol & Cellular Biol
Univ Arizona, Dept Epidemiol & Biostat
Univ Arizona, Anim & Comparat Biomed Sci
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationBhagwandin C, Ashbeck EL, Whalen M, Bandola-Simon J, Roche PA, Szajman A, et al. (2018) The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. PLoS ONE 13(10): e0204898. https://doi.org/10.1371/journal.pone.0204898
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AbstractType 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells. MARCH1 was recently found to negatively regulate the cell surface levels of the insulin receptor via ubiquitination. This, in turn, impaired insulin sensitivity in mouse models. Here, we report that MARCH1-deficient (knockout; KO) female mice exhibit excessive weight gain and excessive visceral adiposity when reared on standard chow diet, without increased inflammatory cell infiltration of adipose tissue. By contrast, male MARCH1 KO mice had similar weight gain and visceral adiposity to wildtype (WT) male mice. MARCH1 KO mice of both sexes were more glucose tolerant than WT mice. The levels of insulin receptor were generally higher in insulin-responsive tissues (especially the liver) from female MARCH1 KO mice compared to males, with the potential to account in part for the differences between male and female MARCH1 KO mice. We also explored a potential role for MARCH1 in human type 2 diabetes risk through genetic association testing in publicly-available datasets, and found evidence suggestive of association. Collectively, our data indicate an additional link between immune function and diabetes, specifically implicating MARCH1 as a regulator of lipid metabolism and glucose tolerance, whose function is modified by sex-specific factors.
NoteOpen access journal.
VersionFinal published version
SponsorsNational Institutes of Health [1R56AI080756-01A2, CA87969, CA55075, DK58845]; University of Arizona; Intramural Research Program of the National Institutes of Health; Gene and Environment Initiatives in Type 2 Diabetes through the NIH Genes, Environment and Health Initiative [GEI] [U01HG004399]; NIH GEI [U01HG004424]; Northwestern University's Center for Genetic Medicine, Northwestern University; Northwestern Memorial Hospital; eMERGE Coordinating Center [U01HG04603]; NIH, NHGRI eMERGE Network [U01HG004609]; NIH [U01HG004424]; National Human Genome Research Institute (NHGRI); National Institute of General Medical Sciences (NIGMS); Vanderbilt CTSA from NCRR/NIH [UL1RR024975]
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