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PLoS One. 2018 Oct 24;13(10):e0204898. doi: 10.1371/journal.pone.0204898. eCollection 2018.

The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner.

Author information

1
Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America.
2
University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America.
3
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.
4
Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.
5
Mel and Enid Zuckerman College of Public Health, Department of Epidemiology and Biostatistics, University of Arizona, Tucson, Arizona, United States of America.
6
Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan.
7
Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America.

Abstract

Type 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.

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