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

Date Published: October 24, 2018

Publisher: Public Library of Science

Author(s): Candida Bhagwandin, Erin L. Ashbeck, Michael Whalen, Joanna Bandola-Simon, Paul A. Roche, Adam Szajman, Sarah Mai Truong, Betsy C. Wertheim, Yann C. Klimentidis, Satoshi Ishido, Benjamin J. Renquist, Lonnie Lybarger, Makoto Kanzaki.


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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Metabolic syndrome represents one of the most pressing public health concerns worldwide. A general feature of metabolic syndrome is insulin resistance, hyperinsulinemia, and hyperglycemia [1, 2]. Insulin normally enhances glucose uptake by white adipose tissue and muscle [3], while suppressing hepatic gluconeogenesis [4] and encouraging whole body glucose disposal [5, 6]. Insulin-resistance, in turn, leads to a dysregulation of glucose metabolism and chronically results in overt type 2 diabetes mellitus [1].

Until recently, our knowledge of MARCH1 function came from the study of its role in antigen presentation to T cells [23, 34]. However, at least in overexpression studies, MARCH1 could regulate other molecules, as well [21]. Nagarajan, et al. recently found that MARCH1 causes degradation of the insulin receptor. MARCH1 loss improved insulin sensitivity in male and female mice on a normal chow diet, and MARCH1 did not alter weight gain or adiposity in male mice on chow diet [27]. We made similar findings in male mice, but noted that female chow-fed MARCH1 KO mice gained more weight and had more VAT than WT controls. The enhanced glucose uptake and resulting lipogenesis may explain the increased adiposity in female mice, but this same mechanism would be expected to induce similar effects in male mice. The increased adipose tissue lipid storage in females would reduce ectopic fat deposits and improve insulin action [35].




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