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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0204898
JournalPLoS One
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2018

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ubiquitin-protein ligase
Ubiquitin-Protein Ligases
glucose tolerance
Membranes
Lipids
Glucose
gender
mice
lipids
Medical problems
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
adiposity
Insulin Receptor
insulin resistance
Adiposity
adipose tissue
Insulin
Tissue
Weight Gain

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Bhagwandin, C., Ashbeck, E. L., Whalen, M., Bandola-Simon, J., Roche, P. A., Szajman, A., ... Lybarger, L. (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

The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. / Bhagwandin, Candida; Ashbeck, Erin L.; Whalen, Michael; Bandola-Simon, Joanna; Roche, Paul A.; Szajman, Adam; Truong, Sarah Mai; Wertheim, Betsy C.; Klimentidis, Yann C; Ishido, Satoshi; Renquist, Benjamin J; Lybarger, Lonnie.

In: PLoS One, Vol. 13, No. 10, e0204898, 01.10.2018.

Research output: Contribution to journalArticle

Bhagwandin, C, Ashbeck, EL, Whalen, M, Bandola-Simon, J, Roche, PA, Szajman, A, Truong, SM, Wertheim, BC, Klimentidis, YC, Ishido, S, Renquist, BJ & Lybarger, L 2018, 'The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner', PLoS One, vol. 13, no. 10, e0204898. https://doi.org/10.1371/journal.pone.0204898
Bhagwandin C, Ashbeck EL, Whalen M, Bandola-Simon J, Roche PA, Szajman A et al. The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. PLoS One. 2018 Oct 1;13(10). e0204898. https://doi.org/10.1371/journal.pone.0204898
Bhagwandin, Candida ; Ashbeck, Erin L. ; Whalen, Michael ; Bandola-Simon, Joanna ; Roche, Paul A. ; Szajman, Adam ; Truong, Sarah Mai ; Wertheim, Betsy C. ; Klimentidis, Yann C ; Ishido, Satoshi ; Renquist, Benjamin J ; Lybarger, Lonnie. / The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. In: PLoS One. 2018 ; Vol. 13, No. 10.
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