PUBLICATION

Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

Authors
Mousavy Gharavy, S.N., Owen, B.M., Millership, S.J., Chabosseau, P., Pizza, G., Martinez-Sanchez, A., Tasoez, E., Georgiadou, E., Hu, M., Fine, N.H.F., Jacobson, D.A., Dickerson, M.T., Idevall-Hagren, O., Montoya, A., Kramer, H., Mehta, Z., Withers, D.J., Ninov, N., Gadue, P.J., Cardenas-Diaz, F.L., Cruciani-Guglielmacci, C., Magnan, C., Ibberson, M., Leclerc, I., Voz, M., Rutter, G.A.
ID
ZDB-PUB-210126-14
Date
2021
Source
Diabetologia   64(4): 850-864 (Journal)
Registered Authors
Ninov, Nikolay, Voz, Marianne
Keywords
C2CD4A/B, Follicle-stimulating hormone, Genome-wide association studies, Glucose homeostasis, Type 2 diabetes
MeSH Terms
  • Mice, Inbred C57BL
  • Insulin-Secreting Cells/metabolism*
  • Homeostasis
  • Male
  • Animals
  • Pituitary Gland/metabolism*
  • Follicle Stimulating Hormone/blood
  • Weight Gain
  • Biomarkers/blood
  • Female
  • Insulin/blood
  • Zebrafish Proteins/blood
  • Zebrafish Proteins/genetics
  • Blood Glucose/genetics
  • Blood Glucose/metabolism*
  • Zebrafish/blood
  • Zebrafish/genetics
  • Genotype
  • Sex Characteristics
  • Humans
  • Mice, Knockout
  • Phenotype
(all 22)
PubMed
33492421 Full text @ Diabetologia
Abstract
Variants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B.
CRISPR/Cas9-induced global C2cd4b-knockout mice and zebrafish larvae with c2cd4a deletion were used to study the role of this gene in glucose homeostasis. C2 calcium dependent domain containing protein (C2CD)4A and C2CD4B constructs tagged with FLAG or green fluorescent protein were generated to investigate subcellular dynamics using confocal or near-field microscopy and to identify interacting partners by mass spectrometry.
Systemic inactivation of C2cd4b in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female C2cd4b mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC, p = 0.01) and defective in vivo, but not in vitro, insulin secretion (p = 0.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (p = 0.003). In sharp contrast, male C2cd4b null mice displayed essentially normal glucose tolerance but an increase in body weight (p < 0.001) and fasting blood glucose (p = 0.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic beta cell function at larval stages in C2cd4a null zebrafish. Fasting blood glucose levels were also unaltered in adult C2cd4a-null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca2+. Binding partners for both included secretory-granule-localised PTPRN2/phogrin.
Our studies suggest that C2cd4b may act centrally in the pituitary to influence sex-dependent circuits that control pancreatic beta cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in humans.
The datasets generated and/or analysed during the current study are available in the Biorxiv repository ( www.biorxiv.org/content/10.1101/2020.05.18.099200v1 ). RNA-Seq (GSE152576) and proteomics (PXD021597) data have been deposited to GEO ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152576 ) and ProteomeXchange ( www.ebi.ac.uk/pride/archive/projects/PXD021597 ) repositories, respectively.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
tud202TgTransgenic Insertion
    ulg064TgTransgenic Insertion
      ulg065
        Small Deletion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        c2cd4aCRISPR1-c2cd4aCRISPR
        c2cd4aCRISPR2-c2cd4aCRISPR
        1 - 2 of 2
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        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        GCaMPEFGGCaMP
        RFPEFGRFP
        1 - 3 of 3
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        Mapping
        No data available