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

AIMS/HYPOTHESIS: 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. METHODS: CR...

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Autores principales: Mousavy Gharavy, S. Neda, Owen, Bryn M., Millership, Steven J., Chabosseau, Pauline, Pizza, Grazia, Martinez-Sanchez, Aida, Tasoez, Emirhan, Georgiadou, Eleni, Hu, Ming, Fine, Nicholas H. F., Jacobson, David A., Dickerson, Matthew T., Idevall-Hagren, Olof, Montoya, Alex, Kramer, Holger, Mehta, Zenobia, Withers, Dominic J., Ninov, Nikolay, Gadue, Paul J., Cardenas-Diaz, Fabian L., Cruciani-Guglielmacci, Céline, Magnan, Christophe, Ibberson, Mark, Leclerc, Isabelle, Voz, Marianne, Rutter, Guy A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829492/
https://www.ncbi.nlm.nih.gov/pubmed/33492421
http://dx.doi.org/10.1007/s00125-020-05350-x
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author Mousavy Gharavy, S. Neda
Owen, Bryn M.
Millership, Steven J.
Chabosseau, Pauline
Pizza, Grazia
Martinez-Sanchez, Aida
Tasoez, Emirhan
Georgiadou, Eleni
Hu, Ming
Fine, Nicholas H. F.
Jacobson, David A.
Dickerson, Matthew T.
Idevall-Hagren, Olof
Montoya, Alex
Kramer, Holger
Mehta, Zenobia
Withers, Dominic J.
Ninov, Nikolay
Gadue, Paul J.
Cardenas-Diaz, Fabian L.
Cruciani-Guglielmacci, Céline
Magnan, Christophe
Ibberson, Mark
Leclerc, Isabelle
Voz, Marianne
Rutter, Guy A.
author_facet Mousavy Gharavy, S. Neda
Owen, Bryn M.
Millership, Steven J.
Chabosseau, Pauline
Pizza, Grazia
Martinez-Sanchez, Aida
Tasoez, Emirhan
Georgiadou, Eleni
Hu, Ming
Fine, Nicholas H. F.
Jacobson, David A.
Dickerson, Matthew T.
Idevall-Hagren, Olof
Montoya, Alex
Kramer, Holger
Mehta, Zenobia
Withers, Dominic J.
Ninov, Nikolay
Gadue, Paul J.
Cardenas-Diaz, Fabian L.
Cruciani-Guglielmacci, Céline
Magnan, Christophe
Ibberson, Mark
Leclerc, Isabelle
Voz, Marianne
Rutter, Guy A.
author_sort Mousavy Gharavy, S. Neda
collection PubMed
description AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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 Ca(2+). Binding partners for both included secretory-granule-localised PTPRN2/phogrin. CONCLUSIONS/INTERPRETATION: 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. DATA AVAILABILITY: 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. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-020-05350-x.
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spelling pubmed-78294922021-01-25 Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis Mousavy Gharavy, S. Neda Owen, Bryn M. Millership, Steven J. Chabosseau, Pauline Pizza, Grazia Martinez-Sanchez, Aida Tasoez, Emirhan Georgiadou, Eleni Hu, Ming Fine, Nicholas H. F. Jacobson, David A. Dickerson, Matthew T. Idevall-Hagren, Olof Montoya, Alex Kramer, Holger Mehta, Zenobia Withers, Dominic J. Ninov, Nikolay Gadue, Paul J. Cardenas-Diaz, Fabian L. Cruciani-Guglielmacci, Céline Magnan, Christophe Ibberson, Mark Leclerc, Isabelle Voz, Marianne Rutter, Guy A. Diabetologia Article AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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 Ca(2+). Binding partners for both included secretory-granule-localised PTPRN2/phogrin. CONCLUSIONS/INTERPRETATION: 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. DATA AVAILABILITY: 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. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-020-05350-x. Springer Berlin Heidelberg 2021-01-25 2021 /pmc/articles/PMC7829492/ /pubmed/33492421 http://dx.doi.org/10.1007/s00125-020-05350-x Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mousavy Gharavy, S. Neda
Owen, Bryn M.
Millership, Steven J.
Chabosseau, Pauline
Pizza, Grazia
Martinez-Sanchez, Aida
Tasoez, Emirhan
Georgiadou, Eleni
Hu, Ming
Fine, Nicholas H. F.
Jacobson, David A.
Dickerson, Matthew T.
Idevall-Hagren, Olof
Montoya, Alex
Kramer, Holger
Mehta, Zenobia
Withers, Dominic J.
Ninov, Nikolay
Gadue, Paul J.
Cardenas-Diaz, Fabian L.
Cruciani-Guglielmacci, Céline
Magnan, Christophe
Ibberson, Mark
Leclerc, Isabelle
Voz, Marianne
Rutter, Guy A.
Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
title Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
title_full Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
title_fullStr Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
title_full_unstemmed Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
title_short Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
title_sort sexually dimorphic roles for the type 2 diabetes-associated c2cd4b gene in murine glucose homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829492/
https://www.ncbi.nlm.nih.gov/pubmed/33492421
http://dx.doi.org/10.1007/s00125-020-05350-x
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