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Beta-cell-specific C3 deficiency exacerbates metabolic dysregulation and insulin resistance in obesity

King, Ben C. LU orcid ; Colineau, Lucie LU ; Slaby, Julia LU ; Kolodziej, Olga LU ; Dandavate, Vaishnavi LU orcid ; Olsson, Robin LU orcid ; Fex, Malin LU and Blom, Anna M. LU orcid (2026) In Molecular Metabolism 103.
Abstract

Background: C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool of C3 also protects beta-cells from cytokine-induced apoptosis. Methods: We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. These mice were placed on high-fat diet (HFD), blood glucose and insulin measurements taken over time, and tissues examined at endpoint by qPCR and immunofluorescence. Results: While no differences were found... (More)

Background: C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool of C3 also protects beta-cells from cytokine-induced apoptosis. Methods: We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. These mice were placed on high-fat diet (HFD), blood glucose and insulin measurements taken over time, and tissues examined at endpoint by qPCR and immunofluorescence. Results: While no differences were found between in baseline metabolic performance when comparing floxed controls and beta-C3KO mice, significant differences were found when mice were put on high-fat diet (HFD). Beta-C3-KO mice gained more weight, exhibited higher fasting blood glucose and insulin levels, and showed signs of adipose tissue inflammation and insulin resistance. Consistent with previous results showing that C3 alleviates beta-cell stress, increased amounts of unprocessed pro-insulin were found in the circulation of HFD-fed beta-C3-KO mice, as well as in islets from these mice. Beta-C3-KO HFD mouse islets also had a higher proportion of insulin staining, and isolated islets released more insulin in vitro. Conclusion: The interaction of increased insulin secretion and HFD leads to enhanced weight gain. Cell-intrinsic expression of C3 is important for optimal function of mouse pancreatic beta-cells under metabolic pressure in vivo.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Beta-cell, C3, Insulin resistance, Obesity
in
Molecular Metabolism
volume
103
article number
102302
publisher
Elsevier
external identifiers
  • scopus:105025255468
  • pmid:41386533
ISSN
2212-8778
DOI
10.1016/j.molmet.2025.102302
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s)
id
58690f2a-7ef1-453a-a63f-abcea61cb4ea
date added to LUP
2026-03-24 16:22:09
date last changed
2026-04-07 17:41:39
@article{58690f2a-7ef1-453a-a63f-abcea61cb4ea,
  abstract     = {{<p>Background: C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool of C3 also protects beta-cells from cytokine-induced apoptosis. Methods: We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. These mice were placed on high-fat diet (HFD), blood glucose and insulin measurements taken over time, and tissues examined at endpoint by qPCR and immunofluorescence. Results: While no differences were found between in baseline metabolic performance when comparing floxed controls and beta-C3KO mice, significant differences were found when mice were put on high-fat diet (HFD). Beta-C3-KO mice gained more weight, exhibited higher fasting blood glucose and insulin levels, and showed signs of adipose tissue inflammation and insulin resistance. Consistent with previous results showing that C3 alleviates beta-cell stress, increased amounts of unprocessed pro-insulin were found in the circulation of HFD-fed beta-C3-KO mice, as well as in islets from these mice. Beta-C3-KO HFD mouse islets also had a higher proportion of insulin staining, and isolated islets released more insulin in vitro. Conclusion: The interaction of increased insulin secretion and HFD leads to enhanced weight gain. Cell-intrinsic expression of C3 is important for optimal function of mouse pancreatic beta-cells under metabolic pressure in vivo.</p>}},
  author       = {{King, Ben C. and Colineau, Lucie and Slaby, Julia and Kolodziej, Olga and Dandavate, Vaishnavi and Olsson, Robin and Fex, Malin and Blom, Anna M.}},
  issn         = {{2212-8778}},
  keywords     = {{Beta-cell; C3; Insulin resistance; Obesity}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Molecular Metabolism}},
  title        = {{Beta-cell-specific C3 deficiency exacerbates metabolic dysregulation and insulin resistance in obesity}},
  url          = {{http://dx.doi.org/10.1016/j.molmet.2025.102302}},
  doi          = {{10.1016/j.molmet.2025.102302}},
  volume       = {{103}},
  year         = {{2026}},
}