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

## TL;DR

Removing C3 in pancreatic beta-cells worsens obesity-related metabolic issues and insulin resistance in mice.

## Contribution

Beta-cell-specific C3 knockout mice reveal a novel role for C3 in protecting against obesity-induced metabolic dysfunction.

## Key findings

- Beta-C3-KO mice on high-fat diet gained more weight and had higher blood glucose and insulin levels.
- Increased proinsulin and insulin levels were observed in Beta-C3-KO mice, indicating impaired beta-cell function.
- C3 deficiency in beta-cells may worsen glucose control in obese individuals treated with C3 inhibitors.

## Abstract

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.

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.

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.

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.

•We investigated functions of protein C3 by creating a beta-cell specific C3 knockout mouse (Beta-C3-KO).•We previously showed that C3–KO clonal beta-cells have decreased autophagy and increased insulin content and secretion.•Beta-C3-KO mice gained more weight on high fat diet (HFD), with higher serum insulin and proinsulin levels.•An interaction between increased insulin and high calory availability (HFD) could be responsible for weight gain.•Obese patients may require monitoring if treated with C3 inhibitors, as beta-cell C3 disruption may worsen glucose control.

We investigated functions of protein C3 by creating a beta-cell specific C3 knockout mouse (Beta-C3-KO).

We previously showed that C3–KO clonal beta-cells have decreased autophagy and increased insulin content and secretion.

Beta-C3-KO mice gained more weight on high fat diet (HFD), with higher serum insulin and proinsulin levels.

An interaction between increased insulin and high calory availability (HFD) could be responsible for weight gain.

Obese patients may require monitoring if treated with C3 inhibitors, as beta-cell C3 disruption may worsen glucose control.