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Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fundación La Caixa 2022 HR22-0253. Comunidad de Madrid P2022/BMD-7333 INMUNOVAR-CM Background Type 2 diabetes and obesity are leading causes of death and disability worldwide, being both risk factors for cardiovascular disease. Intestinal immune system is being shown to have a key role in insulin resistance (IR). Polymeric immunoglobulin receptor (PIGR) is a transmembrane protein which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A (IgA) and is widely expressed in mucosal epithelial cells. IgA levels are reduced in obesity and the loss of IgA in mice worsens insulin resistance and increases inflammation in adipose tissue. However, the specific role of PIGR in IR has not been fully elucidated. Aim To analyze the role of PIGR in systemic glucose metabolism. Methods To determine the impact of global silencing of Pigr on whole-body glucose metabolism, we metabolically characterized the Pigr-/- female mouse 60% fat diet (HFD). We performed glucose and insulin tolerance tests. In vivo and ex vivo adiposity was measured by dual x-ray absorptiometry (DXA) and adipose tissue depots weight, fasting glucose and insulin plasma levels were determined at endpoint. Circulating IgA levels were measured by ELISA and IgA deposition in liver and adipose tissue of control and Pigr-/- mice was determined by western blot and immunohistochemistry. Results As previously described, we show that IgA serum levels were highly increased in Pigr -/- mice. Besides, we demonstrate that IgA deposition in liver and adipose tissue was increased in these mice. We demonstrate that global deletion of Pigr results in whole-body glucose intolerance and IR mice fed HFD. Fasting glucose levels (169.24±24.49 mg/dl in Pigr -/- mice vs 142±27mg/dl in control mice) and fasting insulin levels (1.27±0.42 ng/ml in Pigr -/- mice vs 0.92±0.37 ng/ml in control mice) were significantly increased in Pigr -/- mice fed HFD for 17 weeks. No differences were found in lipid profile levels (triglycerides, HDL-c, VLDL+LDL-c and NEFA). Interestingly, Pigr-/- mice show significant increased adiposity (46±4.11 % adiposity vs 50.6±4.9 in control) measured by DXA, which results in a significant increase in body weight (BW), compared to control (BW gain over 20 weeks on HFD: 21.85± 3.06 gr in Pigr -/- mice vs 17.93±2.1 gr). mRNA expression of the β isoform of carbohydrate responsive-element binding protein (ChREBPβ) is significantly reduced (0.5 folds vs control group) in Pigr -/- adipose tissue, which might link the whole-body metabolic phenotype to ChREBP-dependent glucose sensing by adipose tissue. Conclusion Global Pigr deletion results in whole-body glucose intolerance and IR in female mice fed HFD. Our results suggest cell-intrinsic mechanisms of Pigr deletion as well as extracellular components (increased IgA serum levels and deposition in tissues) as potential triggers of systemic glucose metabolism disruption. Management of PIGR levels might be key for glucose-metabolism-related pathologies.
Botija et al. (Wed,) studied this question.