Paneth cells regulate diet-induced obesity and trafficking of inflammatory immune cells into adipose tissues

Abstract

Abstract Paneth cells regulate many key aspects of gastrointestinal health through the antimicrobial products and cytokines they produce. Loss or defective Paneth cell functions leads to dysbiosis and is one of the causes of Inflammatory Bowel Disease (IBD). The prevalence of obesity is growing in the general population and among recently diagnosed IBD patients, leading to the speculation that obesity increases IBD incidence, but the underlying mechanisms remain to be elucidated. We addressed whether Paneth cells of the small intestine play a role in the development of obesity. For this purpose, control wild-type C57BL/6 and Sox9ΔIEC mice, which lack Paneth cells due to Sox9 gene deletion within the intestinal epithelium (Sox9ΔIEC mice), were fed a high fat diet for 13 weeks. Though the consumption of food was similar between the 2 groups, weekly measurement of body weight showed that Sox9ΔIEC mice gained weight much faster and ultimately became more obese than the wild-type mice. The Sox9ΔIEC mice also developed larger abdominal fats, which included increased numbers of inflammatory macrophages (p<0.05) and neutrophils (p<0.05). Interestingly, B cells were the most increased (p<0.01) immune cells population in white fat tissues of Sox9ΔIEC mice. When compared to control mice, the Sox9ΔIEC mice displayed impaired glucose tolerance (p<0.0001) indicating that these mice also developed a metabolic disorder. Finally, the in vivo FITC-dextran permeability assay showed that Sox9ΔIEC mice on high-fat diet have increased intestinal permeability (p<0.05). These results suggest a new role for Paneth cells as regulators of diet-induced obesity via their impact on gut immune homeostasis and recruitment of immune cells into omental fat tissues.