Distinct housing conditions reveal a major impact of adaptive immunity on the course of obesity-induced type 2 diabetes

Abstract

Obesity is associated with adipose tissue inflammation, insulin resistance and the development of type 2 diabetes. However, our knowledge is mostly based on conventional murine models and promising pre-clinical studies rarely translated into successful therapies. There is a growing awareness of the limitations of studies in laboratory mice, housed in abnormally hygienic specific pathogen-free (SPF) conditions, as relevant aspects of the human immune system remain unappreciated. Here, we assessed the impact of housing conditions on adaptive immunity and metabolic disease processes during high-fat diet. We therefore compared diet-induced obesity in SPF mice with those housed in non-SPF, so called "antigen exposed" (AE) conditions. Surprisingly, AE mice fed a high-fat diet maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. In contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of high-fat diet AE mice accompanied by the development of nonalcoholic steatohepatitis-like liver pathology. Thus, our data demonstrate the impact of housing conditions on metabolic alterations. Studies in AE mice, in which physiological microbial exposure was restored, could provide a tool for revealing therapeutic targets for immune-based interventions for type 2 diabetes patients. Christiane Gras and Francesca Liersch for assistance with experimental procedures and Benjamin Tiburzy from Biolegend for helpful comments on the gating strategy. Furthermore, we thank Mario Thiele for assistance with pancreas sections. Author ContributionsStatement: J.S.-K. planned the study, wrote the manuscript, performed experiments and analyzed data, J.K. did immunostaining of liver and pancreas sections, S.B. helped with metabolic experiments, M.S. contributed to the selection of antibody panels and provided help with flow cytometry analysis, M.v.-H. contributed to conception and design of the study, A.K. performed CD3 staining of pancreas sections, K.S.-B. contributed to the invention of the AE mouse model, K.M. planned and carried out the clinical study "Effects of negative energy balance on muscle mass regulation"

Virus-like particles containing multiple antigenic proteins of Toxoplasma gondii induce memory T cell and B cell responses

“…Cells from individual mouse were separately incubated with Fc Block (clone 2.4G2; BD Biosciences, CA, USA) to block non-specific binding at 4°C for 15 min, and then stained at 4°C for 30 min with different combinations of FITC, PE, PE-Cy5, PE-Cy7 or APC conjugated anti-CD3e (145-2c11), anti-CD4 (GK1.5), anti-CD8a (53–6.7) (BD Biosciences, CA, USA). For memory T cell responses, anti-CD44 (IM7) and anti-CD62L (MEL-14) were used (BD Biosciences, CA, USA) as indicated [28]. For memory B cell responses, anti-CD45R/B220 (RA3-6B2), anti-CD27 (LG-3A10) and anti-IgG1 (A85-1) were used (BD Biosciences, CA, USA) [29].…”