Paper of the Month
MAY 2018 – Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes
In May Clinician Scientist Julia Sbierski-Kind and her Team were awarded with the Paper of the Month.
Sbierski-Kind J, Kath J, Brachs S, Streitz M, von Herrath MG, Kühl AA, Schmidt-Bleek K, Mai K, Spranger J, Volk HD. Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes. Front Immunol. 2018; 9: 1069. Published online 2018 May 28. doi: 10.3389/fimmu.2018.01069
Obesity is associated with adipose tissue inflammation, insulin resistance, and the development of type 2 diabetes (T2D). However, our knowledge is mostly based on conventional murine models and promising preclinical 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 (HFD). 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 HFD maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. By contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of HFD AE mice accompanied by the development of non-alcoholic 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 T2D patients.
Im May Clinician Scientist Julia Sbierski-Kind and her team were awarded with the Paper of the Month.
What do you research? What is at the core of your research? What is the motivation behind your research?
Obesity can lead to the development of insulin resistance and type 2 diabetes mellitus as the result of an inflammatory response in visceral adipose tissue. Our research is using animal models to better understand the changes that take place in the immune cells of visceral adipose tissue and the liver. New active substances that fight diseases often appear promising in specific pathogen-free animal models, but clinical studies rarely succeed in translating these into human therapies. We therefore performed flow cytometric and histological analyses as well as metabolic phenotyping of high-fat diet mice in a non-specific pathogen-free (antigen-exposed) animal model, which does a better job of simulating the human immune system. What drives us is the desire to develop an animal model that is better translatable to clinical studies, so that we can ultimately discover new therapeutic and immune-based approaches for treating obesity and type 2 diabetes mellitus
What is the central message of your publication and how does your study differ from the work of other scientists in this field?
Up to now, most animal experiments have been carried out in specific pathogen-free mice, but have often had only limited success in terms of translatability to clinical studies. Our study is mainly about the metabolic and immunological characterization of antigen-exposed mice, which were housed not only in pens equipped with open ventilation systems but also next to sheep and pigs, and thus about the investigation into the impact of housing conditions on pathogen-induced adaptive immunity and metabolic disease processes during high-fat diet consumption. We found that mice housed in non-specific pathogen-free conditions maintained increased insulin levels to compensate for insulin resistance triggered by obesity. By contrast, higher proportions of effector/memory T cell subsets in blood and liver led to the development of nonalcoholic steatohepatitis in these mice.
Who did you collaborate with on this publication? Who were the key participants?
The project began initially as a collaboration between the Department of Endocrinology, Diabetes and Nutrition of Charité – Universitätsmedizin Berlin, headed by Prof. Joachim Spranger, and the Berlin-Brandenburg Center for Regenerative Therapies (BCRT), headed by Prof. Hans-Dieter Volk. Our work is founded on the idea of creating a more realistic model of the human immune system through mice subjected to continuous antigen exposure. This principle was already tested by Katharina Schmidt-Bleek’s research group at the Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration with regard to the impact on bone regeneration. The current work came about through close collaboration with Matthias von Herrath, who was an Einstein Visiting Fellow at the BCRT from 2015 to 2016. In this connection, Julia Sbierski-Kind did a short research stint at Matthias von Herrath’s lab at the La Jolla Institute for Allergy and Immunology in California. In addition, we closely collaborated with Anja Kühl of the iPATH Berlin – Core Unit Immunopathology for Experimental Models.
What are the next steps for the project and what are the possible implications of your findings for patients?
With the help of genetically modified mice, we are currently investigating the reasons for the persistence of increased insulin levels in antigen-exposed mice, which was also reflected in islet cell hyperplasia in the pancreas. Here cytoprotective interleukins – ones that are not only characteristic to type 2 immunity but also responsible for maintaining the metabolic homeostasis of non-adipose tissue – may play a role. Pathogens such as parasites could possibly trigger a type 2 immune response in antigen-exposed animals, ultimately having a beneficial impact on glucose tolerance. In addition, we are collaborating with the clinical scientist Reiner Jumpertz on another project that is looking at the immune responses that occur in adipose tissue and the gut and liver during changes in the microbiome of previously germ-free mice in connection with obesity and calorie restriction. The results of this research should provide insights into how to realize immune-based clinical interventions for patients with type 2 diabetes mellitus.