Abstract
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.
Highlights
Type 2 diabetes (T2D) is a metabolic disease that is strongly associated with obesity and often preceded by insulin resistance
Blood from antigen exposed” (AE) mice was enriched in effector memory T cells and, correspondingly, showed lower percentages of naïve T cells compared to specific pathogen-free (SPF) mice (Figures 3A–C)
The total amount of leukocytes and T cells was higher in AE compared to SPF mice
Summary
Type 2 diabetes (T2D) is a metabolic disease that is strongly associated with obesity and often preceded by insulin resistance. Obesity leads to adipose tissue dysfunction along with triglyceride accumulation, adipocyte hypertrophy, adipokine/cytokine secretion, hypoxia, endoplasmic reticulum stress, and impaired mitochondrial function, resulting in the activation of pro-inflammatory. Hypoxia associated with adipocyte hypertrophy leads to the activation of NFκB-dependent pro-inflammatory responses in adipocytes and the expression of alarmin receptors. Obesity and obesity-related complications activate both the innate and adaptive arms of the immune system and lead to the recruitment of immune cells in metabolically active organs [9]. Recent data suggest the involvement of adaptive immunity, represented by T cells [17, 18], showing the complexity of obesity-associated intratissue inflammation [19]. The causal impact of inflammation and immune responsiveness as well as the chronological order of inflammatory events remain largely unknown
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