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 (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.

White adipose tissue inflammation is not attenuated by short-term calorie restriction in obese humans

“…They have shown that cytotoxic CD8 + T cells and Treg cells play opposing roles in IR and WAT inflammation. In line with these findings, we previously observed that effector memory CD8 + T cells correlate significantly with glucose tolerance, measured via intraperitoneal glucose tolerance tests in high-fat diet fed mice (55). In conclusion, the present study supports the hypothesis that proinflammatory immune action in SAT plays an important role in determining IR.…”

Innate and Adaptive Immunity Alterations in Metabolic Associated Fatty Liver Disease and Its Implication in COVID-19 Severity

“…In this sense, comparison between mice living in specific pathogen-free (SPF) conditions with those housed on non-SPF showed that the latter had higher memory and effector T cells both under normal and HFD. These results were also observed in the liver: more than 95 and 85% of CD4+ and CD8+ T cells, respectively, expressed the effector memory T cell phenotype in non-SPF mice on HFD, which was accompanied by severe steatosis, lobular inflammation, hepatocellular ballooning and destroyed lobule structure while only some SPF mice displayed a mild fat accumulation in the liver ( 137 ). On the other hand, mice following a HFD showed reduced antigen-specific humoral and cellular immune responses after receiving hepatitis B vaccine due to diminish antigen processing and presentation ( 138 ).…”

Individual Effector/Regulator T Cell Ratios Impact Bone Regeneration

“…Recently, we established a new model of non-SPF housing conditions inducing a fast switch to a more “experienced” T cell immunity with enhanced levels of T EFF cells (24, 37). Briefly, mice were transferred toward a non-barrier housing exposing them to environmental pathogens.…”