Biology subjects

Caslin, H. L.

Publications and source records attributed to Caslin, H. L..

6 recordsLinked to original sources

bioRxiv2026

Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain

BackgroundWeight gain and loss induce adipose CD8+ T cell exhaustion, which persists and may worsen glucose tolerance following weight regain. Because exercise can reduce T cell exhaustion in the blood, we hypothesized that exercise during weight loss would attenuate adipose CD8+ T cell exhaustion and glucose tolerance following weight regain. MethodsMale C57Bl/6J mice were fed low-fat or high-fat diets over 8 to 9-week cycles to generate lean, obese, weight loss, or weight cycled groups. Additional weight loss and weight cycled groups were provided exercise wheels during the weight loss phase. ResultsAs expected, weight loss increased total and exhausted CD8+ T cells by flow cytometry. Mice that ran the most during weight loss had the lowest proportion of exhausted CD8+ T cells. Notably, exercise reduced the proportion of exhausted CD8+ T cells even after the cessation of exercise and weight regain in all mice. However, exercise did not improve glucose tolerance or macrophage inflammation following weight regain. Moreover, exercise did not affect the induction of innate immune memory in adipose macrophages following weight loss. ConclusionThe addition of exercise to a weight loss intervention remarkably reduced exhausted CD8+ T cells in the adipose tissue even after the cessation of exercise and weight regain. While exercise did not affect macrophage inflammation or glucose tolerance following weight regain, these results illuminate new questions about the persistence and mechanisms by which exercise reduces tissue CD8+T cell exhaustion and the direct role of macrophages in modulating glucose tolerance with weight cycling.

immunology↗

bioRxiv2026

Weight loss increases adipose dendritic cells, non-classical antigen presenting proteins, and cytotoxic effector cells

Weight cycling (i.e. cycles of weight gain, loss, and regain) is a growing health concern that has been shown to worsen risk of diabetes beyond that of obesity. Dendritic cells play a causal role in obesity-associated inflammation and metabolic disease. However, whether dendritic cells are impacted by weight cycling is not known. Here, we aimed to test the hypothesis that antigen presentation increases in dendritic cells with weight cycling. C57Bl/6J male mice were put on nutrient-matched low-fat or high-fat diets to elicit lean, weight gain, weight loss, and weight cycled groups. Adipose tissue immune cell populations and proteins related to signal 1, 2, and 3 of antigen presentation were analyzed by single cell-RNA sequencing and flow cytometry. Total adipose tissue dendritic cells, conventional type I and II dendritic cells, and monocyte-derived dendritic cells all increased with weight loss. Regarding major histocompatibility complex (MHC) protein expression, non-classical MHCIb proteins (Qa1, Qa2 and CD1d) were also highest in the weight loss group. Dendritic cells expressing the costimulatory molecule CD86 and the cytokine TNF were highest in the weight loss group. Finally, we assessed effector immune cell populations in the adipose tissue to understand the functional role of antigen presentation. CD8+ T cells, natural killer (NK) T cells, and NK cells also increased consistently with weight loss, but showed evidence of exhaustion. In sum, weight loss, but not weight cycling expands dendritic cells, increases signals for non-classical antigen presentation, and expands CD8+ T cells, NKT cells, and NK cells in the adipose tissue.

immunology↗

bioRxiv2024

Weight loss-induced adipose macrophage memory improves local Staphylococcus aureus clearance in male mice

Different stimuli can induce innate immune memory to improve pathogen defense or worsen cardiometabolic disease. However, it is less clear if the same stimuli can induce both the protective and detrimental effects of innate immune memory. We previously showed that weight loss induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. In this study, we investigated the effect of weight loss on macrophage cytokine production and overall survival in a mouse model of infection. Male C57Bl/6J mice were put on high-fat or low-fat diets over 18 weeks to induce weight gain or weight loss. Lean mice served as controls. All mice were then infected IV with 2.5x10^6 CFU Staphylococcus aureus. Tissues were collected from 10 mice/group at day 3 and the remaining animals were followed for survival. Weight gain mice had the highest blood neutrophils and the highest bacterial burden in the kidney. However, there was no significant difference in survival. The weight loss group had the highest plasma TNF- and a significant reduction in bacterial burden in the adipose tissue that correlated with increased adipose macrophage cytokine production. Thus, weight loss-induced adipose macrophage memory may both improve local S.aureus clearance and worsen diabetes risk upon weight regain. Collectively, these findings support the notion that innate immune memory is an evolutionarily protective mechanism that also contributes to the development of cardiometabolic diseases.

immunology↗

bioRxiv2023

Single cell RNA-sequencing suggests a novel lipid associated mast cell population following weight cycling

We previously demonstrated that weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Interestingly, we did not detect an increase in total mast cell numbers in weight cycled mice by Toluidine blue or flow cytometry, however, further subcluster analysis of our dataset showed that our initial mast cell cluster consisted of two unique populations. One population had very high expression of classical mast cell markers and another had elevated lipid handling and antigen presentation genes with a concomitant reduction in classical mast cell genes. This new "lipid-associated" mast cell cluster accounted for most of the mast cells in the weight cycled group. We induced a similar phenotype in vitro using repeated exposure to adipose tissue conditioned media to mimic weight gain and weight regain. Upon repeated exposure to adipose tissue conditioned media, bone marrow-derived mast cells had increased lipid droplets and reduced expression of cKit and Fc{varepsilon}R1 compared to control cells. Moreover, we analyzed mast cells in a pilot study of subcutaneous adipose tissue from four obese, prediabetic women. We found two mast cell populations that appear similar to the murine populations detected by sequencing. The population with reduced cKit and Fc{varepsilon}R1 was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid-associated macrophages, which have been shown to play a role in diverse diseases from obesity and atherosclerosis to Alzheimers disease. Future studies will focus on isolation of these cells from mice and humans to better determine their lineage, differentiation, and functional roles.

immunology↗

bioRxiv2022

Weight cycling induces innate immune memory in adipose tissue macrophages

Weight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages. We first treated bone marrow derived macrophages in a culture model of innate immune memory. Priming the cells with palmitic acid or adipose tissue conditioned media increased maximal glycolysis, oxidative phosphorylation, and increased LPS-induced TNF and IL-6 production. While weight loss improved glucose tolerance, adipose macrophages retained elevated LPS-induced cytokine production. In a model of weight cycling, adipose macrophages had elevated metabolism and secreted higher levels of basal TNF. Together, these data suggest that obesity and subsequent weight loss can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling.

immunology↗

bioRxiv2021

Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and subsequent weight regain.

Most individuals do not maintain weight loss, and weight regain increases cardio-metabolic risk beyond that of obesity. Adipose inflammation directly contributes to insulin resistance; however, immune-related changes that occur with weight loss and weight regain are not well understood. Single cell RNA-sequencing was completed with CITE-sequencing and biological replicates to profile changes in murine immune subpopulations following obesity, weight loss, and weight cycling. Weight loss normalized glucose tolerance, however, type 2 immune cells did not repopulate adipose following weight loss. Many inflammatory populations persisted with weight loss and increased further following weight regain. Obesity drove T cell exhaustion and broad increases in antigen presentation, lipid handing, and inflammation that persisted with weight loss and weight cycling. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. Thus, we have created an open-access interactive portal for our processed data to improve accessibility for the research community.

immunology↗