The role of CD8+ T cells in weight loss and weight cycling

Abstract

Nearly half of adults in the United States report having tried to lose weight in the past year, yet approximately 70% of adults are considered overweight. Recent literature supports the notion that weight regain is common and that body weight variability increases risk for obesity-associated disease progression. Despite significant efforts to understand the chronic inflammatory environment in adipose tissue, the primary nutrient storage organ, during obesity, adipose tissue immune cells have not been thoroughly characterized during settings of weight loss and weight regain (i.e weight cycling). We utilized Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and a novel mouse model of weight loss and weight cycling to identify changes in immune cell abundance and transcriptional status during obesity, weight loss, and weight cycling. Obesity was associated with an increase in lipid-associated macrophages and effector memory CD8+ T cells and a reduction in regulatory CD4+ T cells. Interestingly, weight loss failed to restore regulatory T cells or reduce abundance of lipid-associated macrophages and CD8+ T cells. By sequencing paired T cell receptor α and β chains, we also identified clonal enrichment for CD8+ T cells with a unique expression profile characterized by exhaustion markers and expression of granzyme K. Gzmk+ CD8+ T cells were further clonally enriched by weight cycling and three unique clonotypes were identified that had been previously annotated in type I diabetes datasets. Assessments of systemic insulin action and secretion identified a defect in pancreatic islet insulin secretion in weight cycled animals that was further confirmed by ex vivo islet perifusion assays. Transcriptomics performed on isolated islets revealed reductions in expression of critical β cell transcription factors and reduced insulin granule loading was observed by electron microscopy. Taken together, these data suggest a link between clonal T cell enrichment in adipose tissue and subsequent impaired islet function that leads to impaired regulation of blood glucose in weight cycled mice.