Ketogenesis activates metabolically protective ?d T cells in visceral adipose tissue [scRNA-Seq]

Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), that is extremely high in fat with very-low carbohydrates, drives the host into using ß-hydroxybutyrate (BHB) for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis impacts adipose tissue to control inflammation and energy homeostasis. Using single-cell RNA sequencing of adipose tissue-resident immune cells, we identified that KD expands metabolically protective ?d T cells that restrain inflammation. However, a long-term KD caused obesity, impaired metabolic health and depleted the adipose resident ?d T cells. Moreover, mice lacking ?d T cells have impaired glucose homeostasis. We conclude that ?d T cells are mediators of protective immunometabolic responses that link fatty acid driven fuel utilization to reduced adipose tissue inflammation. Overall design: Mice were fed a chow vs KD for one week. The adipose tissue-resident immune compartment was idenitifed by iv labeling and then assessed by scRNAseq.