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), which is extremely high in fat with very low carbohydrates, drives the host into using β-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid–driven fuel use to reduced adipose tissue inflammation.

酮体是必不可少的替代燃料，可以让人类在饥饿和长时间运动引起的葡萄糖稀缺时期存活下来。广泛使用的生酮饮食 (KD) 含有极高的脂肪和极低的碳水化合物，驱使宿主使用 β-羟基丁酸来产生 ATP 并降低 NLRP3 介导的炎症。然而，KD 的极高脂肪成分提出了生酮如何影响脂肪组织以控制炎症和能量稳态的问题。在这里，通过使用脂肪组织驻留免疫细胞的单细胞 RNA 测序，我们表明 KD 可扩展抑制炎症的代谢保护性 γδ T 细胞。值得注意的是，小鼠长期随意喂养 KD 会导致肥胖、损害代谢健康并耗尽脂肪驻留的 γδ T 细胞。此外，缺乏 γδ T 细胞的小鼠葡萄糖稳态受损。我们的结果表明，γδ T 细胞是保护性免疫代谢反应的介质，将脂肪酸驱动的燃料使用与减少脂肪组织炎症联系起来。