Tregs in visceral adipose tissue up-regulate circadianclock expression to promote fitness and enforce a diurnal rhythm of lipolysis

Regulatory T cells (T-regs) in nonlymphoid organs provide critical brakes on inflammation and regulate tissue homeostasis. Although so-called tissue T-regs are phenotypically and functionally diverse, serving to optimize their performance and survival, up-regulation of pathways related to circadian rhythms is a feature they share. Yet the diurnal regulation of Tregs and its consequences are controversial and poorly understood. Here, we profiled diurnal variations in visceral adipose tissue (VAT) and splenic T-regs in the presence and absence of coreclock genes. VAT, but not splenic, Tregs up-regulated their cell-intrinsic circadian program and exhibited diurnal variations in their activation and metabolic state. BMAL1 deficiency specifically in Tregs led to constitutive activation and poor oxidative metabolism in VAT, but not splenic, T-regs. Disruption of core-clock components resulted in loss of fitness: BMAL1-deficient VAT Tregs were preferentially lost during competitive transfers and in heterozygous TregBmal1. females. After 16 weeks of high-fat diet feeding, VAT inflammation was increased in mice harboring BMAL1-deficient T-regs, and the remaining cells lost the transcriptomic signature of bona fide VAT T-regs. Unexpectedly, VAT T-regs suppressed adipocyte lipolysis, and BMAL1 deficiency specifically in T-regs abrogated the characteristic diurnal variation in adipose tissue lipolysis, resulting in enhanced suppression of lipolysis throughout the day. These findings argue for the importance of the cell-intrinsic clock program in optimizing VAT Treg function and fitness.

Automated summary

This study reveals the diurnal regulation of regulatory T cells (T-regs) in nonlymphoid organs and identifies the importance of the cell-intrinsic clock program. BMAL1 deficiency in T-regs leads to impaired function and fitness, as well as disrupted adipose tissue lipolysis.