T regs in visceral adipose tissue up-regulate circadian-clock 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 T regs 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 core-clock genes. VAT, but not splenic, T regs up-regulated their cell-intrinsic circadian program and exhibited diurnal variations in their activation and metabolic state. BMAL1 deficiency specifically in T regs 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 T regs were preferentially lost during competitive transfers and in heterozygous T reg Bmal1 Δ 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 T reg function and fitness.