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) in nonlymphoid organs provide critical brakes on inflammation and regulate tissue homeostasis. Although so-called "tissue T" 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 and its consequences are controversial and poorly understood. Here, we profiled diurnal variations in visceral adipose tissue (VAT) and splenic T in the presence and absence of core-clock genes. VAT, but not splenic, T up-regulated their cell-intrinsic circadian program and exhibited diurnal variations in their activation and metabolic state. BMAL1 deficiency specifically in T led to constitutive activation and poor oxidative metabolism in VAT, but not splenic, T. Disruption of core-clock components resulted in loss of fitness: BMAL1-deficient VAT T were preferentially lost during competitive transfers and in heterozygous T females. After 16 weeks of high-fat diet feeding, VAT inflammation was increased in mice harboring BMAL1-deficient T, and the remaining cells lost the transcriptomic signature of bona fide VAT T. Unexpectedly, VAT T suppressed adipocyte lipolysis, and BMAL1 deficiency specifically in T 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 function and fitness.