Circadian clock dysfunction in human omental fat links obesity to metabolic inflammation

Whether chronic inflammation contributes to metabolic disease through the dysregulation of circadian systems remains incompletely understood in humans. Here the authors show that circadian clock function is perturbed in adipose tissue from individuals with obesity, and that inhibition of NFkB improves clock function. To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-kappa B pathway in human adipose tissue. The circadian clock function is impaired in omental fat from obese patients. ChIP-seq analyses reveal that the core clock activator, BMAL1 binds to several thousand target genes. NF-kappa B competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-kappa B consensus motifs. Obesity relocalizes BMAL1 occupancy genome-wide in human omental fat, thereby altering the transcription of numerous target genes involved in metabolic inflammation and adipose tissue remodeling. Eventually, clock dysfunction appears at early stages of obesity in mice and is corrected, together with impaired metabolism, by NF-kappa B inhibition. Collectively, our results reveal a relationship between NF-kappa B and the molecular clock in adipose tissue, which may contribute to obesity-related complications.

Automated summary

The study demonstrates that circadian clock function is disrupted in adipose tissue of individuals with obesity, and inhibition of NFkB can improve clock function. Investigating the interplay between circadian clocks and the NF-kappa B pathway in human adipose tissue reveals a relationship between NF-kappa B and the molecular clock, which may contribute to obesity-related complications.