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

• Published in: Nature communications Vol. 12; no. 1; p. 2388
• Main Authors: Maury, Eleonore, Navez, Benoit, Brichard, Sonia M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 14/5; 38; 38/15; 42; 45/88; 631/208/199; 631/337/572/2102; 631/443/319/1642/393; 631/80/105; 64/110; 96/31; 96/95; Adipocytes - immunology; Adipocytes - metabolism; Adiponectin - genetics; Adipose tissue; Adult; Animals; ARNTL Transcription Factors - metabolism; Biological clocks; Biopsy; BMAL1 protein; Case-Control Studies; Cells, Cultured; Chromatin; Chromatin Immunoprecipitation Sequencing; Circadian Clocks - genetics; Circadian Clocks - immunology; Circadian rhythm; Circadian rhythms; Complications; Diet, High-Fat - adverse effects; Disease Models, Animal; Female; Gene Expression Regulation; Genes; Genomes; Humanities and Social Sciences; Humans; Inflammation; Inflammation - immunology; Inflammation - pathology; Intra-Abdominal Fat - immunology; Intra-Abdominal Fat - pathology; Male; Mesenchymal Stem Cells; Metabolic disorders; Metabolism; Mice, Transgenic; Middle Aged; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Obesity; Obesity - complications; Obesity - immunology; Obesity - metabolism; Obesity - pathology; Occupancy; Omentum - immunology; Omentum - pathology; Pathogenesis; Period Circadian Proteins - genetics; Primary Cell Culture; Science; Science (multidisciplinary); Transcription; Transcription, Genetic
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22571-9

To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-κB 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-κB competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-κB 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-κB inhibition. Collectively, our results reveal a relationship between NF-κB and the molecular clock in adipose tissue, which may contribute to obesity-related complications. 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.