The diurnal rhythm of adipose tissue gene expression is reduced in obese patients with type 2 diabetes

Animal studies have linked disturbed adipose tissue clock gene rhythms to the pathophysiology of the metabolic syndrome. However, data on molecular clock rhythms in human patients are limited. Therefore, in a standardized real life setting, we compared diurnal gene expression profiles in subcutaneous adipose tissue between obese patients with type 2 diabetes and age-matched healthy lean control subjects, using RNA sequencing. In patients, 1.8% (303 genes) of expressed genes showed significant diurnal rhythms, compared to 8.4% (1421 genes) in healthy controls. In patients, the core clock genes showed reduced amplitude oscillations. Enrichment analysis revealed a loss of rhythm in canonical metabolic pathways including AMPK signaling and cAMP mediated signaling in patients. In conclusion, we provide the first transcriptomics atlas of human adipose tissue diurnal rhythms, and show evidence of decreased diurnal clock and metabolic gene expression rhythms in subcutaneous adipose tissue of obese patients with type 2 diabetes. Overall design: We provided 6 obese patients with type 2 diabetes and 6 age matched healthy lean control subjects with three identical meals per day at fixed timepoints (Zeitgeber Time (ZT) 0:30, ZT 6:00 and ZT 11:30, with ZT 0:00 representing wake-up time) for three days. Subcutaneous adipose tissue samples from the four peri-umbilical quadrants were obtained at four time points (day 2: ZT 15:30, day 3: ZT 0:15, ZT 5:45 and ZT 11:15).