Transcriptional dynamics in type 2 diabetes progression is linked with circadian, thermogenic, and cellular stress in human adipose tissue

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues are known for their remarkable catabolic capacity, and their ability to diminish blood glucose plasma concentration. Beige adipose tissue can be differentiated from adipose-derived stem cells or through transdifferentiation from white adipocytes. However, the impact of T2D progression on beige adipocytes' functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, obese, prediabetic obese, and obese subjects diagnosed with T2D, reveals a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX is a potential transcription factor that links inflammation with the circadian clock and thermogenesis during the progression of T2D. This study unveils an unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during the progression of T2D. These findings could open new research venues for developing chrono-pharmaceutical strategies to treat and prevent T2D.