CEBPb expression pattern regulates RAP1 protein levels in adipose tissue of obese patients and distinguishes subjects with metabolic impairment

The prevalence of obesity and its associated mortality/morbidity has dramatically increased in the last decades, however, factors involved in the development of metabolic complications of obesity are still to be fully elucidated. It has been shown in mouse that a deletion of the telomeric protein RAP1 could have a pathogenic role in obesity and metabolic syndrome (MS). The aim of the present work was to evaluate RAP1 expression in human adipose tissues. RAP1 expression was evaluated in visceral (VAT) and subcutaneous (ScAT) adipose tissue of 49 obese patients and 14 metabolically healthy normal-weight subjects, demonstrating a significantly reduced RAP1 expression in VAT from obese subjects with MS compared to metabolically healthy obese and controls. No differences were found in RAP1 expression in ScAT. To explore the cause of the reduced RAP1 expression in VAT of obese patients, predicted transcription factors were investigated, using predictive algorithms, and the adipogenic transcription factor CEBPb was selected, given that previous studies demonstrated the inhibition of target genes’ transcription following an increased ratio between the inhibiting isoform (LIP, liver-enriched transcriptional inhibitory protein) and the activating isoform (LAP, liver-enriched transcriptional activating protein) of CEBPb. A higher LIP/LAP ratio was found in VAT from obese patients compared to controls. Moreover, obese patients with higher LIP/LAP ratio showed an unfavorable metabolic profile compared to obese patients with lower LIP/LAP ratio. ChIP analysis confirmed that CEBPb can bind RAP1 promoter. The role of RAP1 in metabolism seems to be independent from its telomeric role. In the present work, a significantly shorter telomere length has been found in VAT from obese patients with MS compared to controls, while no difference was found between obese patients with and without MS, suggesting that metabolic changes between obese patients with and without metabolic impairment, associated with RAP1 reduced expression, are not due to abnormal telomere length. In conclusion, present data highlight a role of the altered expression pattern of CEBPb in RAP1 reduced expression in VAT, a mechanism potentially involved in the development of obesity and its metabolic comorbidities.