Molecular background of FTO genotype, anatomical origin, rosiglitazone and irisine determined browning of human adipocytes

Regulatory elements and pathways responsible for determining brown adipocyte and adipose tissue differentiation at specific anatomical sites are more diverse than originally thought. More knowledge of the FTO allele driven regulatory pathways in brown adipose tissue would provide possible pharmaceutical targets in obese patients, particularly those carrying the risk alleles. Ex vivo differentiated, DN derived stem cell populations, compared to those derived from subcutaneous neck fat, keep their higher browning potential displayed by phenotypic, UCP1 content and ProFAT as well as BATLAS scores. It has been revealed that characteristic gene expression profile and associated pathways of brown adipocytes are determined by partially overlapping effects of tissue site-specific commitments of the stem cells, PPARg stimulation and the FTO status of donors. Global RNA sequencing was also performed on human subcutaneous and deep neck depot adipocytes differentiated in the presence of irisin, a myokine, which has been reported to modulate thermogenicity in mature adipocytes. Irisin did not exert an effect on characteristic thermogenic genes, while data indicated upregulation of gene expression in the cytokine signalling pathways. Out of the several upregulated cytokines upon irisin treatment, CXCL1, the highest upregulated, was found to be released throughout the entire differentiation period.