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.

调控特定解剖部位棕色脂肪细胞（brown adipocyte）与脂肪组织分化的调控元件及通路，其多样性远超此前学术认知。进一步阐明棕色脂肪组织（brown adipose tissue）中受FTO等位基因（FTO allele）驱动的调控通路，可为肥胖患者——尤其是携带风险等位基因的群体——提供潜在的药物干预靶点。相较于源自皮下颈部脂肪的干细胞群，体外分化的DN来源干细胞群仍保留更高的棕色化潜能，该潜能可通过表型特征、解偶联蛋白1（UCP1）含量、ProFAT评分及BATLAS评分得以体现。现有研究揭示，棕色脂肪细胞的特征性基因表达谱及其关联通路，由干细胞组织部位特异性定向、PPARγ刺激以及供体FTO基因型三种效应的部分重叠所决定。研究团队还对经鸢尾素（irisin，一种可调控成熟脂肪细胞产热活性的肌因子（myokine））诱导分化的人皮下及颈部深层脂肪库脂肪细胞开展了全局RNA测序（Global RNA sequencing）。结果显示，鸢尾素未对特征性产热基因产生调控作用，但测序数据表明细胞因子信号通路中的基因表达出现上调。在鸢尾素处理后上调的多种细胞因子中，上调幅度最高的CXCL1被证实可在整个分化周期中持续释放。