FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis

Abstract

Brown adipocytes, abundant in deep-neck (DN) area in humans, are thermogenic with anti-obesity potential. FTO pro-obesity rs1421085 T-to-C single-nucleotide polymorphism (SNP) shifts differentiation program towards white adipocytes in subcutaneous fat. Human adipose-derived stromal cells were obtained from subcutaneous neck (SC) and DN fat of nine donors, of which 3-3 carried risk-free (T/T), heterozygous or obesity-risk (C/C) FTO genotypes. They were differentiated to white and brown (long-term Peroxisome proliferator-activated receptor gamma (PPARγ) stimulation) adipocytes; then, global RNA sequencing was performed and differentially expressed genes (DEGs) were compared. DN and SC progenitors had similar adipocyte differentiation potential but differed in DEGs. DN adipocytes displayed higher browning features according to ProFAT or BATLAS scores and characteristic DEG patterns revealing associated pathways which were highly expressed (thermogenesis, interferon, cytokine, and retinoic acid, with UCP1 and BMP4 as prominent network stabilizers) or downregulated (particularly extracellular matrix remodeling) compared to SC ones. Part of DEGs in either DN or SC browning was PPARγ-dependent. Presence of the FTO obesity-risk allele suppressed the expression of mitochondrial and thermogenesis genes with a striking resemblance between affected pathways and those appearing in ProFAT and BATLAS, underlining the importance of metabolic and mitochondrial pathways in thermogenesis. Among overlapping regulatory influences that determine browning and thermogenic potential of neck adipocytes, FTO genetic background has a thus far not recognized prominence.

miR-146a regulates TLR1/2 and 4 induced inflammation and links it with proliferation in human SZ95 sebocytes

“…To obtain global transcriptome data high throughput mRNA sequencing analysis was performed on Illumina sequencing platform as described previously 22,42,43 . Total RNA sample quality was checked on Agilent BioAnalyzer using Eukaryotic Total RNA Nano Kit according to the manufacturer's protocol.…”

Modeling Adipogenesis: Current and Future Perspective

“…In addition, models utilized to study adipogenesis subcategorized into cell lines and adipose-derived stem cells (ADSCs) with brief description into variable methods used to induce differentiation. Below are featured highlight of each adipose tissue subtypes summarized from other studies [ 95 , 96 , 97 ].…”

Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes

“…To see how genes in the expanded sets are involved in the formation of a particular adipocyte phenotype, their relative expression profiles are shown on three separate heatmaps, namely Brown (1053), Linker (498) and White (2154) genes, as they are manifested according to the FTO obesity-risk genotypes in the above-mentioned study with human neck adipocytes (18) (Figure 2A). The majority of the genes belonging to the Brown pathways have higher expression in the more thermogenic samples (red box): 540 genes, e.g.…”

“…Based on this we further investigated all annotated genes of the enriched pathways, presuming that it may leads to more generally applicable conclusions than single-state studies. To see and analyse the relative expression profile of these genes in adipocytes, we used transcriptional data from our recent study (18) on ex vivo differentiated primary human subcutaneous (SC) and deep neck (DN) brown adipocytes, with or without FTO rs1421085 intronic SNP (obesity-risk allele).…”