Key result
FTO obesity-risk allele reduces browning potential in human neck adipocytes by suppressing mitochondrial genes.
Why the study?
Brown adipocytes in the human deep-neck area have thermogenic, anti-obesity potential, and the FTO pro-obesity rs1421085 single-nucleotide polymorphism shifts differentiation toward white adipocytes in subcutaneous fat.
Does the FTO obesity-risk allele influence the browning and thermogenic potential of human neck adipocytes?
Does the FTO obesity-risk allele influence the browning and thermogenic potential of human neck adipocytes?
The FTO obesity-risk allele significantly suppresses mitochondrial and thermogenic gene expression in human neck adipocytes, highlighting its genetic prominence in determining browning potential.
Hypothesis-generating for FTO effects on browning; requires human in vivo validation before any clinical consideration.
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.
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Tóth et al. (2020) studied Adipocyte browning (n=9). FTO rs1421085 obesity-risk allele (C/C) vs. FTO risk-free allele (T/T) was evaluated on Differential gene expression (DEGs) and browning potential (ProFAT/BATLAS scores). The presence of the FTO obesity-risk allele suppressed the expression of mitochondrial and thermogenesis genes in human neck adipocytes, significantly reducing their browning potential.
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