Abstract
Brown adipocytes, abundant in deep-neck (DN) area in humans, are thermogenic with anti-obesity potential. FTO pro-obesity rs1421085 T-to-C 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 9 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 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, retinoic acid, with UCP1 and BMP4 as prominent network stabilizers) or downregulated (particularly extracellular matrix remodelling) 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 which determine browning and thermogenic potential of neck adipocytes, FTO genetic background has a so far not recognized prominence.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Declarations of interest: none
The title and abstract have been shortened; new elements and references were added to Discussion.
Abbreviations
- ATP
- adenosine triphosphate
- ANOVA
- analysis of variance
- BMI
- body mass index
- BMP
- bone morphogenetic protein
- BAT
- brown adipose tissue
- CPT
- carnitine palmitoyltransferase
- CIDEA
- cell death-inducing DFFA-like effector A
- CKMT
- creatine kinase, mitochondrial
- cAMP
- 3′,5′-cyclic adenosine monophosphate
- C
- cytosine
- DN
- deep neck
- DEG
- differentially expressed gene
- ECAR
- extracellular acidification rate
- ECM
- extracellular matrix
- FTO
- fat mass and obesity-associated
- hASC
- human adipose-derived stromal cells
- IL
- hASC interleukin
- KLF11
- Kruppel-like factor 11
- OC
- oxygen consumption
- OCR
- oxygen consumption rate
- PM20D1
- peptidase M20 domain containing 1
- PPARγ
- peroxisome proliferator-activated receptor gamma
- PCR
- polymerase chain reaction
- SNP
- single nucleotide polymorphism
- SC
- subcutaneous
- T
- thymine
- TBX1
- T-Box 1
- UCP1
- uncoupling protein 1
- ZICI
- Zic family member 1