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1 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 adi
Endre Kristóf
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Tóth, B.B.; Arianti, R.; Shaw, A.; Vámos, A.; Veréb, Z.; Póliska, S.; Győry, F.; Bacso, Z.; Fésüs, L.; Kristóf, E.; et al. FTO Intronic SNP. Encyclopedia. Available online: https://encyclopedia.pub/entry/826 (accessed on 18 November 2024).
Tóth BB, Arianti R, Shaw A, Vámos A, Veréb Z, Póliska S, et al. FTO Intronic SNP. Encyclopedia. Available at: https://encyclopedia.pub/entry/826. Accessed November 18, 2024.
Tóth, Beáta B., Rini Arianti, Abhirup Shaw, Attila Vámos, Zoltán Veréb, Szilárd Póliska, Ferenc Győry, Zsolt Bacso, László Fésüs, Endre Kristóf, et al. "FTO Intronic SNP" Encyclopedia, https://encyclopedia.pub/entry/826 (accessed November 18, 2024).
Tóth, B.B., Arianti, R., Shaw, A., Vámos, A., Veréb, Z., Póliska, S., Győry, F., Bacso, Z., Fésüs, L., Kristóf, E., & Vereb, Z. (2020, May 14). FTO Intronic SNP. In Encyclopedia. https://encyclopedia.pub/entry/826
Tóth, Beáta B., et al. "FTO Intronic SNP." Encyclopedia. Web. 14 May, 2020.
FTO Intronic SNP
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This entry is adapted from the peer-reviewed paper 10.3390/cells9040987

Browning of white adipose tissue shifts adipocytes from energy storage white to energy expenditure beige types. The balance between the two adipocyte populations in white adipose tissue is highly determined by noncoding variants of the Fat mass and obesity-associated (FTO) locus which has the strongest association with obesity. The rs1421085 FTO risk allele results in a loss of ARID5B repression of IRX3 and IRX5 which promotes excess white adipocyte formation. Recent studies have revealed the presence of brown adipose tissues at several anatomical sites in humans including the deep-neck (DN).  We found that the characteristic gene expression profile and associated pathways of DN brown adipocytes were determined by partially overlapping effects of tissue site specific commitments of the stem cells, PPARγ stimulation and the FTO status of donors. The presence of FTO rs1421085 risk alleles had a strong influence, manifested during differentiation, on browning resulting in compromised expression of metabolic and mitochondrial genes as well as pathways which are decisive in thermogenesis.

adipocyte browning deep-neck FTO obesity-risk allele thermogenesis obesity mitochondria

1. History

Brown and beige adipocytes play a major role in maintaining the constant core body temperature of hibernating, small, and newborn animals, as well as in humans without shivering[1][2]. Their heat production is mainly mediated by uncoupling protein 1 (UCP1), a mitochondrial carrier protein, which uncouples ATP synthesis from the respiratory chain activity[1][3]. The stimulation of thermogenesis leads to increased energy expenditure that can ameliorate the energy balance during obesity and type 2 diabetes mellitus[4][5].

In adult humans, specific adipose depots are enriched in brown adipocytes; these expanse to 1–1.5% of total body mass and are mostly found in the perirenal, deep-neck (DN), and paravertebral regions[6]. It is still unrevealed whether these thermogenic fat depots represent the classical brown or the beige type of adipocytes by origin and function, even after recent intense studies of DN tissue, which could be compared to paired subcutaneous (SC) fat samples[7][8][9][10].

Genome-wide association studies (GWAS) have identified fat mass and obesity-associated, FTO as a gene predisposing to obesity[11]. The 2-oxoglutarate dependent dioxygenase enzyme, encoded by the proposed FTO gene, is a member of a family of DNA repair enzymes which plays an important role in fatty acid metabolism and post-translational modifications in addition to the repair mechanism[12]. SNPs appearing in the exons of the gene modify the activity of the enzyme, however, the exact molecular mechanism remained unknown[13]. Overexpression of FTO in mice resulted in a significant increase in fat mass in abdominal white adipose tissue when mice were fed either with a normal or a high-fat diet, as well as an increase in food intake[14]. SGBS human preadipocytes deficient in this enzyme had elevated UCP1 expression and uncoupled respiration, without any changes in mitochondrial mass or structure when they were differentiated to white adipocytes[15].

2. Development

The ratio of brown and white adipocytes is partially determined during the early differentiation of mesenchymal progenitors into adipocyte subtypes, which is strongly influenced by genetic predisposition[16]. A recent GWAS of body fat distribution identified 98 independent adiposity loci which potentially could affect the appearance of thermogenic fat[17]. In a detailed study by Claussnitzer et al. it has been described that single nucleotide polymorphism (SNP) rs1421085 underlies the genetic association between the FTO locus and obesity and the presence of the C risk-allele of the FTO locus results in a cell autonomous, IRX3 and IRX5 dependent shift in the gene expression programs toward white instead of brown adipocyte with lipid-storage and a decrease in thermogenesis. When the T/T healthy genotype is carried at the rs1421085 position, the ARIDB5 repressor is able to bind to this site not allowing IRX3 and 5 expression which allows adipocyte precursors to be committed for browning differentiation[18]. In parallel, IRX5 knockout mice had reduced fat mass and were protected from diet-induced fat accumulation. In addition, IRX5 knockdown increased the mitochondrial respiration in isolated murine adipocytes[19]. On the contrary, it was also shown that IRX3 promotes the browning of white adipocytes as directly bound to UCP1 promoter and its rare variants are associated with human obesity risk[20].

3. Influences

We screened and compared global gene expression patterns by RNA sequencing of human adipose-derived stromal cells (hASCs)-derived white and brown (in response to sustained PPARγ stimulation) differentiated adipocytes. The hASCs were isolated from paired DN and SC adipose tissue samples of nine donors, three of each FTO rs1421085 genotype: T/T-risk-free, T/C-heterozygous, and C/C-obesity-risk. DN adipocytes displayed higher browning features and characteristic differentially expressed gene patterns revealing associated pathways which were highly expressed (thermogenesis, interferon, cytokine, retinoic acid) or downregulated (particularly extracellular matrix remodeling) as compared to SC ones. In our study, IRX3 was significantly higher expressed in samples with FTO obesity-risk alleles that support its suppressive role in thermogenesis. Interestingly, DN progenitors and differentiated adipocytes had also lower expression of the IRX family members, including IRX1-3 and 5-6 as compared to SC adipocytes, irrespective to their FTO allele status, which suggests that an FTO rs1421085 SNP-independent mechanism in DN samples suppresses IRX gene expression. Finally, we found that the expression of metabolic, mitochondrial, and thermogenic genes, with SLC2A4, EHHADH, PPARGC1A, CPT1B, and FABP4 as prominent network stabilizers, was strikingly compromised by the FTO rs1421085 genotypes of the progenitors.

References

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  2. Shingo Kajimura; Bruce M. Spiegelman; Patrick Seale; Brown and Beige Fat: Physiological Roles beyond Heat Generation.. Cell Metabolism 2015, 22, 546-59, 10.1016/j.cmet.2015.09.007.
  3. Andriy Fedorenko; Polina V. Lishko; Yuriy Kirichok; Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria. Cell 2012, 151, 400-13, 10.1016/j.cell.2012.09.010.
  4. Matthew Harms; Patrick Seale; Brown and beige fat: development, function and therapeutic potential. Nature Medicine 2013, 19, 1252-1263, 10.1038/nm.3361.
  5. Andrew Whittle; Miguel López; Antonio Vidal-Puig; Using brown adipose tissue to treat obesity – the central issue. Trends in Molecular Medicine 2011, 17, 405-411, 10.1016/j.molmed.2011.04.001.
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  7. Per-Arne Svensson; Margareta Jernås; Kajsa Sjöholm; Jenny M. Hoffmann; Bengt E. Nilsson; Magnus Hansson; Lena M.S. Carlsson; Gene expression in human brown adipose tissue. International Journal of Molecular Medicine 2011, 27, 227-232, 10.3892/ijmm.2010.566.
  8. Aaron M. Cypess; Andrew P. White; Cecile Vernochet; Tim Schulz; Ruidan Xue; Christina A. Sass; Tian Liang Huang; Carla Roberts-Toler; Lauren S. Weiner; Cathy Sze; et al.Aron T. ChackoLaura N. DeschampsLindsay M. HerderNathan TruchanAllison L. GlasgowAshley R. HolmanAlina GavrilaPer-Olof HasselgrenMarcelo A. MoriMichael MollaYu-Hua Tseng Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nature Medicine 2013, 19, 635-639, 10.1038/nm.3112.
  9. Jun Wu; Pontus Boström; Lauren Sparks; Li Ye; Jang Hyun Choi; An-Hoa Giang; Melin Khandekar; Kirsi A Virtanen; Pirjo Nuutila; Gert Schaart; et al.Kexin HuangHua TuWouter D. Van Marken LichtenbeltJoris HoeksSven EnerbäckPatrick SchrauwenBruce M. Spiegelman Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.. Cell 2012, 150, 366-76, 10.1016/j.cell.2012.05.016.
  10. N.Z. Jespersen; Therese Juhlin Larsen; Lone Peijs; Søren Daugaard; Preben Homøe; Annika Loft; Jasper M. A. De Jong; Neha Mathur; B. Cannon; Jan Nedergaard; et al.Bente Klarlund PedersenKirsten MollerCamilla Scheele A Classical Brown Adipose Tissue mRNA Signature Partly Overlaps with Brite in the Supraclavicular Region of Adult Humans. Cell Metabolism 2013, 17, 798-805, 10.1016/j.cmet.2013.04.011.
  11. Timothy M. Frayling; Nicholas J Timpson; Michael Weedon; Eleftheria Zeggini; Rachel M. Freathy; Cecilia M Lindgren; John R. B. Perry; Katherine S. Elliott; Hana Lango; Nigel W. Rayner; et al.Beverley ShieldsLorna W. HarriesJeffrey C. BarrettSian EllardChristopher J. GrovesBridget KnightAnn-Marie PatchAndy R. NessShah EbrahimDebbie LawlorSusan M. RingYoav Ben-ShlomoMarjo‐Riitta JarvelinUlla SovioAmanda BennettDavid MelzerLuigi FerrucciRuth J. F. LoosInês BarrosoNicholas J. WarehamFredrik KarpeKatharine R. OwenLon R. CardonMark WalkerGraham A. HitmanColin PalmerAlex S F DoneyAndrew D. MorrisGeorge Davey SmithAndrew T. HattersleyMark I. McCarthyThe Wellcome Trust Case Control Consortium A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity. Science 2007, 316, 889-894, 10.1126/science.1141634.
  12. Thomas Gerken; Christophe A. Girard; Yi-Chun Loraine Tung; Celia J. Webby; Vladimir Saudek; Kirsty S. Hewitson; Giles S. H. Yeo; Michael A. McDonough; Sharon Cunliffe; Luke A. McNeill; et al.Juris GalvanovskisPatrik RorsmanPeter RobinsXavier PrieurAnthony Patrick CollMarcella MaZorica JovanovicI. Sadaf FarooqiBarbara SedgwickInês BarrosoTomas LindahlChris P. PontingFrances M AshcroftStephen O'rahillyChristopher J. Schofield The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase. Science 2007, 318, 1469-1472, 10.1126/science.1151710.
  13. Katherine Fawcett; Inês Barroso; The genetics of obesity: FTO leads the way. Trends in Genetics 2010, 26, 266-74, 10.1016/j.tig.2010.02.006.
  14. Chris Church; Lee Moir; Fiona McMurray; Christophe Girard; Gareth Banks; Lydia Teboul; Sara Wells; Jens C. Bruning; Patrick M. Nolan; Frances M. Ashcroft; et al.Roger D Cox Overexpression of Fto leads to increased food intake and results in obesity. Nature Genetics 2010, 42, 1086-92, 10.1038/ng.713.
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Subjects: Cell Biology; Genetics & Heredity; Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Beáta B. Tóth
,
Rini Arianti
,
Abhirup Shaw
,
Attila Vámos
,
Zoltán Veréb
,
Szilárd Póliska
,
Ferenc Győry
,
Zsolt Bacso
,
László Fésüs
,
Endre Kristóf
,
Zoltan Vereb
View Times: 920
Revisions: 3 times (View History)
Update Date: 30 Oct 2020
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