Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI, Zeltser LM, Chung WK, Leibel RL. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294: R1185–R1196, 2008. First published February 6, 2008; doi:10.1152/ajpregu.00839.2007 (http://ajpregu.physiology.org/cgi/content/full/294/4/R1185).
In the Abstract, the sentence “The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA” should read “The A allele of rs8050136 preferentially bound CUTL1 in human fibroblast DNA”. On page R1193 we state “Moreover, CUTL1 preferentially bound to DNA fragments carrying the ‘C’ allele of rs8050136”. This should read “Moreover, CUTL1 preferentially bound to DNA fragments carrying the ‘A’ allele of rs8050136”.
There have been discrepancies in the literature regarding the associations of obesity-related phenotypes with alleles of rs8050136. Scuteri et al. (2) associate the “C” allele with lower body mass index (BMI), whereas Tschritter et al. (3) associated the “C” allele of rs8050136 with higher BMI than the “A” allele. However, Tschritter et al. (3) inadvertently reversed the “A” and “C” alleles of rs8050136 in their paper (Erratum to: Diabetologia, Online: http://www.springerlink.com/content/k1150t348206t665/fulltext.pdf). The “A” (obesity-risk) allele of rs9939609 [Frayling et al. (1)] is in linkage disequilibrium (LD) with “A” allele of rs8050136 (McCarthy M, personal communication). Thus, it appears that the “A” allele of rs8050136 is the obesity-risk allele.
Our in vivo data indicate that Fto/Ftm are reduced in liver and adipose tissue of genetically obese mice and in hypothalamus and adipose tissue of fasted genetically obese and wild-type mice, consistent with one or both of these genes mediating suppressive effects on energy intake. As indicated in our manuscript, the transcription factor, CUTL1, binds preferentially to the “A” allele of rs8050136 in human fibroblasts, and RNAi-mediated knockdown of CUTL1 in these cells reduces the expression of FTO/FTM. To fit the physiological model that we proposed based on our in vivo and in vitro data, CUTL1 should preferentially bind to the rs8050136 allele associated with resistance to obesity. Since it does not, alternative models must be considered.
CUTL1 has the ability to increase or decrease transcription in specific cellular contexts. It is possible that, contrary to its stimulatory effects in skin fibroblasts, CUTL1 tonically suppresses FTO/FTM expression in neuronal or other (e.g., adipocyte) cell types. Enhanced binding/action at the “A” (obesity-risk allele) would lead to lower expression levels of FTO/FTM. This response is consistent with decreased expression levels of Fto/Ftm in genetically obese mice. It is also possible that CUTL1 is exerting its effects via another CUTL1 binding site in LD with rs8050136. There are multiple potential CUTL1 binding sites within the ∼47 kb region of LD (www.genomatix.de/online_help/help_matinspector/matinspector_help.html). Alternatively, FTO/FTM transcriptional control by CUTL1 is not functionally relevant in this context. Further experiments are clearly needed.
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