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- Timmons, James A., et al.
(författare)
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Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans
- 2010
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 108:6, s. 1487-1496
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Tidskriftsartikel (refereegranskat)abstract
- Timmons JA, Knudsen S, Rankinen T, Koch LG, Sarzynski M, Jensen T, Keller P, Scheele C, Vollaard NB, Nielsen S, Akerstrom T, MacDougald OA, Jansson E, Greenhaff PL, Tarnopolsky MA, van Loon LJ, Pedersen BK, Sundberg CJ, Wahlestedt C, Britton SL, Bouchard C. Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans. J Appl Physiol 108: 1487-1496, 2010. First published February 4, 2010; doi:10.1152/japplphysiol.01295.2009.-A low maximal oxygen consumption ((V) over dotO(2max)) is a strong risk factor for premature mortality. Supervised endurance exercise training increases (V) over dotO(2max) with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts (V) over dotO(2max) training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous (V) over dotO(2max) response. Two independent preintervention RNA expression data sets were generated (n = 41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in (V) over dotO(2max) (""predictor"" genes). The HERITAGE Family Study (n = 473) was used for genotyping. We discovered a 29-RNA signature that predicted (V) over dotO(2max) training response on a continuous scale; these genes contained similar to 6 new single-nucleotide polymorphisms associated with gains in (V) over dotO(2max) in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., ""reciprocal"" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in (V) over dotO(2max), corresponding to similar to 50% of the estimated genetic variance for (V) over dotO(2max). In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. (V) over dotO(2max) responses to endurance training can be predicted by measuring a similar to 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.
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| 2. |
- Gerin, Isabelle, et al.
(författare)
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On the role of FOX transcription factors in adipocyte differentiation and insulin-stimulated glucose uptake.
- 2009
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Ingår i: The Journal of biological chemistry. - 0021-9258. ; 284:16, s. 10755-63
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we explore the effects of several FOX and mutant FOX transcription factors on adipocyte determination, differentiation, and metabolism. In addition to Foxc2 and Foxo1, we report that Foxf2, Foxp1, and Foxa1 are other members of the Fox family that show regulated expression during adipogenesis. Although enforced expression of FOXC2 inhibits adipogenesis, Foxf2 slightly enhances the rate of differentiation. Constitutively active FOXC2-VP16 inhibits adipogenesis through multiple mechanisms. FOXC2-VP16 impairs the transient induction of C/EBPbeta during adipogenesis and induces expression of the transcriptional repressor Hey1 as well as the activator of Wnt/beta-catenin signaling, Wnt10b. The constitutive transcriptional repressor, FOXC2-Eng, enhances adipogenesis of preadipocytes and multipotent mesenchymal precursors and determines NIH-3T3 and C2C12 cells to the adipocyte lineage. Although PPARgamma ligand or C/EBPalpha are not necessary for stimulation of adipogenesis by FOXC2-Eng, at least low levels of PPARgamma protein are absolutely required. Finally, expression of FOXC2-Eng in adipocytes increases insulin-stimulated glucose uptake, further expanding the profound and pleiotropic effects of FOX transcription factors on adipocyte biology.
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