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- Jimenez, Maria A, et al.
(författare)
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Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascade
- 2007
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 27:2, s. 743-757
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Tidskriftsartikel (refereegranskat)abstract
- The Ebf (O/E) family of helix-loop-helix transcription factors plays a significant role in B lymphocyte and neuronal development. The three primary members of this family, Ebf1, 2, and 3, are all expressed in adipocytes, and Ebf1 promotes adipogenesis when overexpressed in NIH 3T3 fibroblasts. Here we report that these three proteins have adipogenic potential in multiple cellular models and that peroxisome proliferator-activated receptor (PPAR) is required for this effect, at least in part due to direct activation of the PPAR1 promoter by Ebf1. Ebf1 also directly binds to and activates the C/EBP promoter, which exerts positive feedback on C/EBP expression. Despite this, C/EBP is dispensable for the adipogenic action of Ebf proteins. Ebf1 itself is induced by C/EBPß and , which bind and activate its promoter. Reduction of Ebf1 and Ebf2 proteins by specific short hairpin RNA blocks differentiation of 3T3-L1 cells, suggesting a critical role for these factors and the absence of functional redundancy between members of this family. Altogether, these data place Ebf1 within the known transcriptional cascade of adipogenesis and suggest critical roles for Ebf1 and Ebf2.
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| 2. |
- Majithia, Amit R, et al.
(författare)
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Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 111:36, s. 32-13127
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Tidskriftsartikel (refereegranskat)abstract
- Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF < 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D.
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