Dissertation
AMP-Activated protein kinase and epigenetic modifications governing adipogenesis
Doctor of Philosophy (PhD), Washington State University
01/2016
Handle:
https://hdl.handle.net/2376/117191
Abstract
Obesity is a worsening problem affecting a large proportion of world population. Especially, the percentage of obese women dramatically climbed in the past three decades. It is well-recognized that maternal obesity (MO) has a lasting and profound negative impact on the health of offspring, which needs to be addressed. AMPK is a key energy gauge maintaining energy metabolism and accumulating evidence links metabolic changes to cell differentiation, but its role in adipogenesis has not been examined. We hypothesized that AMPK regulates adipogenesis by controlling the level of key metabolites. First, we found that AMPK activity in fetal tissue was suppressed by MO, which was associated with enhanced adipogenesis during fetal development. ZFP423 is a key transcription factor initiating white adipogenesis. Intriguingly, the Zfp423 promoter bears bivalent characteristics, with both inhibitory H3K27me3 and permissive H3K4me histone modifications. We found that MO reduced H3K27me3 and increased H3K4me3 in the Zfp423 promoter, and the associated DNA methylation was reduced in MO fetuses, providing an explanation for the enhanced adipogenesis during fetal development. We further studied the effect of AMPK on brown adipogenesis. Unlike promoting white adipogenesis in fetus, MO down-regulates the development of brown adipose tissue (BAT). Supportively, AMPKa1 is required for brown adipogenesis by promoting Prdm16 expression. Moreover, intracellular a-ketoglutarate content dramatically decreased in the fetus of MO and AMPKa1 KO mice. We further found that a-ketoglutarate is required for TET catalyzed DNA demethylation in the Prdm16 promoter and brown adipogenesis. Additionally, the disruption of isocitrate dehydrogenase 2 (IDH2) caused by AMPKa1 ablation was identified as a key factor decreasing a-ketoglutarate content in the cells. In summary, AMPK has a duel role in adipogenesis, which promotes white but inhibits brown adipogenesis. Our study delineates a clear link between energy metabolism and cell fate decision and positions AMPK in the center of the regulatory network of adipogenesis.
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Details
- Title
- AMP-Activated protein kinase and epigenetic modifications governing adipogenesis
- Creators
- Qiyuan Yang Yang
- Contributors
- Min Du (Advisor)Meijun Zhu (Committee Member)Dan Rodgers (Committee Member)Zhihua Jiang (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Animal Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 169
- Identifiers
- 99900581433201842
- Language
- English
- Resource Type
- Dissertation