Adipose metabolic dysfunction commonly occurs after middle age, frequently coupled with obesity, and when age further increases, progressive loss of adipose tissue incurs. Recent studies show that both adipose metabolic dysfunction after middle age and loss of adipose tissue in elders are associated with insufficient ability to generate new adipocytes. Adipogenic progenitor cells in adipose tissue are the source of new adipocytes, and their diminishing ability to differentiate into adipocytes leads to age-related adipose metabolic syndrome. ZFP423 is the key transcription factor committing progenitors to the adipogenic lineage. We just found that zfp423 gene has two promoters, with the distal promoter tightly regulated by DNA methylation, and the adipogenic commitment of progenitors involves active DNA demethylation in the zfp423 distal promoter. The ten-eleven translocation hydroxylases (TETs) is the key mediator of active DNA demethylation, which requires the presence of 2-oxoglutarate, an intermediate of the Krebs cycle. The 2-oxoglutarate concentration profoundly declines during aging. Our central hypothesis is that aging impairs DNA demethylation in the zfp423 distal promoter, impeding adipogenic differentiation of progenitor cells via a 2-oxoglutarate/TET dependent mechanism.
Specific aims are: 1) Analyze DNA demethylation in the zfp423 distal promoter of young and old progenitors, and 2) Test 2-oxoglutarate/TET system in impaired adipogenesis due to aging. The proposed work is novel because, for the first time, we will examine that epigenetic changes occurring in the zfp423 promoter of adipogenic progenitors have a key role in adipogenic differentiation of progenitor cells, and we further propose that the declining 2- oxoglutarate concentration due to aging hampers adipogenic differentiation of progenitors. Knowledge obtained will fill an important gap in our understanding of aging in adipose tissue, and will provide a key therapeutic target, such as using available 2-oxoglutarate supplements, to prevent metabolic dysfunction and loss of adipose tissue during aging. In addition, given that similar impairment of progenitor differentiation during aging occurs in other tissues, such as muscle and bone, our proposed mechanisms will likely be applicable to these tissues too, generating transforming impacts for preventing age-related deterioration of tissue functions.
Adipose senescence during aging leads to metabolic dysfunction and inflammation, but the underlying mechanisms have not been well established. We propose that the impairment in the generation of new adipocytes from progenitor cells is the major reason, and further suggest the involvement of epigenetic changes in such impairment. Our studies will provide molecular target for preventive efforts to prevent adipose senescence, and will likely have applications to the senescence of progenitor cells in other tissues leading to frailty, such as muscle and bones.
Showing the most recent 10 out of 14 publications
