There is currently an urgent demand for new strategies to treat and prevent obesity and its associated diseases. A promising approach to combat these metabolic disorders is through enhancing the endogenous cellular mechanisms that can increase energy expenditure. Thermogenic brown and beige adipose tissue is specialized to burn energy through lipid catabolism to produce heat. In mice and humans, increasing the activity of these fat cells leads to increased energy expenditure and decreased body fat mass. Recently, a novel role for the histone reader Zinc And Double PHD Fingers 3 (DPF3) in brown and beige fat has emerged. DPF3 is a subunit in the mammalian BAF ATP-dependent chromatin remodeling complex. This complex, which acquires tissue-specific functions through combinatorial assembly of non-catalytic subunits, dynamically alters chromatin structure to facilitate access of transcriptional machinery to regulatory elements in the genome. Dpf3 expression is enriched in brown and beige adipocytes, and Dpf3 depletion in brown adipocytes blunts expression of key brown fat-specific genes that regulate energy expenditure. This proposal will test the hypothesis that DPF3 anchors the BAF chromatin-remodeling complex to transcriptionally activate thermogenic genes and support the increased respiratory capacity of brown and beige adipocytes.
The first aim will elucidate the mechanisms by which DPF3 controls brown adipocyte differentiation through analysis of nucleosome positioning and recruitment of brown fat-specific transcription factors in the presence and absence of DPF3. Further, high-throughput genomic approaches followed by candidate-based analysis will be employed to identify and functionally characterize novel genes regulated by DPF3-directed BAF complexes.
The second aim will determine the role of DPF3 in the physiological function of thermogenic adipocytes through quantitative assessment of mitochondrial metabolism and oxygen consumption in Dpf3 gain- and loss-of-function cell culture models. In addition, a Dpf3 knockout mouse strain will be analyzed to determine if null animals can activate brown and beige adipose tissue in response to metabolic stresses such as cold, ?3-adrenergic stimulation, and high-fat diet. Together, the aims outlined in this proposal will reveal novel mechanisms by which DPF3 regulates the function of thermogenic adipocytes and define new epigenetic avenues that may be amenable to therapeutic intervention.
The rapidly increasing prevalence of obesity and its comorbidities embody a significant medical and public health challenge. Thermogenic brown and beige adipocytes can be stimulated to expend energy, and as such, understanding the pathways that regulate their activity has great potential to uncover strategies to suppress obesity. The proposed studies will reveal novel mechanisms by which tissue-specific chromatin remodeling complexes regulate the development and function of these thermogenic adipocytes, with the goal of expanding the existing repertoire of potential therapeutic targets to combat metabolic diseases.
| Shapira, Suzanne N; Lim, Hee-Woong; Rajakumari, Sona et al. (2017) EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex. Genes Dev 31:660-673 |
| Shapira, Suzanne N; Seale, Patrick (2017) Enhancing brown fat with NFIA. Nat Cell Biol 19:1006-1007 |
