Zinc Finger Protein 949 as a Potential Transcriptional Suppressor of Adipocyte Hypertrophy - Resubmission - 1 - PROJECT SUMMARY Background: The cellular events that cause adipocytes to accumulate excessive amounts of triglycerides (hypertrophy), a key characteristic of obesity, remain largely unknown. We have discovered that mice with targeted genetic deletion of adipose tissue diaphanous 1 are protected from diet-induced obesity and exhibit reliably higher expression of the gene zinc finger protein 949 (Zfp949) in both brown and white adipose tissues. The literature on the physiological role of Zfp949 is limited to its roles as a transcriptional suppressor of embryonic development. Preliminary data from our laboratory demonstrate that lowering the expression of Zfp949 in adipocytes prevents triglycerides accumulation when exposed to excess fatty acids. Thus, this novel model of adipocyte hypertrophy will allow us to identify the genes, protein and lipids that contribute to adipocyte obesity. Furthermore, the proposed studies aim to determine whether overexpression of Zfp949 represents a therapeutic target for the treatments and/or prevention of obesity. Hypothesis: In line with a common function of proteins in the zinc finger family, and based on a published report supporting this role, we hypothesize that Zfp949 suppresses genes and proteins that promote lipid accumulation in adipocytes and thus, overexpression will be protective from fatty acid-induced hypertrophy. Approach: We will leverage RNA sequencing, proteomic and lipidomic studies for unbiased assessment of the genes, proteins and lipids that underlie adipocyte hypertrophy. This multi-omic approach will identify the cellular processes that promote lipid accumulation in adipocytes. Similarly, we will also harness those tools to assess whether or not overexpressing Zfp949 represents a potential therapeutic approach to treat obesity. Significance: One of the limitations to being able to study the cellular processes that take place in adipocytes during hypertrophy is that it is not possible to isolate hypertrophied adipocytes from subjects in vivo thus hindering our full understanding of the causes of obesity. The innovative question and cellular model will allow us to unveil the underlying cellular processes that cause adiposity and obesity. In light of the lack of effective and safe treatments for obesity, the fast growing prevalence of this disease, and its link as a major risk factor for cardiovascular disease and diabetes, if is of paramount importance to better understand the cellular processes underlying obesity, which the proposed studies aim to address. The clinical significance rests on the notion that the results of the proposed studies will identify key genes, proteins and metabolic pathways that promote lipid accumulation in adipocytes as well as identify the specific lipid species that contribute to adipocyte hypertrophy, which via established collaborations, can then be validated in future proposals in samples from obese human subjects and may be targeted as potential therapeutic candidates to treat those disorders.
