Neddylation in Adipose Tissue Development and Obesity

The ongoing obesity epidemic and its associated health comorbidities has raised awareness of the complex physiology of adipose tissue. Obesity represents an increase in de novo adipocyte formation (hyperplasia) and expansion (hypertrophy). Adipogenesis program has been extensively studied, but much still remain unknown about the key steps governing the initiation of adipogenesis and mature adipocyte turnover. Neddylation (the conjugation of an ubiquitin-like NEDD8 to target protein) is mediated by an E1 activating enzyme (a heterodimer of NAE1 and UBA3), followed by E2 and E3 enzymes in a process analogous to ubiquitination. Neddylation controls many essential processes and are involved in various pathological diseases. However, very little is known about the role of neddylation in adipose tissue development and maintenance. This proposal will focus on identifying the molecular mechanisms of how neddylation plays an essential role in adipogenesis as well as adipocyte maintenance, which has important implications on obesity and its associated cardiovascular diseases. The proposed experiments will entail the characterization of two models of adipose tissue specific NAE1 deficient mice as well as an assortment of genetic (including CRISPR/Cas9), pharmacological, biochemical, molecular and cellular techniques to identify the molecular targets of neddylation in regulating the essential pathways for adipogenesis and adipocyte turnover both in vitro and in vivo. The specific aims of this application are 1) to establish the importance of neddylation in regulating PKA mediated CREB-C/EBPbeta;-PPARgamma signaling thus adipogenesis; 2) to test the biological function of neddylation in regulating adipose tissue development and energy balance; 3) to understand the crucial role of neddylation in regulating mature adipocyte maintenance and obesity. Our use of innovative approaches to answer these questions could uncover neddylation as a hitherto novel post-translational modification essential for adipose tissue development and maintenance. Our proposed study will be the first detailed analysis of the role of neddylation enzymes in adipose tissue. We expect that new findings from this proposal will provide novel insights into our understanding of the pathophysiology of adipose tissue and its implications on obesity and cardiovascular diseases. (AHA Program: Career Development Award)