This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Obesity is a primary risk factor for type 2 diabetes, metabolic syndrome and cardiovascular diseases such as hypertension. Adipose tissues express high levels of the peroxisome proliferator-activated receptor, PPARgamma, the master switch in adipose cell formation. Recent studies show that modulation of PPARgamma levels improves insulin sensitivity and protects against insulin resistance associated with aging. Our studies indicate that regulation of PPARgamma levels by the ubiquitin-proleasome system is linked to control of PPARgamma activity. In addition, we have learned that modification of PPARgamma in the Nterminal AF-1 domain by the ubiquitin-like protein, SUMO-1, affects PPARgamma stability and activity.These studies suggest that modulation of PPARgamma activity by ubiquitin and ubiquitin-like proteins plays an important role in adipogenesis and the development of obesity. However, these studies have used the murine 3T3-L1 adipocyte cell line and there is evidence that adipogenesis may differ between muririe andhuman systems. In this study, we propose to begin characterizing the relationship between PPARgainma activity and ubiquitin-proteasome-dependent degradation using adult stem cells isolated from human liposuction aspirates. These primary cell cultures, identified as Adipose Derived Adult Stem (ADAS) cells, are an abundant resource that can be reproducibly induced to undergo adipogenesis. We will employ this primary cell culture system to examine the relationship between PPARgamma activity and ubiquitindependent turnover in a human-based, clinically relevant cell line. We hypothesize that ubiquitin-dependent degradation is an important regulator of PPARgamma activity and that PPARgamma is also modified bySUMO-1 in the human ADAS-derived adipocyte.
Specific aim 1 will focus on examining the ubiquitylation and SUMOylation status of PPARgamma under basal and ligand-activated conditions.
Specific aim 2 will focus on examining PPARgamma turnover in adipocytes derived from subcutaneous and visceral fat depots.
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