Obesity is at epidemic proportions in the US, with 64.5% of the adult population considered overweight. Kentucky, a state with numerous superfund sites on the national priority list, has the 4th highest prevalence of obesity in the nation. Obesity predisposes to cardiovascular diseases such as hypertension. Polychlorinated Biphenyls (PCBs), highly lipophilic superfund chemicals that concentrate in adipose tissue, have also been linked to hypertension. When exposed to PCBs, obese individuals have higher adipose accumulation that lean subjects; however, the impact of sequestration of PCBs in the excess lipid pools of adipocytes with obesity is unknown. During weight loss, reductions in fat mass result in release of PCBs into the bloodstream and at the adipocyte. Preliminary data demonstrates effects of co-planar and noncoplanar PCBs to increase the expression of adipocyte differentiation factors (PPARgamma) and adipokines involved in obesity-related hypertension (angiotensinogen). The working hypothesis of this proposal is that the effect of PCBs to regulate adipocyte differentiation and the adipocyte renin-angiotensin system is influenced by obesity and weight loss, culminating in adverse consequences of PCBs on adipocyte function and blood pressure control.
In specific aim 1, the effect of PCBs differing in lipophilicity, structure, and receptor affinities on adipose differentiation and the adipocyte renin-angiotensin system will be examined. These studies will determine if sequestration of PCBs in the lipid pools of adipocytes impacts their ability to interact with receptor targets and influence adipocyte function.
In specific aim 2, a rat model of diet-induced obesity will be used to determine the in vitro and in vivo effect of PCB exposure on the development of obesity and hypertension. Hypertrophied adipocytes from obese rats are anticipated to sequester large amounts of PCBs, potentially impacting the development of obesity and the subsequent hypertension that develops in obese rats.
In specific aim 3, we will determine the effect of prior PCB exposure on adipocyte differentiation, the adipocyte renin-angiotensin system, and blood pressure during weight loss in a rat model of diet-induced obesity and hypertension. Release of PCBs from the large lipid pools of obese rats with weight loss is anticipated to increase PCB toxicity. Results from these studies will increase our understanding of adipose PCB accumulation and disease.
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