This image courtesy of Odyssey Magazine.
Lisa Cassis (Project Leader)
Obesity is at epidemic proprotions 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 a high prevalence of obesity, type 2 diabetes, and cardiovascular diseases. Several epidemiologic studies link exposures to polychlorinated biphenyls (PCBs) to the development of type 2 diabetes, a primary cause of morbidity in the obese population.
Because of their lipophilic nature, PCBs accumulate markedly in adipose tissue. As a result, the total body burden of PCBs is increased with obesity. Notably, upon weight loss, PCBs redistribute out of adipose lipid stores. As a result, liberated PCBs move into the blood and can act at receptors in target tissues. We have demonstrated that the pronounced ability of fat cells to accumulate PCBs contributes to a state of low-grade inflammation in adipose tissue, manifest in the form of insulin resistance. When mice are administered low to moderate doses of PCBs at levels that are found in type 2 diabetics, glucose homeostasis becomes impaired. Moreover, PCBs result in more pronounced impairment of glucose uptake by fat cells. Remarkably, when mice were made obese from consumption of a high fat diet, PCB effects were diminished until mice lost weight. Upon weight loss, PCBs impaired glucose uptake by adipocytes, blunting the beneficial effects of weight loss to improve glucose homeostasis.
Our goal is to use nutritionally relevant concepts to prevent and/or mitigate harmful effects of PCBs to promote insulin resistance. We have found that the plant polyphenol, resveratrol, can prevent effects of PCBs to decrease glucose uptake in adipocytes, and improve glucose homeostasis in mice exposed to PCBs. We are currently in the midst of studies defining mechanisms for protective effects of resveratrol, and determining the precise role of the fat cell in the ability of PCBs to impair insulin responses. Results from these studies may identify environmental exposures that contribute to the development of type 2 diabetes. In addition, we aim to identify nutritionally relevant therapeutic approaches that can prevent and/or eliminate diabetes-promoting effects of these environmental toxicants.
UK Superfund Research Student Nicki Baker
Dr. Baker completed the PhD in nutritional sciences in 2013. Her research focused on the role of PCBs as mediators of insulin resistance. She demonstrated that coplanar PCBs that are ligands of the aryl hydrocarbon receptor (AhR) promote insulin resistance at adipocytes and impair glucose homeostasis in lean mice. She then administered PCBs to mice made obese from consumption of a high fat diet. While PCB levels in obese mice were increased compared to lean controls, the harmful effects of PCBs to impair glucose homeostasis was no longer evident. However, upon weight loss, PCBs redistributed from adipose lipids and impaired glucose homeostasis. Since more than 65% of the overweight US population strives to lose weight, her findings have significant implications on potential negative effects of liberated PCBs in obese subjects. To treat this problem, Dr. Baker focused on the plant polyphenol, resveratrol, a constituent of red wine and chocolate, two of her favorite food groups. Resveratrol protected against PCB-induced increases in oxidative stress in fat cells, restored insulin-stimulated glucose uptake, and totally prevented effects of PCBs to impair glucose homeostasis in mice. These results suggest that resveratrol could be used as a therapeutic intervention in the treatment of PCB-induced insulin resistance. Dr. Baker was the recipient of the 2012 Karen Wetterhahn Superfund Research Award. Results from her studies were published in Environmental Health Perspectives, and findings from studies focused on resveratrol have been submitted for publication.
Nicki with previous Wetterhahn Awardees
Nicki Baker - Wetterhahn Presentation
PROJECT STUDENT AND POSTDOCTORAL RESEARCHERS