Project #3: Polychlorinated Biphenyls, Nutrition, and Diabetes
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 a high prevalence of obesity, type 2 diabetes, and cardiovascular diseases. Several epidemiological 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.
- Deficiency of aryl hydrocarbon receptor in adipocytes augments the development of diet-induced obesity
- Jackson E, Shoemaker R, Larian N, Cassis L. (2017). Adipose Tissue as a Site of Toxin Accumulation. Comprehensive Physiology 7(4):1085-1135.
- Baker NA, Shoemaker R, English V, Larian N, Sunkara M, Morris AJ, Walker M, Yiannikouris F, Cassis LA. (2015). Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice. Environmental Health Perspectives 123(10):944-50.
UK Superfund Graduate Trainee Nika Larian