(Project 3 - Cassis) Recent studies demonstrate a strong association between serum levels of polychlorinated biphenyls (PCBs) and an increased odds ratio for type 2 diabetes (T2D). This proposal tests the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhR) to increase expression of proinflammatory cytokines, resulting in reductions in glucose uptake and the development of insulin resistance. Further, we hypothesize that the polyphenol, resveratrol, can be used to prevent and/or treat PCB-induced elevations in adipocyte proinflammatory cytokine expression and impaired glucose homeostasis during weight loss. We demonstrated that administration of coplanar PCBs to low fat fed male and female mice induces glucose and insulin intolerance associated with adipose-specific elevations in tumor necrosis factor-? (TNF-?). Remarkably, when mice were made obese from consumption of a high fat (HF) diet, effects of PCB to impair glucose homeostasis were lost when lipophilic PCBs were sequestered at higher levels within adipose tissue lipids. However, upon weight loss, PCBs impaired glucose and insulin tolerance, limiting beneficial effects of weight loss to improve glucose homeostasis. These results suggest that obesity increases body burden of PCBs, and that release of PCBs during weight loss from adipose lipids may be harmful in the context of T2D. The anti-oxidant polyphenol and putative AhR antagonist, resveratrol, abolished acute effects of PCBs to impair glucose tolerance in mice, and protected against PCB-induced reductions in insulin signaling and glucose uptake in adipocytes.
Aim 1 will define the role of adipocyte AhR in PCB-induced impairment of glucose and insulin tolerance in lean male and female mice, and in obese mice experiencing weight loss. Results from these studies will define whether the enhanced accumulation of lipophilic PCBs to adipose tissue results in adipocyte-specific impairment of glucose uptake.
Aim 2 will define the adipocyte-specific effects of resveratrol on PCB-induced impairment of glucose homeostasis in obese male and female mice exhibiting weight loss. Results from this aim will determine if resveratrol acts to protect against PCB-induced impairment of glucose uptake and insulin resistance through an adipocyte-specific mechanism, and whether this therapeutic strategy have utility in the setting of weight loss. The impact of this research is identification of mechanisms linking PCB exposures to T2D and development of a therapeutic strategy, resveratrol, to protect against harmful effects of PCBs on glucose homeostasis in lean subjects, as well as obese subjects experiencing weight loss.

Public Health Relevance

(Project 3 - Cassis) The overall impact of this research is to identify mechanisms whereby polychlorinated biphenyls (PCBs), lipophilic environmental toxins, promote the development of insulin resistance and type 2 diabetes. Moreover, our approach will identify whether the natural polyphenol, resveratrol, can be used as an interventional strategy to protect against harmful effects of PCBs on glucose homeostasis in lean subjects, and in obese subjects experiencing weight loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
2P42ES007380-17A1
Application #
8649940
Study Section
Special Emphasis Panel (ZES1-LKB-K (S))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
17
Fiscal Year
2014
Total Cost
$348,187
Indirect Cost
$96,188
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Murphy, Margaret O; Petriello, Michael C; Han, Sung Gu et al. (2016) Exercise protects against PCB-induced inflammation and associated cardiovascular risk factors. Environ Sci Pollut Res Int 23:2201-11
Perkins, Jordan T; Petriello, Michael C; Newsome, Bradley J et al. (2016) Polychlorinated biphenyls and links to cardiovascular disease. Environ Sci Pollut Res Int 23:2160-72
Platt, Kristen M; Charnigo, Richard J; Shertzer, Howard G et al. (2016) Branched-Chain Amino Acid Supplementation in Combination with Voluntary Running Improves Body Composition in Female C57BL/6 Mice. J Diet Suppl 13:473-86
Wahlang, Banrida; Petriello, Michael C; Perkins, Jordan T et al. (2016) Polychlorinated biphenyl exposure alters the expression profile of microRNAs associated with vascular diseases. Toxicol In Vitro 35:180-7
Pennell, Kelly G; Scammell, Madeleine K; McClean, Michael D et al. (2016) Field data and numerical modeling: A multiple lines of evidence approach for assessing vapor intrusion exposure risks. Sci Total Environ 556:291-301
Hunt, Gary; Stegeman, John; Robertson, Larry (2016) PCBs: exposures, effects, remediation, and regulation with special emphasis on PCBs in schools. Environ Sci Pollut Res Int 23:1971-4
Liu, Dandan; Perkins, Jordan T; Hennig, Bernhard (2016) EGCG prevents PCB-126-induced endothelial cell inflammation via epigenetic modifications of NF-κB target genes in human endothelial cells. J Nutr Biochem 28:164-70
Kania-Korwel, Izabela; Lehmler, Hans-Joachim (2016) Chiral polychlorinated biphenyls: absorption, metabolism and excretion-a review. Environ Sci Pollut Res Int 23:2042-57
Petriello, Michael C; Hoffman, Jessie B; Sunkara, Manjula et al. (2016) Dioxin-like pollutants increase hepatic flavin containing monooxygenase (FMO3) expression to promote synthesis of the pro-atherogenic nutrient biomarker trimethylamine N-oxide from dietary precursors. J Nutr Biochem 33:145-53
Baker, Nicki A; Shoemaker, Robin; English, Victoria et al. (2015) Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice. Environ Health Perspect 123:944-50

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