A growing body of epidemiological and laboratory evidence suggests a connection between exposure to environmental chemicals, including insecticides and development of obesity and type 2 diabetes. However, among insecticides, neonicotinoids have not been extensively examined for their potential contribution to obesity and its associated pathologies. The long-term goal is to elucidate the underlying causes of obesity and type 2 diabetes. The objective of this project is to determine the potential contribution of imidacloprid (a neonicotinoid insecticide) on the development of obesity and diabetes. The central hypothesis is exposure to imidacloprid will impair lipid metabolism and glucose homeostasis along with dietary factors, resulting in potentiated weight gain and impaired insulin responses. The rationale that underlies the proposed research is that by understanding biochemical mechanisms of environmental chemicals (imidacloprid in this case) on development of obesity and its health impacts, we will be able to direct more efficient prevention and/or treatment strategies for these pathologies in the future. Additionally, identifying influence of dietary factors along with environmental chemical factors contributing to weight gain will strengthen our current effort to control obesity and its consequent health issues. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing knowledge that will potentially help to reduce human diseases. Based on our preliminary data, the hypothesis will be tested by pursuing the following specific aim: Determine the biochemical mechanisms of imidacloprid exposure on development of obesity and type 2 diabetes. Three approaches will be used: in vivo mouse model (Objective 1) and in vitro adipocyte and myotube models (Objectives 2 &3). In Objective 1, the sex-dependency, dose-response, and interaction with dietary fat of imidacloprid exposure upon weight gain and glucose homeostasis will be determined using the C57BL/6J mouse model. In Objective 2, using 3T3-L1 adipocytes we will determine the mechanism by which exposure to imidacloprid may modulate lipid metabolism, testing our hypothesis that imidacloprid promotes adipogenesis as a result of modulating AMP-activated protein kinase (AMPK) via a calcium- dependent mechanism. In Objective 3, using C2C12 myotubes we will determine the mechanism by which exposure to imidacloprid modulates glucose homeostasis, testing our hypothesis that imidacloprid negatively influences insulin-stimulated glucose metabolism by impairing insulin-receptor substrate-1 (IRS-1) activation via a calcium-dependent mechanism. The innovative aspect of this proposed research is targeting a neonicotinoid insecticide as a potential contributing agent for the development of obesity and its associated pathologies. The results from the proposed research will be significant since the outcome will provide insight into fundamental underlying mechanisms between imidacloprid exposure and potential incidences of obesity and its associated pathologies.

Public Health Relevance

The proposed research is relevant to public health since comprehending the underlying mechanisms of neonicotinoid insecticide exposure on the development of obesity and/or type 2 diabetes will lead to developing strategies for prevention and/or treatment of obesity and its health impact in the future. Thus, the proposed research is relevant to the part of NIH's mission that seeks and applies fundamental knowledge to enhance health, lengthen life and reduce the burdens of illness and disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES023128-01A1
Application #
8768422
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Heindel, Jerrold
Project Start
2014-09-10
Project End
2016-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$227,822
Indirect Cost
$77,822
Name
University of Massachusetts Amherst
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003