Effect of Pesticides on Peroxisome Proliferator-Activated Receptors (PPARs) and Their Association with Obesity and Diabetes

Abstract

Obesity and diabetes mellitus are considered the most important diseases of the XXI century. Recently, many epidemiological studies have linked exposure to pesticides to the development of obesity and type 2 diabetes mellitus. The role of pesticides and their possible influence on the development of these diseases was investigated by examining the relationship between these compounds and one of the major nuclear receptor families controlling lipid and carbohydrate metabolism: the peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ; this was possible through in silico, in vitro, and in vivo assays. The present review aims to show the effect of pesticides on PPARs and their contribution to the changes in energy metabolism that enable the development of obesity and type 2 diabetes mellitus.

Figure 1

Activation of PPARγ and its interaction with lipid metabolism on the adipocyte. El PPARγ is conditioned to C/EBPα activation, once activated the receptor can recognize and bind to a PEP sequence of the genes of Acc, Fas, Ap2 y Lpl, which are involved with lipogenesis, adipocyte differentiation, lipid accumulation, and adipogenesis; lets the secretion of adipokines, therefore, are used as biomarkers of PPARγ activation. Also, the activation can be blocked by the accumulation of Ca⁺² ions and ER activation. Abbreviations: ACC, acetyl Co-A carboxylase; AMPKα, AMP-activated protein kinase; C/EBPα-, CCAAT enhancer binding protein alpha; C/EBP-β, CCAAT enhancer binding protein beta; C/EBP-d, CCAAT enhancer binding protein delta; ER, estrogen receptor; FABP4, fatty acid-binding protein 4; FAS, fatty acid synthase; GLUT-4, glucose transporter type 4; LPL, lipoprotein lipase; PPARγ, peroxisome proliferator-activated receptor gamma; TG, triglycerides.

Figure 2

Effects of pesticides on carbohydrate and fat metabolism involving diabetes and obesity through activation of PPARs. Activation of PPARs by pesticides and their effects have been linked to the development of obesity and diabetes in many tissues: adipocytes (a) show mainly PPARα and PPARγ activation to lipid metabolism; in hepatocytes (b) PPARγ is involved in lipid metabolism, PPARα is associated with peroxisome proliferation to cancer and PPAR β/δ in the carbohydrate metabolism; in pancreatic beta cells (c) the role of PPAR affected by pesticides and the function of these cells is not clear; in myocytes (d) PPAR β/δ activation is essential for the regulation of energy metabolism, but the effects of pesticide exposure are unclear; finally, (e) the disruption of the gut microbiota in the development of obesity and diabetes about PPAR activation is unknown. Abbreviations: ACC, acetyl Co-A carboxylase; ACO, acyl-CoA oxidase; AMPKa, AMP-activated protein kinase alpha; ATP, adenosine triphosphate; C/EBP-α, CCAAT enhancer binding protein alpha; C/EBP-δ, CCAAT enhancer binding protein delta; C/EBP-β, CCAAT enhancer binding protein beta; CPT-1, carnitine palmitoyltransferase I; ER, endoplasmic reticulum, FABP4, fatty acid-binding protein 4; FAS, fatty acid synthase; GLUT-2, glucose transporter type 2; GLUT-4, glucose transporter type 4; LPL, lipoprotein lipase; PPARα, peroxisome proliferator-activated receptor alpha; PPARβ/δ, peroxisome proliferator-activated receptor beta/delta; PPARγ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; RXR, retinoid X receptor; SREBP-1C, sterol regulatory element-binding protein 1, TG, triglycerides.