Journal Article

The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

Green, Alexander E., Wu, Jianhan, Morrison, Katherine M., Tsakiridis, Evangelia E., Kajimura, Shingo, Lally, James S. V., Smith, Brennan K., Wade, Michael G., Llanos, Andrea, McArthur, Andrew G., Zhang, Shuman, Holloway, Alison C., Wang, Bo, Srinivasan, Krishna A., Yabut, Julian M., Steinberg, Gregory R., Patel, Jagdish Suresh, Desjardins, Eric M., Day, Emily A., Raphenya, Amogelang R.

2021

Overview

Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic. Chlorpyrifos is a widely-used pesticide and a common residue on vegetables and fruits. Here the authors show that at non-neurotoxic doses, chlorpyrifos reduces energy expenditure, by inhibiting diet induced thermogenesis, and promotes obesity and insulin resistance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 38/77 / 631/443/319/1642/393 / 692/163/2743/393 / Adipose tissue / Adipose tissue (brown) / Adipose Tissue, Brown - physiopathology / AMP-Activated Protein Kinase Kinases / Animals / BASIC BIOLOGICAL SCIENCES / Chlorpyrifos / Chlorpyrifos - metabolism / Chlorpyrifos - toxicity / Cyclic AMP - metabolism / Diet / Disease resistance / Energy expenditure / Energy intake / Energy Metabolism / Fatty liver / Food additives / Food Contamination - analysis / High fat diet / Humanities and Social Sciences / Humans / Insecticide resistance / Insecticides / Insulin / Insulin resistance / Kinases / Liver diseases / Male / Mice / Mice, Inbred C57BL / Mitochondria / multidisciplinary / Neurotoxicity / Obesity / Obesity - chemically induced / Obesity - metabolism / Obesity - physiopathology / Organophosphates / p38 Mitogen-Activated Protein Kinases - genetics / p38 Mitogen-Activated Protein Kinases - metabolism / Pesticide residues / Pesticides / Pesticides - metabolism / Pesticides - toxicity / Protein kinase / Protein Kinases - genetics / Protein Kinases - metabolism / Proteins / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Thermogenesis / Thermogenesis - drug effects / Toxicants / Uncoupling protein 1 / Uncoupling Protein 1 - genetics / Uncoupling Protein 1 - metabolism