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

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

doi:10.1038/s41467-021-25384-y

Abstract

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.

Highlights

Obesity results from a caloric imbalance between energy intake, absorption and expenditure
Over the last two decades, a number of environmental toxicants have been linked to the development of obesity through their effects on gut microbiota[14], energy intake, or adipogenesis[15,16,17,18], only a few of these studies have examined a role for these agents to contribute to obesity by inhibiting energy expenditure[21,22,23] and/or brown adipose tissue (BAT) thermogenesis[24,25]
Through a step-wise screening of several common food contaminants or additives, we discovered that the organophosphate insecticide chlorpyrifos (CPF) potently suppressed the expression of uncoupling protein 1 (UCP1) and mitochondrial respiration in brown adipocytes at concentrations as low as 1 pM

Summary

Introduction

Obesity results from a caloric imbalance between energy intake, absorption and expenditure. 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. Reductions in BAT thermogenesis by CPF were associated with reductions in cAMP and protein kinases critical for regulating UCP1 and mitophagy These data indicate that the commonly used pesticide CPF, at very low concentrations, suppresses the activation of BAT, suggesting that its use may contribute to the obesity epidemic

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Conclusion