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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.

Obesity is a major risk factor for type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease that arises from a caloric surplus of as little as 10–30 kcal per day. And while increased consumption of energy dense foods and reduced physical activity are commonly thought to be the major contributors to this caloric imbalance, diet-induced thermogenesis is a quantitatively important component of the energy balance equation. In adult humans, recent studies have indicated that diet-induced thermogenesis requires the activation of brown adipose tissue (BAT), however, the determinants regulating this process and why they may differ between individuals are not fully understood. We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce diet-induced thermogenesis through suppression of uncoupling protein 1, the defining protein of human BAT thermogenesis. Through a screening approach of pesticides/toxicants chosen from the Toxcast chem Library, we discovered that the organophosphate insecticide chlorpyrifos potently suppressed the expression of uncoupling protein 1 (UCP1) and mitochondrial respiration in brown adipocytes at concentrations as low as 1 pM. Chloropyrifos-induced suppression of brown adipocyte thermogenesis was also observed in mice fed a diet high in fat and housed at thermoneutrality where it promoted greater obesity, non-alcoholic fatty liver disease and insulin resistance. Reductions in thermogenesis by chlorpyrifos were associated with impaired activation of the β3-adrenergic receptor and protein kinases critical for regulating UCP1 and mitophagy. These data indicate that the commonly used pesticide chlorpyrifos, at doses found within the food supply, suppresses the activation of brown adipose tissue, suggesting that its use may contribute to the obesity epidemic.

Deltamethrin is a commonly used pesticide for the control of mosquito populations. Despite widespread use, the effects of deltamethrin on adiposity and glucose homeostasis have been equivocal with some studies showing increased, decreased and no effect on adiposity and glycemic control. However, no study to date has investigated the effect of deltamethrin in mice housed at thermoneutral temperatures, which is important for modelling metabolic diseases in rodents due to reduced thermal stress and constitutive activation of brown adipose tissue. In the current study we demonstrate for the first time that deltamethrin reduces uncoupling protein-1 expression in brown adipocytes cultured in vitro at concentrations as low as 1pm. Meanwhile, in-vivo deltamethrin does not appear to alter glycemic control or promote adiposity at exposures equivalent to 0.01, 0.1 or 1.0 mg/kg/day. Together, our study demonstrates environmentally relevant exposure to deltamethrin does not exacerbate diet induced obesity or insulin resistance.