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

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

doi:10.1038/s41467-021-25384-y

Cited by 51 publications

(35 citation statements)

References 85 publications

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“…Brown adipocyte is an attractive therapeutic target for the prevention of obesity and related metabolic diseases, including type 2 diabetes [39][40][41]. ciBAs present a promising cell model for the identification of bioactive molecules to promote adipocyte browning and brown adipogenesis in humans [31].…”

Section: Discussionmentioning

confidence: 99%

Chronic Fatty Acid Depletion Induces Uncoupling Protein 1 (UCP1) Expression to Coordinate Mitochondrial Inducible Proton Leak in a Human-Brown-Adipocyte Model

Takeda

Dai

2022

Cells

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Thermogenic brown fat contributes to metabolic health in adult humans. Obese conditions are known to repress adipose-tissue browning and its activity. Herein, we found that chronic fatty acid (FA) depletion induced uncoupling protein 1 (UCP1) expression in the chemical-compound-induced brown adipocytes (ciBAs). The ciBAs, converted from human dermal fibroblasts under FA-free conditions, had low intracellular triglyceride levels and strongly activated UCP1 expression. Prolonged treatment with carnitine also reduced triglyceride accumulation and induced UCP1 expression. Transcriptome analysis revealed that the UCP1 induction was accompanied by the activation of lipid metabolic genes. The FA-depleted conditions repressed mitochondrial proton-leak activity and mitochondrial membrane potential (MMP), despite maintaining a high UCP1 expression. The evidence suggested that UCP1 expression was induced to compensate for the proton-leak activity under low MMP. Our study reports a regulatory mechanism underlying UCP1 expression and mitochondrial-energy status in human brown adipocytes under different nutritional conditions.

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Section: Discussionmentioning

confidence: 99%

Chronic Fatty Acid Depletion Induces Uncoupling Protein 1 (UCP1) Expression to Coordinate Mitochondrial Inducible Proton Leak in a Human-Brown-Adipocyte Model

Takeda

Dai

2022

Cells

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“…Moreover, PDE4B, which is highly expressed in the liver, selectively hydrolyses cAMP ( 27 ). Low levels of cAMP lead to the reduction of mitochondrial function and oxygen consumption, thus promoting NAFLD and insulin resistance ( 54 ). Conversely, GAS5 knockdown elevated cAMP, which could be attributed to PDE4B inhibition.…”

Section: Discussionmentioning

confidence: 99%

LncRNA GAS5 Knockdown Mitigates Hepatic Lipid Accumulation via Regulating MiR-26a-5p/PDE4B to Activate cAMP/CREB Pathway

Wang

et al. 2022

Front. Endocrinol.

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ObjectiveNon-alcoholic fatty liver disease (NAFLD) can be attributed to the dysregulation of hepatic lipid metabolism; however, its cellular and molecular mechanisms remain unclear. This study aims to explore the effect of long non-coding RNA growth arrest specific 5 (GAS5) on hepatic lipid metabolism in fatty liver models.MethodsObese mice, high fat diet-fed mice and free fatty acid-stimulated cells were used for GAS5 expression detection. GAS5 overexpression or knockdown models were established to elucidate the regulatory function of GAS5 in de novo lipogenesis (DNL) and mitochondrial function. Bioinformatic analyses and dual luciferase assays were used to investigate the interaction between GAS5, miR-26a-5p and phosphodiesterase (PDE) 4B. The involvement of the cyclic adenosine monophosphate (cAMP)/cAMP-response element-binding protein (CREB) pathway was evaluated using H89 and forskolin treatment.ResultsGAS5 was activated in vitro and in vivo fatty liver models. Knockdown of GAS5 reduced lipid droplet accumulation, DNL associated enzymes and preserved mitochondrial function, while GAS5 overexpression exacerbated hepatic lipid accumulation. Mechanistically, GAS5 sponged miR-26a-5p to increase PDE4B expression and subsequently modulated DNL and mitochondrial function via the cAMP/CREB pathway.ConclusionDownregulation of GAS5 can activate the cAMP/CREB pathway through miR-26a-5p/PDE4B axis to mitigate hepatic lipid accumulation. This study provides evidence that downregulation of GAS5 may be a potential therapeutic option for the treatment of NAFLD.

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“…In addition, double mutants for fat-5 and cyp-35A2 have shown reduction in lipid content in C. elegans (Imanikia et al 2015). Notably, CPF is known to accumulate in fat (Bakke et al 1976; Eaton et al 2008; Smith et al 1967), due to prolonged half-life (Smith et al 1967), which is further exacerbated by CPF induced accumulation of fat (Howell et al 2016; Wang et al 2021). Cyp-35A2 and cyp-35A3 are not homologous to human CPF metabolizing enzymes (i.e., CYP450 2B6).…”

Section: Discussionmentioning

confidence: 99%

Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos oxon induced dopaminergic neurotoxicity

Sammi

Syeda

Conrow

et al. 2022

Preprint

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Organophosphate (OP) pesticides are widely used in agriculture. While acute cholinergic toxicity has been extensively studied, chronic effects on other neurons are less understood. Here, we demonstrated that the OP pesticide chlorpyrifos (CPF) and its oxon metabolite are dopaminergic neurotoxicants in Caenorhabditis elegans. CPF treatment led to inhibition of mitochondrial complex II, II + III, and V in rat liver mitochondria, while CPF oxon did not (complex II + III, and IV inhibition observed only at high doses). While the effect on C. elegans cholinergic behavior was mostly reversible with toxicant washout, dopamine-associated deficits persisted, suggesting dopaminergic neurotoxicity was irreversible. CPF reduced the mitochondrial content in a dose-dependent manner and the fat modulatory genes cyp-35A2 and cyp-35A3 were found to have a key role in CPF neurotoxicity. These findings were consistent with in vitro effects of CPF and CPF oxon on nuclear receptor signaling and fatty acid/steroid metabolism observed in ToxCast assays. Two-way hierarchical analysis revealed in vitro effects on estrogen receptor (ER,) pregnane X receptor (PXR), and peroxisome proliferator-activated receptor gamma (PPAR gamma) pathways as well as neurotoxicity of chlorpyrifos, malathion, and diazinon, while these effects were not detected in malaoxon and diazoxon. Taken together, our study suggests that mitochondrial toxicity and metabolic effects of CPF, but not CPF-oxon, have a key role of CPF neurotoxicity in the low-dose, chronic exposure. Further mechanistic studies are needed to examine mitochondria as a common target for all OP pesticide parent compounds, since this has important implications on cumulative pesticide risk assessment.

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

Cited by 51 publications

References 85 publications

Chronic Fatty Acid Depletion Induces Uncoupling Protein 1 (UCP1) Expression to Coordinate Mitochondrial Inducible Proton Leak in a Human-Brown-Adipocyte Model

Chronic Fatty Acid Depletion Induces Uncoupling Protein 1 (UCP1) Expression to Coordinate Mitochondrial Inducible Proton Leak in a Human-Brown-Adipocyte Model

LncRNA GAS5 Knockdown Mitigates Hepatic Lipid Accumulation via Regulating MiR-26a-5p/PDE4B to Activate cAMP/CREB Pathway

Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos oxon induced dopaminergic neurotoxicity

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