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Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance.

Lim S, Ahn SY, Song IC, Chung MH, Jang HC, Park KS, Lee KU, Pak YK, Lee HK - PLoS ONE (2009)

Bottom Line: ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption.It also suppressed the insulin-mediated phosphorylation of Akt.These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to mitochondria, we investigated whether chronic exposure to low concentrations of ATZ might cause obesity or insulin resistance by damaging mitochondrial function. Sprague-Dawley rats (n = 48) were treated for 5 months with low concentrations (30 or 300 microg kg(-1) day(-1)) of ATZ provided in drinking water. One group of animals was fed a regular diet for the entire period, and another group of animals was fed a high-fat diet (40% fat) for 2 months after 3 months of regular diet. Various parameters of insulin resistance were measured. Morphology and functional activities of mitochondria were evaluated in tissues of ATZ-exposed animals and in isolated mitochondria. Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level. A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of ATZ-treated rats were swollen with disrupted cristae. ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. It also suppressed the insulin-mediated phosphorylation of Akt. These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.

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Inhibition of insulin signaling by ATZ.L6 cells were treated with ATZ (100 µg/mL) in DMEM containing 0.5% FBS for 24 hours and stimulated with insulin (100 ng/mL) for 30 minutes. The cells were harvested and analyzed by western blotting using anti-Akt or -pAkt antibodies. Akt Thr308 and Ser473 phosphorylation, both important in the insulin-signaling pathway, were blocked by ATZ treatment.
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pone-0005186-g007: Inhibition of insulin signaling by ATZ.L6 cells were treated with ATZ (100 µg/mL) in DMEM containing 0.5% FBS for 24 hours and stimulated with insulin (100 ng/mL) for 30 minutes. The cells were harvested and analyzed by western blotting using anti-Akt or -pAkt antibodies. Akt Thr308 and Ser473 phosphorylation, both important in the insulin-signaling pathway, were blocked by ATZ treatment.

Mentions: To investigate the mechanism by which ATZ-induced mitochondrial dysfunction caused insulin resistance, we analyzed insulin-stimulated Akt phosphorylation in ATZ-treated L6 muscle cells. Pretreatment with ATZ (100 µg/mL) for 24–48 hours abolished insulin-mediated Akt phosphorylation at both Thr308 and Ser473 residues (Fig. 7). Park et al. demonstrated that mitochondrial dysfunction induced by mtDNA depletion suppressed IRS-1 expression, resulting in diminished downstream signaling and glucose transport, and insulin resistance [5]. The suppression of insulin-mediated Akt phosphorylation is clearly linked to the development of insulin resistance in vitro [33] and in vivo [34]. Thus, the reduction in Akt phosphorylation that results from ATZ-mediated inhibition of mitochondrial OXPHOS complex III may help to explain why chronic exposure to ATZ induced weight gain and insulin resistance.


Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance.

Lim S, Ahn SY, Song IC, Chung MH, Jang HC, Park KS, Lee KU, Pak YK, Lee HK - PLoS ONE (2009)

Inhibition of insulin signaling by ATZ.L6 cells were treated with ATZ (100 µg/mL) in DMEM containing 0.5% FBS for 24 hours and stimulated with insulin (100 ng/mL) for 30 minutes. The cells were harvested and analyzed by western blotting using anti-Akt or -pAkt antibodies. Akt Thr308 and Ser473 phosphorylation, both important in the insulin-signaling pathway, were blocked by ATZ treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2664469&req=5

pone-0005186-g007: Inhibition of insulin signaling by ATZ.L6 cells were treated with ATZ (100 µg/mL) in DMEM containing 0.5% FBS for 24 hours and stimulated with insulin (100 ng/mL) for 30 minutes. The cells were harvested and analyzed by western blotting using anti-Akt or -pAkt antibodies. Akt Thr308 and Ser473 phosphorylation, both important in the insulin-signaling pathway, were blocked by ATZ treatment.
Mentions: To investigate the mechanism by which ATZ-induced mitochondrial dysfunction caused insulin resistance, we analyzed insulin-stimulated Akt phosphorylation in ATZ-treated L6 muscle cells. Pretreatment with ATZ (100 µg/mL) for 24–48 hours abolished insulin-mediated Akt phosphorylation at both Thr308 and Ser473 residues (Fig. 7). Park et al. demonstrated that mitochondrial dysfunction induced by mtDNA depletion suppressed IRS-1 expression, resulting in diminished downstream signaling and glucose transport, and insulin resistance [5]. The suppression of insulin-mediated Akt phosphorylation is clearly linked to the development of insulin resistance in vitro [33] and in vivo [34]. Thus, the reduction in Akt phosphorylation that results from ATZ-mediated inhibition of mitochondrial OXPHOS complex III may help to explain why chronic exposure to ATZ induced weight gain and insulin resistance.

Bottom Line: ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption.It also suppressed the insulin-mediated phosphorylation of Akt.These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

ABSTRACT
There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to mitochondria, we investigated whether chronic exposure to low concentrations of ATZ might cause obesity or insulin resistance by damaging mitochondrial function. Sprague-Dawley rats (n = 48) were treated for 5 months with low concentrations (30 or 300 microg kg(-1) day(-1)) of ATZ provided in drinking water. One group of animals was fed a regular diet for the entire period, and another group of animals was fed a high-fat diet (40% fat) for 2 months after 3 months of regular diet. Various parameters of insulin resistance were measured. Morphology and functional activities of mitochondria were evaluated in tissues of ATZ-exposed animals and in isolated mitochondria. Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level. A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of ATZ-treated rats were swollen with disrupted cristae. ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. It also suppressed the insulin-mediated phosphorylation of Akt. These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.

Show MeSH
Related in: MedlinePlus