Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

Scientific Reports, Jun 2015

Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

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Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

Abstract Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice. Introduction Perfluoroalkyl acids (PFAAs) are a family of anthropogenic compounds used worldwide in a number of applications due to their unique physical and chemical characteristics1. Perfluorooctanoic acid (PFOA) is one of the most widely known PFAAs found in human and wildlife serum, with earlier toxicological studies showing its evident effects on body weight, liver weight, serum cholesterol and mortality in rodents1. Peroxisome proliferator activated receptors (PPARs) mediate the effects of eicosanoids, fatty acids and synthetic peroxisome proliferators on gene transcription and play specific roles in lipid metabolism and inflammation regulation2,3,4. Three PPAR isotypes, PPARα, β/δ and γ, have been identified, with PPARα highly expressed in the liver4. PFOA has been reported to induce liver enlargement along with alteration of lipid metabolism genes in rodents. Due to its significant effect on fatty acids β-oxidation, ketogenesis and systemic lipid metabolism, PPARα activation is the most likely reason that PFOA induces hepatomegaly and hepatic lipid metabolism1,3,5. Medical surveillance research and experimental studies have investigated the potential effects of PFOA on liver and lipid metabolism. PFOA exposure appears to be positively associated with serum alanine aminotransferase (ALT) levels and negatively associated with serum high-density lipoprotein cholesterol (HDL-C) levels in fluorochemical production workers6,7. Triglycerides are also positively associated with PFOA in humans, though not consistently across locations8,9. Different from lipid metabolism, only a small number of studies on the effects of PFAAs on glucose metabolism have been reported. Due to the rising prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, there is growing interest in whether environmental pollutants are involved in such diseases10. Medical surveillance studies have implied that environmental exposure might be associated with diabetes mellitus, a metabolic disease characterized by high blood glucose levels11,12. However, several epidemiological studies have reported that PFOA and other PFAAs are not associated with diabetes, but might influence glucose metabolism in humans10,11,13,14,15. Clearly, the association between PFAAs and diabetes remains uncertain, and the study on mechanisms of the potential effects of PFOA on the glucose homeostasis is necessary. Phosphatidylinositol 3-kinases (PI3Ks) can be divided into three classes based on their structural and biochemical features. Class IA PI3Ks (including p110α, p110β and p110δ), as well as the p85 regulatory subunits (including p85α, p85β, p55γ, p55α and p50α), have been suggested to play key roles in the metabolic functions of insulin16,17,18. Phosphoinositide-dependent kinase 1 (PDK1) is one of the best characterized signaling molecules regulated by PI3K and it consequently activates serine/threonine protein kinase (AKT, also known as protein kinase B, PKB), which is important in the transmission of the insulin signal16,19. Because of the key role the liver plays in glucose homeostasis and the evident toxicological effects of PFOA on the liver, we hypothesized that PFOA could disturb glucose homeostasis through interference with hepatic glucose metabolism. Accordingly, we assessed the modulation of the PI3K-AKT signaling pathway in mouse liver after 28 d of PFOA exposure, and further investigated the effects of PFOA on glucose metabolism through tolerance tests and serum proteomics. We found that PFOA exposure for 28 d affected glu (...truncated)


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Shengmin Yan, Hongxia Zhang, Fei Zheng, Nan Sheng, Xuejiang Guo, Jiayin Dai. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice, Scientific Reports, 2015, Issue: 5, DOI: 10.1038/srep11029