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In the liver, CR shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated protein kinase (AMPK). Perfluorooctanesulfonic acid (PFOS), a fluorosurfactant previously used in stain repellents and anti-stick materials, can increase hepatic lipids in mice following relatively low-dose exposures. To test the hypothesis that PFOS administration interferes with CR, adult male C57BL\/6N mice were fed ad libitum or a 25% reduced calorie diet concomitant with either vehicle (water) or 100\u2009\u03bcg PFOS\/kg\/day via oral gavage for 6\u2009weeks. CR alone improved hepatic lipids and glucose tolerance. PFOS did not significantly alter CR-induced weight loss, white adipose tissue mass, or liver weight over 6\u2009weeks. However, PFOS increased hepatic triglyceride accumulation, in both mice fed ad libitum and subjected to CR. This was associated with decreased phosphorylated AMPK expression in liver. Glucagon (100\u2009nM) treatment induced glucose production in hepatocytes, which was further upregulated with PFOS (2.5\u2009\u03bcM) co-treatment. Next, to explore whether the observed changes were related to AMPK signaling, HepG2 cells were treated with metformin or AICAR alone or in combination with PFOS (25\u2009\u03bcM). PFOS interfered with glucose-lowering effects of metformin, and AICAR treatment partially impaired PFOS-induced increase in glucose production. In 3T3-L1 adipocytes, metformin was less effective with PFOS co-treatment. Overall, PFOS administration disrupted hepatic lipid and glucose homeostasis and interfered with beneficial glucose-lowering effects of CR and metformin.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab043","type":"journal-article","created":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T21:45:11Z","timestamp":1617918311000},"page":"82-95","source":"Crossref","is-referenced-by-count":28,"title":["Perfluorooctanesulfonic Acid (PFOS) Thwarts the Beneficial Effects of Calorie Restriction and Metformin"],"prefix":"10.1093","volume":"182","author":[{"given":"Deanna M","family":"Salter","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragati P","family":"Nahar","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6819-8154","authenticated-orcid":false,"given":"Emily","family":"Marques","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-6626","authenticated-orcid":false,"given":"Angela L","family":"Slitt","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"2021071619493473700_kfab043-B1","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.reprotox.2008.05.061","article-title":"Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR alpha) in the mouse","volume":"27","author":"Abbott","year":"2009","journal-title":"Reprod. 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