title: Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria.
abstract: The metabolically inert perfluorinated fatty acids perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) can display fatty acid-like activity in biological systems. The uncoupling protein 1 (UCP1) in brown adipose tissue is physiologically (re)activated by fatty acids, including octanoate. This leads to bioenergetically uncoupled energy dissipation (heat production, thermogenesis). We have examined here the possibility that PFOA/PFOS can directly (re)activate UCP1 in isolated mouse brown-fat mitochondria. In wild-type brown-fat mitochondria, PFOS and PFOA overcame GDP-inhibited thermogenesis, leading to increased oxygen consumption and dissipated membrane potential. The absence of this effect in brown-fat mitochondria from UCP1-ablated mice indicated that it occurred through activation of UCP1. A competitive type of inhibition by increased GDP concentrations indicated interaction with the same mechanistic site as that utilized by fatty acids. No effect was observed in heart mitochondria, i.e., in mitochondria without UCP1. The stimulatory effect of PFOA/PFOS was not secondary to non-specific mitochondrial membrane permeabilization or to ROS production. Thus, metabolic effects of perfluorinated fatty acids could include direct brown adipose tissue (UCP1) activation. The possibility that this may lead to unwarranted extra heat production and thus extra utilization of food resources, leading to decreased fitness in mammalian wildlife, is discussed, as well as possible negative effects in humans. However, a possibility to utilize PFOA-/PFOS-like substances for activating UCP1 therapeutically in obesity-prone humans may also be envisaged.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Shabalina
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Kalinovich
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden. jan@metabol.su.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
mesh_terms: D052437:Adipocytes, Brown / Q000187:drug effects* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D002210:Caprylates / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005466:Fluorocarbons / Q000633:toxicity*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D022722:Thermogenesis / Q000187:drug effects; D013997:Time Factors; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D005466:Fluorocarbons; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D006153:Guanosine Diphosphate; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid; D006861:Hydrogen Peroxide
keywords: Brown adipose tissue mitochondria; Environmental pollution; Membrane potential; Mitochondrial permeabilization; Reactive oxygen species; Uncoupling protein 1