title: Loss of UCP2 impairs cold-induced non-shivering thermogenesis by promoting a shift toward glucose utilization in brown adipose tissue.
abstract: Uncoupling protein 2 (UCP2) was discovered in 1997 and classified as an uncoupling protein largely based on its homology of sequence with UCP1. Since its discovery, the uncoupling function of UCP2 has been questioned and there is yet no consensus on the true function of this protein. UCP2 was first proposed to be a reactive oxygen species (ROS) regulator and an insulin secretion modulator. More recently, it was demonstrated as a regulator of the mitochondrial fatty acid oxidation, which prompted us to investigate its role in the metabolic and thermogenic functions of brown adipose tissue. We first investigated the role of UCP2 in affecting the glycolysis capacity by evaluating the extracellular flux in cells lacking UCP2. We thereafter investigated the role of UCP2 in BAT thermogenesis with positron emission tomography using the metabolic tracers [11C]-acetate (metabolic activity), 2-deoxy-2-[18F]-fluoro-d-glucose (18FDG, glucose uptake) and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid [18FTHA, non-esterified fatty acid (NEFA) uptake]. The effect of the β3-adrenoreceptor (ADRB3) selective agonist, CL316,243 (CL), on BAT18FDG and18FTHA uptakes, as well as11C-acetate activity was assessed in UCP2KOand UCP2WTmice exposed at room temperature or adapted to cold. Our results suggest that despite the fact that UCP2 does not have the uncoupling potential of UCP1, its contribution to BAT thermogenesis and to the adaptation to cold exposure appears crucial. Notably, we found that the absence of UCP2 promoted a shift toward glucose utilization and increased glycolytic capacity in BAT, which conferred a better oxidative/thermogenic activity/capacity following an acute adrenergic stimulation. However, following cold exposure, a context of high-energy demand, BAT of UCP2KOmice failed to adapt and thermogenesis was impaired. We conclude that UCP2 regulates BAT thermogenesis by favouring the utilization of NEFA, a process required for the adaptation to cold.
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Caron
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
authors.forename: Sébastien M
authors.initials: SM
authors.lastname: Labbé
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Pharmacie, Faculté de Pharmacie, Université Laval, Québec, Québec, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Carter
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Roy
authors.affiliation: Département de Médecine Nucléaire et de Radiologie, Centre d'Imagerie Moléculaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Roger
authors.initials: R
authors.lastname: Lecomte
authors.affiliation: Université Paris Descartes, Faculté de Médecine, Institut Cochin, 24, Rue du Faubourg Saint- Jacques, 75014, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricquier
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Pharmacie, Faculté de Pharmacie, Université Laval, Québec, Québec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Picard
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Québec, G1V 4G5, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, Québec, Canada. Electronic address: denis.richard@criucpq.ulaval.ca.
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
mesh_terms: D019342:Acetic Acid / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D003080:Cold Temperature; D004149:Dioxoles / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis / Q000187:drug effects / Q000235:genetics*; D000071246:Uncoupling Protein 2 / Q000172:deficiency / Q000235:genetics*
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D004149:Dioxoles; D005227:Fatty Acids; D019275:Radiopharmaceuticals; D022702:Receptors, Adrenergic, beta-3; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D019788:Fluorodeoxyglucose F18; C071178:14-fluoro-6-thiaheptadecanoic acid; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D005947:Glucose; D019342:Acetic Acid
keywords: Brown adipose tissue; Cold; Energy metabolism; FDG; FTHA; Position emission tomography