{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:19:18Z","timestamp":1790741958697,"version":"4.1.0"},"reference-count":44,"publisher":"The Endocrine Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,6,1]]},"abstract":"<jats:p>Mice expressing the mutant thyroid hormone receptor TR\u03b11R384C, which has a 10-fold reduced affinity to the ligand T3, exhibit hypermetabolism due to an overactivation of the sympathetic nervous system. To define the consequences in the liver, we analyzed hepatic metabolism and the regulation of liver genes in the mutant mice. Our results showed that hepatic phosphoenolpyruvate-carboxykinase was up-regulated and pyruvate kinase mRNA down-regulated, contrary to what observed after T3 treatment. In contrast, mice expressing a mutant TR\u03b11L400R specifically in the liver did not show a dysregulation of these genes; however, when the TR\u03b11L400R was expressed ubiquitously, the hepatic phenotype differed from TR\u03b11R384C animals, suggesting that the localization of the mutation plays an important role for its consequences on glucose metabolism. Furthermore, we observed that glycogen stores were completely depleted in TR\u03b11R384C animals, despite increased gluconeogenesis and decreased glycolysis. Exposure of the mutant mice to high maternal levels of thyroid hormone during fetal development leads to a normal liver phenotype in the adult. Our results show how genetic and maternal factors interact to determine the metabolic setpoint of the offspring and indicate an important role for maternal thyroid hormone in the susceptibility to metabolic disorders in adulthood.<\/jats:p>","DOI":"10.1210\/en.2008-1085","type":"journal-article","created":{"date-parts":[[2009,3,13]],"date-time":"2009-03-13T01:06:24Z","timestamp":1236906384000},"page":"2940-2947","source":"Crossref","is-referenced-by-count":42,"title":["Interference of a Mutant Thyroid Hormone Receptor \u03b11 with Hepatic Glucose Metabolism"],"prefix":"10.1210","volume":"150","author":[{"given":"Milica","family":"Vujovic","sequence":"first","affiliation":[{"name":"Karolinska Institutet (M.V., K.N., B.V., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Nordstro\u0308m","sequence":"first","affiliation":[{"name":"Karolinska Institutet (M.V., K.N., B.V., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Gauthier","sequence":"first","affiliation":[{"name":"Institut de Ge\u0301nomique Fonctionnelle de Lyon (K.G., F.F.), Universite\u0301 de Lyon, Universite\u0301 Lyon 1, Centre National de la Recherche Scientifique, Institut National de la Recherche Agonomique, Ecole Normale Supe\u0301rieure de Lyon, 69007 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fre\u0301de\u0301ric","family":"Flamant","sequence":"first","affiliation":[{"name":"Institut de Ge\u0301nomique Fonctionnelle de Lyon (K.G., F.F.), Universite\u0301 de Lyon, Universite\u0301 Lyon 1, Centre National de la Recherche Scientifique, Institut National de la Recherche Agonomique, Ecole Normale Supe\u0301rieure de Lyon, 69007 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo J.","family":"Visser","sequence":"first","affiliation":[{"name":"Erasmus Medical Center (T.J.V.), Department of Internal Medicine, 3000 DR Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjo\u0308rn","family":"Vennstro\u0308m","sequence":"first","affiliation":[{"name":"Karolinska Institutet (M.V., K.N., B.V., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Mittag","sequence":"first","affiliation":[{"name":"Karolinska Institutet (M.V., K.N., B.V., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2009,3,12]]},"reference":[{"key":"2020071612350995100_R1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1089\/thy.2007.0266","article-title":"Thyroid hormone as a determinant of energy expenditure and the basal metabolic rate.","volume":"18","author":"Kim","year":"2008","journal-title":"Thyroid"},{"key":"2020071612350995100_R2","first-page":"184","article-title":"Thyroid hormone receptors: multiple forms, multiple possibilities.","volume":"14","author":"Lazar","year":"1993","journal-title":"Endocr Rev"},{"key":"2020071612350995100_R3","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1089\/105072503770867174","article-title":"Perspectives in the study of thyroid hormone action on brain development and function.","volume":"13","author":"Bernal","year":"2003","journal-title":"Thyroid"},{"key":"2020071612350995100_R4","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/sj.mp.4001196","article-title":"Lack of thyroid hormone receptor \u03b11 is associated with selective alterations in behavior and hippocampal circuits.","volume":"8","author":"Guadan\u0303o-Ferraz","year":"2003","journal-title":"Mol Psychiatry"},{"key":"2020071612350995100_R5","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1523\/JNEUROSCI.5163-07.2008","article-title":"Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor \u03b11.","volume":"28","author":"Wallis","year":"2008","journal-title":"J Neurosci"},{"key":"2020071612350995100_R6","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1210\/me.2002-0009","article-title":"Requirement for thyroid hormone receptor \u03b2 in T3 regulation of cholesterol metabolism in mice.","volume":"16","author":"Gullberg","year":"2002","journal-title":"Mol Endocrinol"},{"key":"2020071612350995100_R7","doi-asserted-by":"crossref","first-page":"4945","DOI":"10.1210\/endo.139.12.6412","article-title":"Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor \u03b2-deficient mice.","volume":"139","author":"Weiss","year":"1998","journal-title":"Endocrinology"},{"key":"2020071612350995100_R8","first-page":"348","article-title":"The syndromes of resistance to thyroid hormone.","volume":"14","author":"Refetoff","year":"1993","journal-title":"Endocr Rev"},{"key":"2020071612350995100_R9","doi-asserted-by":"crossref","first-page":"5079","DOI":"10.1093\/emboj\/cdf523","article-title":"Retardation of post-natal development caused by a negatively acting thyroid hormone receptor \u03b11.","volume":"21","author":"Tinnikov","year":"2002","journal-title":"EMBO J"},{"key":"2020071612350995100_R10","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1101\/gad.346105","article-title":"Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor \u03b11 can be ameliorated by T3 treatment.","volume":"19","author":"Venero","year":"2005","journal-title":"Genes Dev"},{"key":"2020071612350995100_R11","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1038\/sj.emboj.7601882","article-title":"Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor \u03b11.","volume":"26","author":"Sjo\u0308gren","year":"2007","journal-title":"EMBO J"},{"key":"2020071612350995100_R12","doi-asserted-by":"crossref","first-page":"20643","DOI":"10.1016\/S0021-9258(19)47112-3","article-title":"Effect of thyroid hormones on glucokinase gene transcription in rat liver.","volume":"264","author":"Ho\u0308ppner","year":"1989","journal-title":"J Biol Chem"},{"key":"2020071612350995100_R13","first-page":"1257","article-title":"Patterns of liver gene expression governed by TR\u03b2.","volume":"16","author":"Flores-Morales","year":"2002","journal-title":"Mol Endocrinol"},{"key":"2020071612350995100_R14","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/ng1175","article-title":"Hepatocyte nuclear factor 4\u03b1 controls the development of a hepatic epithelium and liver morphogenesis.","volume":"34","author":"Parviz","year":"2003","journal-title":"Nat Genet"},{"key":"2020071612350995100_R15","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1210\/me.2007-0176","article-title":"A point mutation in the activation function 2 domain of thyroid hormone receptor \u03b11 expressed after CRE-mediated recombination partially recapitulates hypothyroidism.","volume":"21","author":"Quignodon","year":"2007","journal-title":"Mol Endocrinol"},{"key":"2020071612350995100_R16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S1043-9471(06)80113-8","article-title":"In situ hybridization techniques to study processing enzyme expression at the cellular level.","volume":"23","author":"Scha\u0308fer","year":"1995","journal-title":"J Neurosci Methods"},{"key":"2020071612350995100_R17","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1210\/me.2005-0256","article-title":"Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism.","volume":"20","author":"Friesema","year":"2006","journal-title":"Mol Endocrinol"},{"key":"2020071612350995100_R18","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1042\/bj0570410","article-title":"Two methods for the determination of glycogen in liver.","volume":"57","author":"Van Der Vies","year":"1954","journal-title":"Biochemical J"},{"key":"2020071612350995100_R19","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1002\/hep.21651","article-title":"WNT\/\u03b2-catenin signaling in liver health and disease.","volume":"45","author":"Thompson","year":"2007","journal-title":"Hepatology"},{"key":"2020071612350995100_R20","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1128\/MCB.26.8.3204-3214.2006","article-title":"Thyroid hormone receptor \u03b11 directly controls transcription of the \u03b2-catenin gene in intestinal epithelial cells.","volume":"26","author":"Plateroti","year":"2006","journal-title":"Mol Cell Biol"},{"key":"2020071612350995100_R21","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1210\/en.2004-1179","article-title":"The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations.","volume":"146","author":"Heuer","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612350995100_R22","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1042\/bj2710585","article-title":"Insulin and tri-iodothyronine induce glucokinase mRNA in primary cultures of neonatal rat hepatocytes.","volume":"271","author":"Narkewicz","year":"1990","journal-title":"Biochem J"},{"key":"2020071612350995100_R23","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.bbrc.2007.07.108","article-title":"Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action.","volume":"361","author":"Chen","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612350995100_R24","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1146\/annurev.biochem.66.1.581","article-title":"Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression.","volume":"66","author":"Hanson","year":"1997","journal-title":"Annu Rev Biochem"},{"key":"2020071612350995100_R25","first-page":"E513","article-title":"Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats","volume":"294","author":"Klieverik","year":"2008","journal-title":"Am J Physiol"},{"key":"2020071612350995100_R26","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1089\/thy.2005.15.899","article-title":"Peripheral metabolism of thyroid hormone and glucose homeostasis.","volume":"15","author":"Chidakel","year":"2005","journal-title":"Thyroid"},{"key":"2020071612350995100_R27","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1146\/annurev.ph.54.030192.004321","article-title":"Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.","volume":"54","author":"Pilkis","year":"1992","journal-title":"Annu Rev Physiol"},{"key":"2020071612350995100_R28","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/nature03439","article-title":"Hypothalamic KATP channels control hepatic glucose production.","volume":"434","author":"Pocai","year":"2005","journal-title":"Nature"},{"key":"2020071612350995100_R29","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1152\/ajplegacy.1975.228.6.1787","article-title":"Effects of hypothalamic stimulation on gluconeogenesis and glycolysis in rat liver.","volume":"228","author":"Shimazu","year":"1975","journal-title":"Am J Physiol"},{"key":"2020071612350995100_R30","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/ar.a.20091","article-title":"Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves.","volume":"280","author":"Puschel","year":"2004","journal-title":"Anat Rec"},{"key":"2020071612350995100_R31","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1042\/bj2550099","article-title":"Zonation of glycogen and glucose syntheses, but not glycolysis, in rat liver.","volume":"255","author":"Chen","year":"1988","journal-title":"Biochem J"},{"key":"2020071612350995100_R32","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1210\/endo.143.3.8706","article-title":"TR\u03b21 protein is preferentially expressed in the pericentral zone of rat liver and exhibits marked diurnal variation.","volume":"143","author":"Zandieh Doulabi","year":"2002","journal-title":"Endocrinology"},{"key":"2020071612350995100_R33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.mce.2004.01.008","article-title":"Hyper and hypothyroidism change the expression and diurnal variation of thyroid hormone receptor isoforms in rat liver without major changes in their zonal distribution.","volume":"219","author":"Zandieh-Doulabi","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"2020071612350995100_R34","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1210\/en.2006-0836","article-title":"A mutant thyroid hormone receptor \u03b1 antagonizes peroxisome proliferator-activated receptor \u03b1 signaling in vivo and impairs fatty acid oxidation.","volume":"148","author":"Liu","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612350995100_R35","first-page":"E899","article-title":"Enhancement of hepatic glycogen by gluconeogenic precursors: substrate flux or metabolic control?","volume":"258","author":"Youn","year":"1990","journal-title":"Am J Physiol"},{"key":"2020071612350995100_R36","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1172\/JCI111610","article-title":"The glucose paradox. Is glucose a substrate for liver metabolism?","volume":"74","author":"Katz","year":"1984","journal-title":"J Clin Invest"},{"key":"2020071612350995100_R37","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1152\/physrev.00024.2006","article-title":"Disordered lipid metabolism and the pathogenesis of insulin resistance.","volume":"87","author":"Savage","year":"2007","journal-title":"Physiol Rev"},{"key":"2020071612350995100_R38","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1177\/0115426505020004369","article-title":"The cancer cachexia syndrome: a review of metabolic and clinical manifestations.","volume":"20","author":"Esper","year":"2005","journal-title":"Nutr Clin Pract"},{"key":"2020071612350995100_R39","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1172\/JCI2890","article-title":"Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.","volume":"102","author":"Orho","year":"1998","journal-title":"J Clin Invest"},{"key":"2020071612350995100_R40","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1017\/S1368980007360928","article-title":"Iodine deficiency and brain development in the first half of pregnancy.","volume":"10","author":"Morreale de Escobar","year":"2007","journal-title":"Public Health Nutr"},{"key":"2020071612350995100_R41","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/j.1365-2826.2004.01243.x","article-title":"Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings.","volume":"16","author":"Zoeller","year":"2004","journal-title":"J Neuroendocrinol"},{"key":"2020071612350995100_R42","doi-asserted-by":"crossref","first-page":"5305","DOI":"10.1210\/en.2007-0677","article-title":"Effects of maternal levels of thyroid hormone (TH) on the hypothalamus-pituitary-thyroid set point: studies in TH receptor \u03b2 knockout mice.","volume":"148","author":"Alonso","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612350995100_R43","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ydbio.2004.03.042","article-title":"Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs.","volume":"272","author":"Tuyl","year":"2004","journal-title":"Dev Biol"},{"key":"2020071612350995100_R44","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cca.2006.07.007","article-title":"Increased insulin sensitivity in intrauterine growth retarded newborns: do thyroid hormones play a role?","volume":"376","author":"Setia","year":"2007","journal-title":"Clin Chim Acta"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/6\/2940\/9009494\/endo2940.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/6\/2940\/9009494\/endo2940.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,3]],"date-time":"2021-10-03T05:10:42Z","timestamp":1633237842000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/150\/6\/2940\/2456385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,12]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2009,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2008-1085","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,12]]}}}