{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:21:14Z","timestamp":1784557274837,"version":"3.55.0"},"reference-count":0,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,6,1]]},"abstract":"<jats:p>Thyroid dysfunctions are associated with liver diseases ranging, in severity, from insulin resistance (IR) to hepatocellular carcinoma. The pathogenic mechanisms appear complex and are not attributable, exclusively, to the impaired thyroid hormone (TH) signalling. Using a mouse model of human congenital hypothyroidism, young double heterozygote for both NK2 homeobox 1 (Nkx2-1)- and Paired box 8 (Pax8)-null mutations (DHTP) mice, and single heterozygous Pax8+\/\u2212 and Nkx2-1+\/\u2212 mice, we studied the liver pathways, the endocrine and metabolic factors affected in conditions of different dysthyroidisms. Young Nkx2-1+\/\u2212 females displayed a slight hyperthyroidism and, in liver, increased TH signalling (i.e. increased expression of Dio1 and Tr\u03b21) and lipogenic gene expression, with triglycerides accumulation. Hypothyroid DHTP and euthyroid Pax8+\/\u2212 females shared liver and skeletal muscle IR and hepatic hypothyroidism (i.e. reduced expression of Mct8, Dio1 and TR\u03b21), activation of AKT and increased expression of glutathione peroxidase 4. Oxidative stress and reduced mitochondrial COX activity were observed in DHTP mice only. Pax8+\/\u2212 females, but, unexpectedly, not DHTP ones, displayed transcriptional activation of the hepatic (and renal) gluconeogenic pathway, hypercortisolemia, fasting hyperglycaemia and hyperinsulinemia, reduced serum \u03b2-hydroxybutyrate, associated with hepatic AMPK activation. DHTP mice showed hypercholesterolemia and activation of mTOR. Collectively, the data indicate that heterozygote mutations of Pax8 and Nkx2-1 genes may produce multiple dysmetabolisms, even under systemic euthyroidism. Differential liver pathways and multiple hormonal axes are affected with implications for energy and nutrient homeostasis. The identified players may be specific target in the management of thyroid dysfunction-associated dysmetabolisms in terms of prevention\/counteraction of IR, type 2 diabetes and related comorbidities.<\/jats:p>","DOI":"10.1530\/joe-22-0053","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T10:51:45Z","timestamp":1647341505000},"page":"115-132","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":4,"title":["Pax8 and Nkx2-1 haploinsufficiencies differentially affect liver metabolic pathways"],"prefix":"10.1530","volume":"253","author":[{"given":"Antonia","family":"Giacco","sequence":"first","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Peluso","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Cioffi","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Iervolino","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Mercurio","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Roberto","sequence":"additional","affiliation":[{"name":"2Biogem Scarl, Istituto di Ricerche Genetiche \u2018Gaetano Salvatore',Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Reale","sequence":"additional","affiliation":[{"name":"2Biogem Scarl, Istituto di Ricerche Genetiche \u2018Gaetano Salvatore',Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Colella","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"},{"name":"2Biogem Scarl, Istituto di Ricerche Genetiche \u2018Gaetano Salvatore',Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"De Felice","sequence":"additional","affiliation":[{"name":"3Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy"},{"name":"4Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Moreno","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Ambrosino","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"},{"name":"2Biogem Scarl, Istituto di Ricerche Genetiche \u2018Gaetano Salvatore',Ariano Irpino, Italy"},{"name":"3Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0592-9033","authenticated-orcid":true,"given":"Elena","family":"Silvestri","sequence":"additional","affiliation":[{"name":"1Department of Science and Technology, University of Sannio, Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Journal of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/joe.bioscientifica.com\/view\/journals\/joe\/253\/3\/JOE-22-0053.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/joe.bioscientifica.com\/downloadpdf\/journals\/joe\/253\/3\/JOE-22-0053.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:57:41Z","timestamp":1784555861000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/joe\/article\/253\/3\/115-132\/5521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":0,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.1530\/joe-22-0053","relation":{},"ISSN":["0022-0795","1479-6805"],"issn-type":[{"value":"0022-0795","type":"print"},{"value":"1479-6805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,1]]}}}