title: Hypothyroidism compromises hypothalamic leptin signaling in mice.
abstract: The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism.
authors.affiliation: Leibniz Institute for Age Research/Fritz Lipmann Institute e.V., Beutenbergstr. 11, D-07745 Jena/Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Groba
authors.forename: Steffen
authors.initials: S
authors.lastname: Mayerl
authors.forename: Alies A
authors.initials: AA
authors.lastname: van Mullem
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Veerle M
authors.initials: VM
authors.lastname: Darras
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Habenicht
authors.forename: Heike
authors.initials: H
authors.lastname: Heuer
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007037:Hypothyroidism / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D020738:Leptin / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D054369:Agouti-Related Protein; D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin; D011988:Receptors, Thyroid Hormone; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013963:Thyroid Hormones; D011333:Pro-Opiomelanocortin