title: 3,5-Diiodo-L-thyronine (3,5-t2) exerts thyromimetic effects on hypothalamus-pituitary-thyroid axis, body composition, and energy metabolism in male diet-induced obese mice.
abstract: Effective and safe antiobesity drugs are still needed in face of the obesity pandemic worldwide. Recent interventions in rodents revealed 3,5-diiodo-L-thyronine (3,5-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T3 administration. Accordingly, 3,5-T2 has been proposed as a potential hypolipidemic agent for treatment of obesity and hepatic steatosis. In contrast to other observations, our experiments revealed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice. 3,5-T2 treatment exerted a negative feedback regulation on the hypothalamus-pituitary-thyroid axis, similar to T3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver of 3,5-T2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T3-like changes in gene expression and increased type I-deiodinase activity after application of 3,5-T2 (2.5 μg/g body weight). Reduced hepatic triglyceride and serum cholesterol concentrations reflected enhanced lipid metabolism. Desired increased metabolic rate and reduction of different fat depots were, however, compromised by increased food intake preventing significant body weight loss. Moreover, enlarged heart weights indicate potential cardiac side effects of 3,5-T2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity.
authors.affiliation: Department of Experimental Diabetology (W.J., P.W., A.S.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; Deutsches Zentrum für Diabetesforschung (DZD) (W.J., A.S.), 85764 Neuherberg, Germany; Institut für Experimentelle Endokrinologie (J.L., F.W., C.S.H., U.S., J.K.), Campus Virchow-Klinikum, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; and Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms Universität Bonn, 53115 Bonn, Germany.
authors.forename: Wenke
authors.initials: W
authors.lastname: Jonas
authors.forename: Julika
authors.initials: J
authors.lastname: Lietzow
authors.forename: Franziska
authors.initials: F
authors.lastname: Wohlgemuth
authors.forename: Carolin S
authors.initials: CS
authors.lastname: Hoefig
authors.forename: Petra
authors.initials: P
authors.lastname: Wiedmer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects*; D004041:Dietary Fats / Q000633:toxicity; D004104:Diiodothyronines / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D059467:Transcriptome; D015431:Weight Loss
chemical_list: D004041:Dietary Fats; D004104:Diiodothyronines; C030103:3,5-diiodothyronine