Genetic Background Strongly Influences the Impact of Carrying the Thr92Ala-DIO2 Polymorphism in the Male Mouse.

Autor:	Gabriel de Almeida G; Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago Medical Center, Chicago, IL 60637, USA., Bolin AP; Department of Pharmacology, Biomedical Science Institute, University of São Paulo, São Paulo 05508, Brazil., Batistuzzo A; Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago Medical Center, Chicago, IL 60637, USA., Fonseca TL; Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago Medical Center, Chicago, IL 60637, USA., Ribeiro MO; Human Developmental Sciences Graduate Program, Center for Biological and Health Sciences, Presbyterian Mackenzie University, São Paulo, SP 01302, Brazil., Bianco AC; Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago Medical Center, Chicago, IL 60637, USA.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2024 May 27; Vol. 165 (7).
DOI:	10.1210/endocr/bqae064
Abstrakt:	About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)
Databáze:	MEDLINE
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