Cargando…

SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue

Thyroid hormone (TH) plays an essential role in normal development. TH action requires binding to its receptor. There are two types of thyroid hormone receptor, alpha (THRA) and beta (THRB). THRB is important for regulation of the Hypothalamic-Pituitary-Thyroid axis and regulating cholesterol metabo...

Descripción completa

Detalles Bibliográficos
Autores principales: Abe, Kiyomi, Gastelum, Gilberto, Li, Chengju, Rubinos, Harmie, Yamada, Alexandr, Liu, Yan-Yun, Brent, Gregory A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207797/
http://dx.doi.org/10.1210/jendso/bvaa046.1108
_version_ 1783530689309704192
author Abe, Kiyomi
Gastelum, Gilberto
Li, Chengju
Rubinos, Harmie
Yamada, Alexandr
Liu, Yan-Yun
Brent, Gregory A
author_facet Abe, Kiyomi
Gastelum, Gilberto
Li, Chengju
Rubinos, Harmie
Yamada, Alexandr
Liu, Yan-Yun
Brent, Gregory A
author_sort Abe, Kiyomi
collection PubMed
description Thyroid hormone (TH) plays an essential role in normal development. TH action requires binding to its receptor. There are two types of thyroid hormone receptor, alpha (THRA) and beta (THRB). THRB is important for regulation of the Hypothalamic-Pituitary-Thyroid axis and regulating cholesterol metabolism. THRA is involved in the development and the function of brain, adipose tissue, small intestine, bone and heart. Both THRA and THRB are post-translationally modified by small ubiquitin-like modifier (SUMO). Previously, we showed in an in vitro model that mutation of a THRA sumoylation motif impairs proliferation and differentiation of human primary white adipocytes. This is due to interference of the desumolyated THRA in the cell cycle at G1/S phase and disruption of PPAR signaling. To determine the in vivo effects of a desumoylated THRA, we generated a mouse model carrying a mutation of the THRA gene, which eliminates SUMO conjugation at lysine (K) 283. At 12 weeks of age, there was no difference in body composition (body weight, fat mass, and lean mass) in THRA mutant mice compared to wild-type (WT). From 12 weeks onward mutant mice and WT did not have significant change body weight compared to Wt mice. However, THRA sumoylation mutant mice had much lower percent body fat. Dissected WAT fat pads from mutant mice were significantly smaller compared to WT mice. Histological analysis showed that the cell size of white adipose tissue in mutant mice was significantly smaller than that in Wt mice as well. Serum leptin levels in the mutant mice were significantly lower than that in mice, consistent with reduced fat mass. We isolated fat stem cells from stromal vesicular fraction of 6 week old mice and found that the number of fat stem cells was significant less in mutant mice compared to those in WT mice. This data suggest that de-sumoylated THRA is associated with reduced fat stem cells at a young age, resulting in reduced adipose tissue mass in adult. THRA sumoylation is important for thyroid hormone modulation of fat mass. Reference: (1) Yan-Yun Liu et al, JBC 2012 (2) Yan-Yun Liu et al., JBC 2015
format Online
Article
Text
id pubmed-7207797
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-72077972020-05-13 SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue Abe, Kiyomi Gastelum, Gilberto Li, Chengju Rubinos, Harmie Yamada, Alexandr Liu, Yan-Yun Brent, Gregory A J Endocr Soc Steroid Hormones and Receptors Thyroid hormone (TH) plays an essential role in normal development. TH action requires binding to its receptor. There are two types of thyroid hormone receptor, alpha (THRA) and beta (THRB). THRB is important for regulation of the Hypothalamic-Pituitary-Thyroid axis and regulating cholesterol metabolism. THRA is involved in the development and the function of brain, adipose tissue, small intestine, bone and heart. Both THRA and THRB are post-translationally modified by small ubiquitin-like modifier (SUMO). Previously, we showed in an in vitro model that mutation of a THRA sumoylation motif impairs proliferation and differentiation of human primary white adipocytes. This is due to interference of the desumolyated THRA in the cell cycle at G1/S phase and disruption of PPAR signaling. To determine the in vivo effects of a desumoylated THRA, we generated a mouse model carrying a mutation of the THRA gene, which eliminates SUMO conjugation at lysine (K) 283. At 12 weeks of age, there was no difference in body composition (body weight, fat mass, and lean mass) in THRA mutant mice compared to wild-type (WT). From 12 weeks onward mutant mice and WT did not have significant change body weight compared to Wt mice. However, THRA sumoylation mutant mice had much lower percent body fat. Dissected WAT fat pads from mutant mice were significantly smaller compared to WT mice. Histological analysis showed that the cell size of white adipose tissue in mutant mice was significantly smaller than that in Wt mice as well. Serum leptin levels in the mutant mice were significantly lower than that in mice, consistent with reduced fat mass. We isolated fat stem cells from stromal vesicular fraction of 6 week old mice and found that the number of fat stem cells was significant less in mutant mice compared to those in WT mice. This data suggest that de-sumoylated THRA is associated with reduced fat stem cells at a young age, resulting in reduced adipose tissue mass in adult. THRA sumoylation is important for thyroid hormone modulation of fat mass. Reference: (1) Yan-Yun Liu et al, JBC 2012 (2) Yan-Yun Liu et al., JBC 2015 Oxford University Press 2020-05-08 /pmc/articles/PMC7207797/ http://dx.doi.org/10.1210/jendso/bvaa046.1108 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Steroid Hormones and Receptors
Abe, Kiyomi
Gastelum, Gilberto
Li, Chengju
Rubinos, Harmie
Yamada, Alexandr
Liu, Yan-Yun
Brent, Gregory A
SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
title SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
title_full SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
title_fullStr SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
title_full_unstemmed SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
title_short SUN-746 Thyroid Hormone Receptor Alpha Sumoylation Is Important for the Development of Adipose Tissue
title_sort sun-746 thyroid hormone receptor alpha sumoylation is important for the development of adipose tissue
topic Steroid Hormones and Receptors
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207797/
http://dx.doi.org/10.1210/jendso/bvaa046.1108
work_keys_str_mv AT abekiyomi sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue
AT gastelumgilberto sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue
AT lichengju sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue
AT rubinosharmie sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue
AT yamadaalexandr sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue
AT liuyanyun sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue
AT brentgregorya sun746thyroidhormonereceptoralphasumoylationisimportantforthedevelopmentofadiposetissue