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The partial inhibition of hypothalamic IRX3 exacerbates obesity

BACKGROUND: The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abr...

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Autores principales: de Araujo, Thiago Matos, Razolli, Daniela S., Correa-da-Silva, Felipe, de Lima-Junior, Jose C., Gaspar, Rodrigo S., Sidarta-Oliveira, Davi, Victorio, Sheila C., Donato, Jose, Kim, Young-Bum, Velloso, Licio A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354701/
https://www.ncbi.nlm.nih.gov/pubmed/30522931
http://dx.doi.org/10.1016/j.ebiom.2018.11.048
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author de Araujo, Thiago Matos
Razolli, Daniela S.
Correa-da-Silva, Felipe
de Lima-Junior, Jose C.
Gaspar, Rodrigo S.
Sidarta-Oliveira, Davi
Victorio, Sheila C.
Donato, Jose
Kim, Young-Bum
Velloso, Licio A.
author_facet de Araujo, Thiago Matos
Razolli, Daniela S.
Correa-da-Silva, Felipe
de Lima-Junior, Jose C.
Gaspar, Rodrigo S.
Sidarta-Oliveira, Davi
Victorio, Sheila C.
Donato, Jose
Kim, Young-Bum
Velloso, Licio A.
author_sort de Araujo, Thiago Matos
collection PubMed
description BACKGROUND: The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity. METHODS: Bioinformatics tools were used to evaluate the correlations between hypothalamic Irx3 and neurotransmitters, markers of thermogenesis and obesity related phenotypes. Droplet-sequencing analysis in >20,000 hypothalamic cells was used to explore the types of hypothalamic cells expressing Irx3. Lentivirus was used to inhibit hypothalamic Irx3 and the resulting phenotype was studied. FINDINGS: IRX3 is expressed predominantly in POMC neurons. Its expression is inhibited during prolonged fasting, as well as when mice are fed a high-fat diet. The partial inhibition of hypothalamic Irx3 using a lentivirus resulted in increased diet-induced body mass gain and adiposity due to increased caloric intake and reduced energy expenditure. INTERPRETATION: Contrary to the results obtained when lean mice are submitted to complete inhibition of Irx3, partial inhibition of hypothalamic Irx3 in obese mice causes an exacerbation of the obese phenotype. These data suggest that at least some of the Irx3 functions in the hypothalamus are regulated according to a hormetic pattern, and modulation of its expression can be a novel approach to modifying the body's energy-handling regulation. FUND: Sao Paulo Research Foundation grants 2013/07607-8 (LAV) and 2017/02983-2 (JDJ); NIH grants R01DK083567 (YBK).
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spelling pubmed-63547012019-02-07 The partial inhibition of hypothalamic IRX3 exacerbates obesity de Araujo, Thiago Matos Razolli, Daniela S. Correa-da-Silva, Felipe de Lima-Junior, Jose C. Gaspar, Rodrigo S. Sidarta-Oliveira, Davi Victorio, Sheila C. Donato, Jose Kim, Young-Bum Velloso, Licio A. EBioMedicine Research paper BACKGROUND: The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity. METHODS: Bioinformatics tools were used to evaluate the correlations between hypothalamic Irx3 and neurotransmitters, markers of thermogenesis and obesity related phenotypes. Droplet-sequencing analysis in >20,000 hypothalamic cells was used to explore the types of hypothalamic cells expressing Irx3. Lentivirus was used to inhibit hypothalamic Irx3 and the resulting phenotype was studied. FINDINGS: IRX3 is expressed predominantly in POMC neurons. Its expression is inhibited during prolonged fasting, as well as when mice are fed a high-fat diet. The partial inhibition of hypothalamic Irx3 using a lentivirus resulted in increased diet-induced body mass gain and adiposity due to increased caloric intake and reduced energy expenditure. INTERPRETATION: Contrary to the results obtained when lean mice are submitted to complete inhibition of Irx3, partial inhibition of hypothalamic Irx3 in obese mice causes an exacerbation of the obese phenotype. These data suggest that at least some of the Irx3 functions in the hypothalamus are regulated according to a hormetic pattern, and modulation of its expression can be a novel approach to modifying the body's energy-handling regulation. FUND: Sao Paulo Research Foundation grants 2013/07607-8 (LAV) and 2017/02983-2 (JDJ); NIH grants R01DK083567 (YBK). Elsevier 2018-12-03 /pmc/articles/PMC6354701/ /pubmed/30522931 http://dx.doi.org/10.1016/j.ebiom.2018.11.048 Text en © 2018 Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
de Araujo, Thiago Matos
Razolli, Daniela S.
Correa-da-Silva, Felipe
de Lima-Junior, Jose C.
Gaspar, Rodrigo S.
Sidarta-Oliveira, Davi
Victorio, Sheila C.
Donato, Jose
Kim, Young-Bum
Velloso, Licio A.
The partial inhibition of hypothalamic IRX3 exacerbates obesity
title The partial inhibition of hypothalamic IRX3 exacerbates obesity
title_full The partial inhibition of hypothalamic IRX3 exacerbates obesity
title_fullStr The partial inhibition of hypothalamic IRX3 exacerbates obesity
title_full_unstemmed The partial inhibition of hypothalamic IRX3 exacerbates obesity
title_short The partial inhibition of hypothalamic IRX3 exacerbates obesity
title_sort partial inhibition of hypothalamic irx3 exacerbates obesity
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354701/
https://www.ncbi.nlm.nih.gov/pubmed/30522931
http://dx.doi.org/10.1016/j.ebiom.2018.11.048
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