The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context
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...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2019-01-01
|
Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418305528 |
id |
doaj-1a028ddde26a48dd856115e0c8d5febb |
---|---|
record_format |
Article |
spelling |
doaj-1a028ddde26a48dd856115e0c8d5febb2020-11-25T01:56:44ZengElsevierEBioMedicine2352-39642019-01-0139448460The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in contextThiago Matos de Araujo0Daniela S. Razolli1Felipe Correa-da-Silva2Jose C. de Lima-Junior3Rodrigo S. Gaspar4Davi Sidarta-Oliveira5Sheila C. Victorio6Jose Donato, Jr7Young-Bum Kim8Licio A. Velloso9Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Brazil; Divison of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USALaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), BrazilLaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), BrazilLaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), BrazilLaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), BrazilLaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), BrazilLaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), BrazilDepartment of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, BrazilDivison of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USALaboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Brazil; Corresponding author at: Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), 13084-970 Campinas, SP, Brazil.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).http://www.sciencedirect.com/science/article/pii/S2352396418305528 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thiago Matos de Araujo Daniela S. Razolli Felipe Correa-da-Silva Jose C. de Lima-Junior Rodrigo S. Gaspar Davi Sidarta-Oliveira Sheila C. Victorio Jose Donato, Jr Young-Bum Kim Licio A. Velloso |
spellingShingle |
Thiago Matos de Araujo Daniela S. Razolli Felipe Correa-da-Silva Jose C. de Lima-Junior Rodrigo S. Gaspar Davi Sidarta-Oliveira Sheila C. Victorio Jose Donato, Jr Young-Bum Kim Licio A. Velloso The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context EBioMedicine |
author_facet |
Thiago Matos de Araujo Daniela S. Razolli Felipe Correa-da-Silva Jose C. de Lima-Junior Rodrigo S. Gaspar Davi Sidarta-Oliveira Sheila C. Victorio Jose Donato, Jr Young-Bum Kim Licio A. Velloso |
author_sort |
Thiago Matos de Araujo |
title |
The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context |
title_short |
The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context |
title_full |
The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context |
title_fullStr |
The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context |
title_full_unstemmed |
The partial inhibition of hypothalamic IRX3 exacerbates obesityResearch in context |
title_sort |
partial inhibition of hypothalamic irx3 exacerbates obesityresearch in context |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2019-01-01 |
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). |
url |
http://www.sciencedirect.com/science/article/pii/S2352396418305528 |
work_keys_str_mv |
AT thiagomatosdearaujo thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT danielasrazolli thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT felipecorreadasilva thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT josecdelimajunior thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT rodrigosgaspar thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT davisidartaoliveira thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT sheilacvictorio thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT josedonatojr thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT youngbumkim thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT licioavelloso thepartialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT thiagomatosdearaujo partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT danielasrazolli partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT felipecorreadasilva partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT josecdelimajunior partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT rodrigosgaspar partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT davisidartaoliveira partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT sheilacvictorio partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT josedonatojr partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT youngbumkim partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext AT licioavelloso partialinhibitionofhypothalamicirx3exacerbatesobesityresearchincontext |
_version_ |
1724978253229195264 |