Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The partial inhibition of hypothalamic IRX3 exacerbates obesity

Full text
Author(s):
de Araujo, Thiago Matos [1, 2, 3] ; Razolli, Daniela S. [3] ; Correa-da-Silva, Felipe [3] ; de Lima-Junior, Jose C. [3] ; Gaspar, Rodrigo S. [3] ; Sidarta-Oliveira, Davi [3] ; Victorio, Sheila C. [3] ; Donato, Jr., Jose [4] ; Kim, Young-Bum [1, 2] ; Velloso, Licio A. [3]
Total Authors: 10
Affiliation:
[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 - USA
[2] Harvard Med Sch, Boston, MA - USA
[3] State Univ Campinas UNICAMP, Obes & Comorbid Res Ctr, Lab Cell Signaling, BR-13084970 Campinas, SP - Brazil
[4] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo, SP - Brazil
Total Affiliations: 4
Document type: Journal article
Source: EBIOMEDICINE; v. 39, p. 448-460, JAN 2019.
Web of Science Citations: 5
Abstract

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). (c) 2018 Published by Elsevier B.V. (AU)

FAPESP's process: 17/02983-2 - The role of growth hormone in the brain: relevance for neural functions and in disease
Grantee:Jose Donato Junior
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
Grantee:Licio Augusto Velloso
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC