Dataset Information

IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.

ABSTRACT:

Background

IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity.

Methods

IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were applied to investigate IRX3's effects on UCP1 transcriptional activity. Moreover, genetic analysis of IRX3 was performed in 861 young obese subjects and 916 controls.

Results

IRX3 expression was induced in the browning process and was positively correlated with the browning markers. IRX3 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and also repressed the uncoupled oxygen consumption rate. Further, IRX3 directly bound to UCP1 promoter and increased its transcriptional activity. Moreover, 17 rare heterozygous missense/frameshift IRX3 variants were identified, with a significant enrichment in obese subjects (P=0.038, OR=2.27; 95% CI, 1.02-5.05).

Conclusions

IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.

SUBMITTER: Zou Y

PROVIDER: S-EPMC5652024 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.

Zou Yaoyu Y Lu Peng P Shi Juan J Liu Wen W Yang Minglan M Zhao Shaoqian S Chen Na N Chen Maopei M Sun Yingkai Y Gao Aibo A Chen Qingbo Q Zhang Zhiguo Z Ma Qinyun Q Ning Tinglu T Ying Xiayang X Jin Jiabin J Deng Xiaxing X Shen Baiyong B Zhang Yifei Y Yuan Bo B Kauderer Sophie S Liu Simin S Hong Jie J Liu Ruixin R Ning Guang G Wang Weiqing W Gu Weiqiong W Wang Jiqiu J

EBioMedicine 20170913

<h4>Background</h4>IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity.<h4>Methods</h4>IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were app ...[more]

PMID: 28988979

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Project description:BackgroundStromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood.MethodsTo analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways.ResultsWe found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPβ LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM.ConclusionsIn summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a "domino effect".

Dataset Information

IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.

Background

Methods

Results

Conclusions

Publications

IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.

Similar Datasets

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