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Endocrine Abstracts (2016) 44 OC5.6 | DOI: 10.1530/endoabs.44.OC5.6

SFEBES2016 Oral Communications Diabetes Mellitus and Metabolism (6 abstracts)

IRX3 regulates Adipocyte Browning via Mitochondrial Gene Clusters

Samantha Laber 1, , Thomas Agnew 1 & Roger Cox 1


1MRC Harwell, Oxford, UK; 2University of Oxford, Oxford, UK.


Genome-wide association studies have repeatedly shown that the strongest association with human BMI is arising from variants in the first intron of Fto. It has recently been demonstrated that intronic Fto variants are within an adipocyte-specific enhancer and that risk allele carriers have altered Irx3 and Irx5 expression in early adipogenesis (Claussnitzer et al. NEJM 2015). The aim of our study is to investigate the functional role of Irx3 in adipocytes. We show that silencing of Irx3 in mouse pre-adipocytes causes increased mRNA expression of mitochondrial electron transport chain and biogenesis genes (e.g. Pgc1a, Cox7a, Cox8b, Elovl, Dio2) at day 8 of adipogenic stimulation. A mitochondrial stress test using the Seahorse Bioflux analyser of these differentiated adipocytes shows that siIrx3 increases basal respiration, proton leak, ATP production and maximal respiration compared to control adipocytes, indicative of increased mitochondrial respiration in brown-like adipocytes. To identify the targets of the transcription factor IRX3, we performed ChIP-Seq in early differentiating mouse primary pre-adipocytes of both visceral and subcutaneous white adipocyte depots. In gonadal-derived pre-adipocytes, we identified 2259 peaks in proximal promoter regions (≤ 1 kb) and mitochondrial genes were significantly overrepresented in this data set (P=2.2E-11; PANTHER Overrepresentation Test). The identified mitochondrial genes could be clustered into three groups: mitochondrial ribosomal machinery, mitochondrial complex I assembly/units and mitochondrial membrane transporters. Interestingly, gene ontology of genes identified to be regulated by IRX3 in subcutaneous pre-adipocytes showed a slightly different profile, suggesting a differential role of IRX3 in white adipocytes from different depots. Finally, using publicly available chromatin maps, we found that enhancer marks in human adipocytes are conserved in mouse pre-adipocytes, opening opportunities for novel gene manipulation strategies in vivo in order to mechanistically dissect the Fto regulatory circuitry in mouse. In summary, our findings provide new insight into how alteration of IRX3 affects early adipocyte differentiation.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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