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Tissue-specific 5' heterogeneity of PPARa transcripts and their differential regulation by leptin

Tissue-specific 5' heterogeneity of PPARa transcripts and their differential regulation by leptin
Tissue-specific 5' heterogeneity of PPARa transcripts and their differential regulation by leptin
The genes encoding nuclear receptors comprise multiple 5'untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) ? genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPAR? promoter region and have identified three alternative PPAR? transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPAR? transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPAR? agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3-13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPAR? transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPAR? promoter. Such complexity in the regulation of PPAR? may allow the expression of PPAR? to be finely regulated in response to environmental factors.
1932-6203
Garratt, Emma
66ddd4cb-19a2-4d08-889b-12f418e6878b
Vickers, Mark H.
6e05d089-9742-44f5-b4e1-3a505027d10c
Gluckman, Peter D.
ef2e8b92-0b76-4a12-bd7c-01b0674f94d3
Hanson, Mark A.
1952fad1-abc7-4284-a0bc-a7eb31f70a3f
Burdge, Graham C.
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Garratt, Emma
66ddd4cb-19a2-4d08-889b-12f418e6878b
Vickers, Mark H.
6e05d089-9742-44f5-b4e1-3a505027d10c
Gluckman, Peter D.
ef2e8b92-0b76-4a12-bd7c-01b0674f94d3
Hanson, Mark A.
1952fad1-abc7-4284-a0bc-a7eb31f70a3f
Burdge, Graham C.
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc

Garratt, Emma, Vickers, Mark H., Gluckman, Peter D., Hanson, Mark A., Burdge, Graham C. and Lillycrop, Karen A. (2013) Tissue-specific 5' heterogeneity of PPARa transcripts and their differential regulation by leptin. PLoS ONE, 8 (6), part E67483. (doi:10.1371/journal.pone.0067483). (PMID:23825665)

Record type: Article

Abstract

The genes encoding nuclear receptors comprise multiple 5'untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) ? genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPAR? promoter region and have identified three alternative PPAR? transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPAR? transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPAR? agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3-13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPAR? transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPAR? promoter. Such complexity in the regulation of PPAR? may allow the expression of PPAR? to be finely regulated in response to environmental factors.

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Published date: 25 June 2013
Organisations: Human Development & Health

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Local EPrints ID: 355457
URI: http://eprints.soton.ac.uk/id/eprint/355457
ISSN: 1932-6203
PURE UUID: 5cfa6b93-e64d-42be-8be8-28d897906fc3
ORCID for Emma Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Mark A. Hanson: ORCID iD orcid.org/0000-0002-6907-613X
ORCID for Graham C. Burdge: ORCID iD orcid.org/0000-0002-7665-2967
ORCID for Karen A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

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Date deposited: 23 Aug 2013 09:08
Last modified: 28 Oct 2023 01:47

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Contributors

Author: Emma Garratt ORCID iD
Author: Mark H. Vickers
Author: Peter D. Gluckman
Author: Mark A. Hanson ORCID iD

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