Dataset Information

Tissue-specific 5' heterogeneity of PPAR? transcripts and their differential regulation by leptin.

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.

SUBMITTER: Garratt ES

PROVIDER: S-EPMC3692471 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Garratt Emma S ES Vickers Mark H MH Gluckman Peter D PD Hanson Mark A MA Burdge Graham C GC Lillycrop Karen A KA

PloS one 20130625 6

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) α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing ...[more]

PMID: 23825665

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Project description:Adipose tissue secretes numerous cytokines (termed 'adipokines') that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic 'fat-free' mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat-free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast-twitch muscles, a slowing of contractile dynamics and decreased cross-sectional area of fast twitch fibres compared to wild-type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin-knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild-type mice is dependent on adipose-secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. KEY POINTS: Adipose-derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under-appreciated roles in muscle physiology. Here we use a fat-free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength. Through add-back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation. This expands our understanding of leptin's role in adipose-muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.

Dataset Information

Tissue-specific 5' heterogeneity of PPAR? transcripts and their differential regulation by leptin.

Publications

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

Similar Datasets

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