Aims/hypothesis Dysfunction of lipid metabolism in white adipose tissue can substantially interfere with health and quality of life, for example in obesity and associated metabolic diseases. Therefore, it is important to characterise pathways that regulate lipid handling in adipocytes and determine how they affect metabolic homeostasis. Components of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway are involved in adipocyte physiology and pathophysiology. However, the exact physiological importance of the STAT family member STAT5 in white adipose tissue is yet to be determined. Here, we aimed to delineate adipocyte STAT5 functions in the context of lipid metabolism in white adipose tissue. Methods We generated an adipocyte specific knockout of Stat5 in mice using the Adipoq-Cre recombinase transgene followed by in vivo and in vitro biochemical and molecular studies.Results Adipocyte-specific deletion of Stat5 resulted in increased adiposity, while insulin resistance and gluconeogenic capacity was decreased, indicating that glucose metabolism can be improved by interfering with adipose STAT5 function. Basal lipolysis and fasting-induced lipid mobilisation were diminished upon STAT5 deficiency, which coincided with reduced levels of the rate-limiting lipase of triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL, encoded by Pnpla2) and its coactivator comparative gene identification 58 . In a mechanistic analysis, we identified a functional STAT5 response element within the Pnpla2 promoter, indicating that Pnpla2 is transcriptionally regulated by STAT5. Conclusions/interpretation Our findings reveal an essential role for STAT5 in maintaining lipid homeostasis in white adipose tissue and provide a rationale for future studies into the potential of STAT5 manipulation to improve outcomes in metabolic diseases.
Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signalling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here we present an siRNA JAK-STAT focused screen revealing a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, STAT5b). Amongst these we selected to study the GH-GHR-STAT5-axis because of its known role as a regulator of growth in non-renal tissues. We show that STAT5 loss of function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of Pkd1 status, we overexpressed growth hormone (GH). GH mice showed increased STAT5 activity in renal epithelial cells, correlating with de-novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitations, revealed that STAT5 transcriptionally activated cyclin D1 in GH-stimulated renal epithelial but not control cells, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated GH in Pkd1 nl/nl mice. Collectively, our data identify the GH-STAT5 signalling axis as a novel therapeutic target in ADPKD.
Highlights► Conditional mouse models illuminated the role of hepatic GH-STAT5 and GC-GR signaling in liver function. ► We provide an overview of overlapping and distinct functions of hepatic GH-STAT5 and GC-GR signaling in growth/metabolism. ► Impaired hepatic GH-STAT5 signaling sensitizes hepatocytes to injury and tumorigenic transformation. ► Loss of hepatic GR function causes chronic stress, thereby aggravating liver cancer formation upon impaired STAT5 function.
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