+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling



A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling



Faseb Journal 33(5): 5924-5941



The glucocorticoid receptor (GR) represents the crucial molecular mediator of key endocrine, glucocorticoid hormone-dependent regulatory circuits, including control of glucose, protein, and lipid homeostasis. Consequently, aberrant glucocorticoid signaling is linked to severe metabolic disorders, including insulin resistance, obesity, and hyperglycemia, all of which also appear upon chronic glucocorticoid therapy for the treatment of inflammatory conditions. Of note, long-term glucocorticoid exposure under these therapeutic conditions typically induces glucocorticoid resistance, requiring higher doses and consequently triggering more severe metabolic phenotypes. However, the molecular basis of acquired glucocorticoid resistance remains unknown. In a screen of differential microRNA expression during glucocorticoid-dependent adipogenic differentiation of human multipotent adipose stem cells, we identified microRNA 29a (miR-29a) as one of the most down-regulated transcripts. Overexpression of miR-29a impaired adipogenesis. We found that miR-29a represses GR in human adipogenesis by directly targeting its mRNA, and downstream analyses revealed that GR mediates most of miR-29a's anti-adipogenic effects. Conversely, miR-29a expression depends on GR activation, creating a novel miR-29-driven feedback loop. miR-29a and GR expression were inversely correlated both in murine adipose tissue and in adipose tissue samples obtained from human patients. In the latter, miR-29a levels were additionally strongly negatively correlated with body mass index and adipocyte size. Importantly, inhibition of miR-29 in mice partially rescued the down-regulation of GR during dexamethasone treatment. We discovered that, in addition to modulating GR function under physiologic conditions, pharmacologic glucocorticoid application in inflammatory disease also induced miR-29a expression, correlating with reduced GR levels. This effect was abolished in mice with impaired GR function. In summary, we uncovered a novel GR-miR-29a negative feedback loop conserved between mice and humans, in health and disease. For the first time, we elucidate a microRNA-related mechanism that might contribute to GR dysregulation and resistance in peripheral tissues.-Glantschnig, C., Koenen, M., Gil-Lozano, M., Karbiener, M., Pickrahn, I., Williams-Dautovich, J., Patel, R., Cummins, C. L., Giroud, M., Hartleben, G., Vogl, E., Blüher, M., Tuckermann, J., Uhlenhaut, H., Herzig, S., Scheideler, M. A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 066479452

Download citation: RISBibTeXText

PMID: 30742779

DOI: 10.1096/fj.201801385rr


Related references

Reciprocal regulation of peroxisome proliferator-activated receptor alpha and glucocorticoid receptor forms a new negative feedback loop. 2007

MYC2 Regulates the Termination of Jasmonate Signaling via an Autoregulatory Negative Feedback Loop. Plant Cell 31(1): 106-127, 2019

SENP1 regulates IFN-γ-STAT1 signaling through STAT3-SOCS3 negative feedback loop. Journal of Molecular Cell Biology 9(2): 144-153, 2017

MOTHER OF FT AND TFL1 regulates seed germination through a negative feedback loop modulating ABA signaling in Arabidopsis. Plant Cell 22(6): 1733-1748, 2010

A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia 13(2): 154-166, 2011

A double-negative feedback loop between Wnt-β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma. Journal of Cell Science 126(Pt 24): 5692-5703, 2013

Androgen receptor auto-regulates its expression by a negative feedback loop through upregulation of IFI16 protein. Febs Letters 580(6): 1659-1664, 2006

A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth. Oncotarget 7(14): 18295-18308, 2016

DRAK2 participates in a negative feedback loop to control TGF-β/Smads signaling by binding to type I TGF-β receptor. Cell Reports 2(5): 1286-1299, 2012

Insulin activates RSK (p90 ribosomal S6 kinase) to trigger a new negative feedback loop that regulates insulin signaling for glucose metabolism. Journal of Biological Chemistry 288(43): 31165-31176, 2013

A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F2alpha synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway. Endocrinology 146(11): 4657-4664, 2005

Cushing Syndrome Due to ACTH-Secreting Pheochromocytoma, Aggravated by Glucocorticoid-Driven Positive-Feedback Loop. Journal of Clinical Endocrinology and Metabolism 101(3): 841-846, 2016

REST regulates DYRK1A transcription in a negative feedback loop. Journal of Biological Chemistry 286(12): 10755-10763, 2011

Corp Regulates P53 in Drosophila melanogaster via a Negative Feedback Loop. Plos Genetics 11(7): E1005400, 2015

MicroRNA miR-308 regulates dMyc through a negative feedback loop in Drosophila. Biology Open 2(1): 1-9, 2013