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Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes.

ABSTRACT: REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes REDD1 and protects REDD1 from proteasomal degradation mediated by CUL4A-DDB1 ubiquitin ligase complex. In 3T3-L1 adipocytes, silencing of REDD1 with siRNA induces an increase of mTORC1 activity as well as an inhibition of insulin signaling pathway and lipogenesis. Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. This observation suggests that REDD1 positively regulates insulin signaling through the inhibition of mTORC1 activity. In conclusion, our results demonstrate that insulin increases REDD1 expression, and that REDD1 participates in the biological response to insulin.

SUBMITTER: Regazzetti C

PROVIDER: S-EPMC3525563 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes.

Regazzetti Claire C Dumas Karine K Le Marchand-Brustel Yannick Y Peraldi Pascal P Tanti Jean-François JF Giorgetti-Peraldi Sophie S

PloS one 20121218 12

REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes RED ...[more]

PMID: 23272222

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Project description:Even though cutaneous atrophy is the major adverse effect of topical glucocorticoids, its molecular mechanisms are poorly understood. We found that glucocorticoids strongly increased the expression of REDD1 (regulated in development and DNA damage response 1), a stress-inducible inhibitor of mTOR, in mouse and human epidermis. We found that REDD1 knockout animals are partially resistant to glucocorticoid-induced epidermal and subcutaneous adipose atrophy which correlated with the protection of CD34+ follicular epithelial stem cells as well as p63+ keratinocyte progenitors in REDD1 knockout epidermis during chronic steroid treatment. At the same time, REDD1 knockout did not affect anti- inflammatory effect of glucocorticoids, as evaluated by ear edema test. Expression profiling revealed that ~ 50% of the glucocorticoid receptor (GR) target genes were not activated in epidermis of REDD1 knockouts, however, the negative effect of glucocorticoids on gene expression was similar to that in w.t. animals. Overall, our findings reveal a novel pathway in GR activation by its target gene/protein REDD1; and indicate an important role of REDD1 in glucocorticoid-induced skin atrophy, and maintenance of the epidermis and subcutaneous adipose. In addition, our findings form the foundation for the development of safer topical glucocorticoid treatment regimens by combining this therapy with REDD1 inhibitors. Seven wk old B6D2 females in the telogen stage of the hair cycle were shaved, and treated 3 days later. Glucocorticoid FA was applied topically (2 ug/animal) in 200 ul acetone to the back skin once or up to four applications every third day as described previously (Chebotaev et al., 2007b). Control animals were treated with acetone only. Skin was harvested 24 h after last FA application or 4-8 h after single FA application as indicated in Figure legends. To evaluate the anti-inflammatory effect of glucocorticoid FA in REDD1 KO and w.t. B6x129 mice, we used ear edema test (Schoepe et al., 2010; Schäcke et al., 2004; Park et al., 2006). Seven wk old female animals were pretreated with FA or vehicle applied to the back of the ear lobe one h before application of nonspecific contact irritant croton oil . Mice were sacrificed and ears were harvested nine hours after CO application, the time point at which we observed maximum ear edema in F1 C57Bl x 129 animals (data not shown). Four mm ear punch biopsies were immediately weighted to assess ear edema. Animals were injected i.p. with bromodeoxyuridine 1 hr before skin was harvested. Total RNA from murine epidermis and whole human skin was isolated with RiboPure kit (Ambion). Total RNA from murine s.c. adipose was isolated with RNeasy Lipid Tissue Kit (Qiagen). The RNA samples were treated with TURBOTM DNase (Ambion). Purity of RNA samples isolated from epidermis and s.c. fat was confirmed by the expression of adipose and keratinocyte cell markers.

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Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes.

Publications

Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes.

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