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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
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Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in

Claire Regazzetti1, Karine Dumas, Yannick Le Marchand-Brustel

  • 1INSERM U 1065, Mediterranean Research Centre for Molecular Medicine, Team: Cellular and Molecular Physiopathology of obesity and diabetes, Nice, France.

Plos One
|December 29, 2012
PubMed

Insights

Regulated in development and DNA damage response 1 (REDD1) positively impacts insulin signaling. Insulin boosts REDD1 expression, which then inhibits mTORC1, enhancing the insulin pathway and lipogenesis.

Area of Science:

  • Cellular biology
  • Molecular endocrinology
  • Metabolic signaling

Background:

  • Regulated in development and DNA damage response 1 (REDD1) is a known hypoxia and stress response gene.
  • REDD1 acts as a negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1).
  • mTORC1 plays a role in the negative feedback loop of insulin signaling.

Purpose of the Study:

  • To investigate the role of REDD1 in the insulin signaling pathway.
  • To determine how insulin regulates REDD1 expression and function.

Main Methods:

  • Insulin stimulation assays in human and murine adipocytes and HEK-293 cells.
  • MEK pathway analysis and manipulation.
  • REDD1 silencing using siRNA in 3T3-L1 adipocytes.
  • Assessment of mTORC1 activity and insulin signaling components.
  • Proteasomal degradation studies involving CUL4A-DDB1 ubiquitin ligase complex.

Main Results:

  • Insulin transiently stimulates REDD1 expression via a MEK-dependent pathway in adipocytes.
  • Active MEK stabilizes REDD1, protecting it from proteasomal degradation.
  • REDD1 downregulation increases mTORC1 activity and inhibits insulin signaling and lipogenesis.
  • Rapamycin treatment restores insulin signaling following REDD1 downregulation.

Conclusions:

  • REDD1 positively regulates insulin signaling by inhibiting mTORC1 activity.
  • Insulin-induced REDD1 expression is a key component of the biological response to insulin.
  • REDD1 acts as a crucial link between insulin stimulation and metabolic outcomes.

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