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Experimental Approach to Examine Leptin Signaling in the Carotid Bodies and its Effects on Control of Breathing
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A novel role of the checkpoint kinase ATR in leptin signaling

Elke Ericson1, Charlotte Wennberg Huldt1, Maria Strömstedt1

  • 1Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden.

Molecular and Cellular Endocrinology
|May 19, 2015
PubMed

Insights

Researchers discovered that inhibiting the Ataxia Telangiectasia and RAD3-related protein (ATR) enhances leptin signaling. This occurs because ATR inhibition prevents the induction of Suppressor of Cytokine Signaling 3 (SOCS3), a negative feedback regulator.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Metabolic Regulation

Background:

  • Obesity is a growing global health concern, necessitating a deeper understanding of appetite regulation.
  • Leptin is a key hormone in energy homeostasis, and its signaling pathways are critical targets for study.
  • Signal Transducer and Activator of Transcription 3 (STAT3) is a crucial downstream mediator of leptin signaling.

Purpose of the Study:

  • To identify novel regulators of leptin signaling.
  • To investigate the role of the Ataxia Telangiectasia and RAD3-related protein (ATR) in leptin pathway modulation.
  • To explore potential therapeutic targets for enhancing leptin signaling in obesity.

Main Methods:

  • Compound screening to identify modulators of STAT3 signaling.
  • Exposure of cells to inhibitors of ATR.
  • Analysis of leptin-dependent STAT3 activity.
  • Assessment of Suppressor of Cytokine Signaling 3 (SOCS3) induction.

Main Results:

  • Inhibition of ATR led to increased leptin-dependent STAT3 activity.
  • Cells treated with ATR inhibitors failed to induce SOCS3.
  • This suggests ATR plays a role in the negative feedback regulation of leptin signaling.
  • Identified a novel function for ATR in controlling SOCS3-mediated feedback.

Conclusions:

  • ATR is a previously unrecognized regulator of leptin signaling negative feedback.
  • ATR inhibition offers a potential strategy for augmenting leptin signaling.
  • This finding may lead to new therapeutic interventions for obesity by enhancing leptin sensitivity.
Keywords:
Ataxia Telangiectasia and RAD3 related proteinLeptinSignal Transducer and Activator of Transcription 3 proteinSuppressor of Cytokine Signaling 3

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