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Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor
L R Carpenter1, T J Farruggella, A Symes
1Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Summary
Leptin resistance in obesity may be overcome by blocking SHP-2 phosphatase binding to the Ob receptor. This enhances STAT3 signaling, potentially boosting leptin's weight-reducing effects in obese individuals.
Area of Science:
- Molecular endocrinology
- Obesity research
- Signal transduction pathways
Background:
- Leptin regulates body weight and food intake via the Ob receptor (ObR).
- Obesity is linked to leptin resistance, characterized by elevated leptin levels and impaired ObR response.
- STAT3 activation in the hypothalamus mediates leptin's effects on gene transcription.
Purpose of the Study:
- To investigate the role of SHP-2 phosphatase in ObR signaling.
- To identify key residues in ObR involved in SHP-2 interaction.
- To determine if modulating SHP-2 binding affects STAT3-mediated gene induction.
Main Methods:
- Investigated ObR activation and subsequent tyrosine phosphorylation of SHP-2.
- Utilized site-directed mutagenesis to alter Tyr986 in the ObR cytoplasmic domain.
- Assessed STAT3-mediated gene induction following ObR activation in wild-type and mutant receptors.
Main Results:
- ObR activation induces SHP-2 phosphorylation and binding, mediated by Tyr986.
- Mutation of Tyr986 to Phe abolished SHP-2 phosphorylation and binding to ObR.
- Abrogation of SHP-2 binding dramatically increased STAT3-mediated gene induction.
Conclusions:
- SHP-2 acts as a negative regulator of STAT3-mediated gene induction downstream of ObR.
- Blocking the SHP-2/ObR interaction may represent a therapeutic strategy to enhance leptin sensitivity.
- Targeting the SHP-2 interaction could potentially overcome leptin resistance in obesity.