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Published on: May 4, 2021
[Molecular mechanism of SH2B1 in regulating JAK2/IRS2 during obesity development]
Chaojun Duan1, Can'e Tang, Lan Liao
1Key Laboratory of Cancer Proteomics, Ministry of Health of China, Xiangya Hospital, Central South University, Changsha 410008, China. duancjxy@126.com
Objective:
In order to investigate the effect of SH2B1 on leptin signal transduction JAK2/IRS2 and its biological function.
Methods:
Vitro kinase assay and Western blot were used to analyse tyrosine phosphorylatin of key molecule JAK2 and insulin receptor substrate-2 (IRS2). ELISA was used to measure the plasma leptin levels in mice. The postnatal growth of mice was monitored over 27 weeks.
Results:
SH2B1 dramatically enhanced the leptin-stimulated tyrosine phosphorylation of JAK2 and IRS2 in HEK293 cells stably expressing LRb (HEK239(LRb)). Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hyphothalamic IRS2 were significantly impaired in SH2B1(-/-) mice. The deletion of SH2B1 led to leptin resistance,and fasting and randomly fed plasma leptin levels were respectively 3.2 times and 5.1 times higher in SH2B1(-/-) males than wild-type littermates at 15 weeks of age. SH2B1(-/-) males gained body weight rapidly and exceeded wild-type littermates from 5th week. SH2B1(-/-) (at 21 weeks) was approximately twice heavier than wild-type littermates.
Conclusion:
SH2B1 is an endogenous enhancer of leptin sensitivity and required for maintaining normal bodyweight in mice via leptin JAK2/IRS2 pathway.
Insights
SH2B1 enhances leptin signaling through the JAK2/IRS2 pathway, improving leptin sensitivity. Its absence causes leptin resistance and significant weight gain in mice.
Area of Science:
- Molecular Biology
- Endocrinology
- Physiology
Background:
- Leptin signaling regulates energy balance and body weight.
- The JAK2/IRS2 pathway is crucial for leptin signal transduction.
- The role of SH2B1 in leptin signaling requires further elucidation.
Purpose of the Study:
- To investigate the effect of SH2B1 on leptin signal transduction via JAK2/IRS2.
- To determine the biological function of SH2B1 in regulating body weight and leptin sensitivity.
Main Methods:
- In vitro kinase assays and Western blots analyzed protein phosphorylation.
- ELISA measured plasma leptin levels in wild-type and SH2B1 knockout mice.
- Postnatal growth and body weight were monitored over 27 weeks.
Main Results:
- SH2B1 significantly enhanced leptin-stimulated JAK2 and IRS2 phosphorylation.
- SH2B1 deficiency impaired leptin-induced JAK2/IRS2 activation in mice.
- SH2B1 knockout mice exhibited leptin resistance and rapid weight gain.
Conclusions:
- SH2B1 acts as an endogenous enhancer of leptin sensitivity.
- SH2B1 is essential for maintaining normal body weight through the leptin JAK2/IRS2 pathway.
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