RESUMO
To investigate the association of SH2B1 gene rs7359397 polymorphism with overweight and obesity,as well as some related metabolic indicators in Northwest Chinese. Based on the cohort of China National Diabetes and Metabolic disorders Study(2007-2008) in Shanxi province, totally 1210(including 635 overweight and 167 obese) males and 1711(including 781 overweight and 212 obese) females were participated in this study. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry( MALDI-TOF MS) was adopted as the genotyping method. After adjusting for age, the single nucleotide polymorphism rs7359397 of SH2B1 was found to be associated with overweight and obesity in males. The correlation with overweight accords with the dominant(P=0. 02), overdominant(P=0. 03), and log-additive models(P=0. 025), while the correlation with obesity accords with the dominant(P=0. 0078), overdominant(P=0. 0081), and log-additive models(P=0. 015). rs7359397 showed to have a significant association with body mass index, body fat percentage, fasting serum insulin, homeostasis model assessment of insulin resistance in males;and high density lipoprotein-cholesterol in females(P<0. 05). The results show that SH2B1 rs7359397 polymorphism is associated with overweight, obesity, and related metabolic indicators in males of the population studied.
RESUMO
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 5~(th) 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.