Volume 21 Issue 4
Aug.  2008
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QI-CHEN FANG, WEI-PING JIA, SHU-BING CAI, XIN-YU SHAO, RONG ZHANG, CONG-RONG WANG, YU-QIAN BAO, KUN-SAN XIANG. Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese[J]. Biomedical and Environmental Sciences, 2008, 21(4): 280-285.
Citation: QI-CHEN FANG, WEI-PING JIA, SHU-BING CAI, XIN-YU SHAO, RONG ZHANG, CONG-RONG WANG, YU-QIAN BAO, KUN-SAN XIANG. Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese[J]. Biomedical and Environmental Sciences, 2008, 21(4): 280-285.

Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese

Funds:  国家自然科学基金(30470814)
  • To investigate how F261S mutation identified from Chinese obese patients affects the function of melanocortin 4 receptor (MC4R) and to analyze the obesity-related phenotypes in subjects carrying the F261S mutation. Methods F261S mutant of MC4R was generated by site-directed mutagenesis. Plasmids encoding wild-type or F261S mutant of MC4R were transfected into HEK293 and COS-7 cells to examine their functional characteristics. Signaling properties of F261S MC4R were assessed by measuring intracellular cAMP levels in response to α-MSH stimulation. Cell surface expression of F261S MC4R was compared with that of wild-type MC4R. Clinical examinations were performed in subjects carrying F261S mutation and in non-mutated controls. Results The α-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R. The F261S mutation also led to a significant change in the EC<,50> value compared with the wild-type receptor (P<0.01). Immunofluorescent assay revealed a marked reduction in plasma membrane localization of the MC4R in cells expressing the F261S mutant receptor. The resting metabolic rate and fat composition of the mutant carriers were not significantly different from those of the non-mutated obese controls. Conclusions The decreased response to α-MSH due to the intracellular retention of MC4R may cause early-onset obesity in the F261S pedigree of Chinese.
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    沈阳化工大学材料科学与工程学院 沈阳 110142

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Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese

Funds:  国家自然科学基金(30470814)

Abstract: To investigate how F261S mutation identified from Chinese obese patients affects the function of melanocortin 4 receptor (MC4R) and to analyze the obesity-related phenotypes in subjects carrying the F261S mutation. Methods F261S mutant of MC4R was generated by site-directed mutagenesis. Plasmids encoding wild-type or F261S mutant of MC4R were transfected into HEK293 and COS-7 cells to examine their functional characteristics. Signaling properties of F261S MC4R were assessed by measuring intracellular cAMP levels in response to α-MSH stimulation. Cell surface expression of F261S MC4R was compared with that of wild-type MC4R. Clinical examinations were performed in subjects carrying F261S mutation and in non-mutated controls. Results The α-MSH-stimulated reporter gene activity was significantly reduced in cells expressing F261S MC4R, with a maximal response equal to 57% of wild-type MC4R. The F261S mutation also led to a significant change in the EC<,50> value compared with the wild-type receptor (P<0.01). Immunofluorescent assay revealed a marked reduction in plasma membrane localization of the MC4R in cells expressing the F261S mutant receptor. The resting metabolic rate and fat composition of the mutant carriers were not significantly different from those of the non-mutated obese controls. Conclusions The decreased response to α-MSH due to the intracellular retention of MC4R may cause early-onset obesity in the F261S pedigree of Chinese.

QI-CHEN FANG, WEI-PING JIA, SHU-BING CAI, XIN-YU SHAO, RONG ZHANG, CONG-RONG WANG, YU-QIAN BAO, KUN-SAN XIANG. Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese[J]. Biomedical and Environmental Sciences, 2008, 21(4): 280-285.
Citation: QI-CHEN FANG, WEI-PING JIA, SHU-BING CAI, XIN-YU SHAO, RONG ZHANG, CONG-RONG WANG, YU-QIAN BAO, KUN-SAN XIANG. Intracellular Retention of Human Melanocortin-4 Receptor:A Molecular Mechanism Underlying Early-onset Obesity in F261S Pedigree of Chinese[J]. Biomedical and Environmental Sciences, 2008, 21(4): 280-285.

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