Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

被引:85
作者
Cakir, Isin [1 ,2 ]
Cyr, Nicole E. [1 ]
Perello, Mario [1 ]
Litvinov, Bogdan Patedakis [1 ]
Romero, Amparo [1 ]
Stuart, Ronald C. [1 ]
Nillni, Eduardo A. [1 ,2 ]
机构
[1] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Endocrinol,Dept Med, Providence, RI 02907 USA
[2] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02903 USA
基金
美国国家卫生研究院;
关键词
DIET-INDUCED OBESITY; PROTHYROTROPIN-RELEASING HORMONE; MELANOCYTE-STIMULATING HORMONE; PRO-NEUROPEPTIDE-Y; LEPTIN RESISTANCE; PARAVENTRICULAR NUCLEUS; PROHORMONE CONVERTASES; MESSENGER-RNA; ER STRESS; GLUCOSE-HOMEOSTASIS;
D O I
10.1074/jbc.M113.475343
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to alpha-MSH, thereby decreasing alpha-MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity.
引用
收藏
页码:17675 / 17688
页数:14
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