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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Catalytic Antibody Degradation Of Ghrelin Increases Whole-body Metabolic Rate And Reduces Refeeding In Fasting Mice
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Catalytic Antibody Degradation Of Ghrelin Increases Whole-body Metabolic Rate And Reduces Refeeding In Fasting Mice

机译：Ghrelin的催化抗体降解可提高空腹小鼠的整体代谢率并减少补料

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摘要

Obesity is a chronic, costly, and globally prevalent condition, with excess caloric intake a suspected etiologic factor. Nonsurgical treatments are modestly efficacious, and weight loss maintenance is hampered by anti-famine homeostatic mechanisms. Ghrelin, a gastric hormone linked to meal initiation, energy expenditure, and fuel partitioning, is hypothesized to facilitate weight gain and impede weight loss. Unique among known animal peptides, the serine-3 residue of ghrelin is posttranslationally acylated with an n-octanoic acid, a modification important for the peptide's active blood-brain transport and growth hormone secretagogue receptor-1 agonist activity. Pharmacological degradation of ghrelin would be hypothesized to reduce ghrelin's biological effects. To study endogenous ghrelin's role in appetite and energy expenditure, we generated antibodies that hydrolyze the octanoyl moiety of ghrelin to form des-acyl ghrelin. The most proficient antibody catalyst, GHR-11E11, was found to display a second-order rate constant of 18 M~(-1)·s~(-1) for the hydrolysis of ghrelin to des-acyl ghrelin. l.v. administration of GHR-11E11 (50 mg/kg) maintained a greater metabolic rate in fasting C57BL/6J mice as compared with mice receiving a control antibody and suppressed 6-h refeeding after 24 h of food deprivation. Indirect respiratory measures of metabolism after refeeding and relative fuel substrate utilization were unaffected. The results support the hypothesis that acylated ghrelin stimulates appetite and curbs energy expenditure during deficient energy intake, whereas des-acyl ghrelin does not potently share these functions. Catalytic anti-ghrelin antibodies might thereby adjunctively aid consolidation of caloric restriction-induced weight loss and might also be therapeutically relevant to Prader-Willi syndrome, characterized after infancy by hyperghre-linemia, hyperphagia, and obesity.
机译：肥胖是一种慢性，昂贵且普遍流行的疾病，热量摄入过多是可疑的病因。非手术治疗是适度有效的，并且抗饥荒体内平衡机制阻碍了减肥的维持。 Ghrelin是一种与进餐，能量消耗和燃料分配有关的胃激素，被认为有助于体重增加和阻碍体重减轻。生长激素释放肽的丝氨酸3残基在已知的动物肽中是独特的，被正辛酸翻译后酰化，这对肽的活性血脑转运和生长激素促分泌素1激动剂活性很重要。假设生长素释放肽的药理降解可降低生长素释放肽的生物学作用。为了研究内源性ghrelin在食欲和能量消耗中的作用，我们生成了可水解ghrelin辛酰基部分以形成脱酰基ghrelin的抗体。发现最高效的抗体催化剂GHR-11E11对于生长素释放肽水解为脱酰基生长素释放肽显示出18 M〜（-1）·s〜（-1）的二级速率常数。 l.v.与接受对照抗体的小鼠相比，在禁食的C57BL / 6J小鼠中施用GHR-11E11（50 mg / kg）可以维持更高的代谢率，并且在禁食24小时后可以抑制6小时的补饲。补料后新陈代谢的间接呼吸测量和相对燃料底物利用率均不受影响。结果支持了以下假设：酰化的生长素释放肽在能量摄入不足时会刺激食欲并抑制能量消耗，而去酰基生长素释放肽则无法有效地共享这些功能。催化性抗生长素释放肽抗体可能因此辅助辅助热量限制诱导的体重减轻，并且还可能与婴儿期以高生长激素性贫血，食欲亢进和肥胖症为特征的Prader-Willi综合征在治疗上相关。

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