Wang Wenhua, Andersson Marianne, Iresjö Britt-Marie, Lönnroth Christina, Lundholm Kent
Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Department of Surgery, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden.
Int J Oncol. 2006 Jun;28(6):1393-400.
Ghrelin is a novel brain-gut peptide that stimulates food intake and may secondarily increase body weight via a growth hormone secretagogue receptor (GHS-R). Tumor-bearing mice (MCG101), characterized by anorexia, fat loss and muscle wasting due to increased concentration of PGE2 and proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), were provided ghrelin i.p. at a low (20 microg/day) and high dose (40 microg/day) to examine the ability of ghrelin to counteract tumor-induced anorexia. Immunohistochemical staining and Western blot analyses were used to identify GHS-R expression in the brain as well as its relationship to NPY expression in hypothalamic neurons. GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR. Body composition was determined by carcass extractions. GHS-R expression in hypothalamus and plasma ghrelin levels were significantly increased in freely-fed tumor-bearing mice, while gastric fundus expression of ghrelin was unaltered compared to non-tumor-bearing mice (controls). Ghrelin treatment increased food intake, body weight and whole body fat at both low and high doses of ghrelin in normal controls, while tumor-bearing mice showed improved intake and body composition at the high dose of ghrelin only. Exogenous ghrelin normalized the GHS-R expression in hypothalamus from tumor-bearing mice without alterations in the gastric fundus expression of ghrelin. Tumor growth was not altered by exogenous ghrelin. Our results indicate that MCG 101-bearing mice became ghrelin resistant despite upregulation of hypothalamic GHS-R expression, which confirms similar indirect observations in cancer patients. Thus, other factors downstream of the ghrelin-GHS-R system appear to be more important than ghrelin to explain cancer-induced anorexia.
胃饥饿素是一种新型的脑肠肽，它能刺激食物摄入，并可能通过生长激素促分泌素受体（GHS-R）继而增加体重。携带肿瘤的小鼠（MCG101）表现出厌食、脂肪减少和肌肉消瘦，这是由于PGE2和促炎细胞因子（IL-1β、IL-6、TNF-α）浓度升高所致，给这些小鼠腹腔注射低剂量（20微克/天）和高剂量（40微克/天）的胃饥饿素，以研究胃饥饿素对抗肿瘤诱导的厌食的能力。采用免疫组织化学染色和蛋白质印迹分析来鉴定大脑中GHS-R的表达及其与下丘脑神经元中NPY表达的关系。通过逆转录聚合酶链反应（RT-PCR）对下丘脑的GHS-R mRNA和胃底的胃饥饿素mRNA进行定量。通过胴体提取来测定身体组成。自由进食的携带肿瘤的小鼠下丘脑GHS-R表达和血浆胃饥饿素水平显著升高，而与未携带肿瘤的小鼠（对照）相比，胃底胃饥饿素的表达未发生改变。在正常对照中，低剂量和高剂量的胃饥饿素治疗均增加了食物摄入量、体重和全身脂肪，而携带肿瘤的小鼠仅在高剂量胃饥饿素时食物摄入量和身体组成得到改善。外源性胃饥饿素使携带肿瘤的小鼠下丘脑GHS-R表达恢复正常，而胃底胃饥饿素的表达未发生改变。外源性胃饥饿素未改变肿瘤生长。我们的结果表明，尽管下丘脑GHS-R表达上调，但携带MCG 101肿瘤的小鼠对胃饥饿素产生了抗性，这证实了在癌症患者中类似的间接观察结果。因此，在解释癌症诱导的厌食方面，胃饥饿素-GHS-R系统下游的其他因素似乎比胃饥饿素更重要。
