Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging.
Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging.
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DOI：
10.1371/journal.pone.0016391
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发表时间：
2011-01-26
期刊：
影响因子：
3.7
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Ma X;Lin L;Qin G;Lu X;Fiorotto M;Dixit VD;Sun Y
肥胖是许多西方社会老龄化的标志，也是许多严重年龄相关疾病的前兆。Ghrelin（Ghrl）通过其受体（生长激素促分泌素受体，GHS-R）显示刺激GH分泌和食欲。令人惊讶的是，我们以前的研究表明，Ghrl-/-小鼠对寒冷和禁食应激的体温调节反应受损，而Ghsr-/-小鼠是适应性的。为了阐明机制，我们分析了年轻（3-4个月）和老年（10-12个月）Ghrl-/-和Ghsr-/-小鼠的完整代谢谱。无论年龄如何，无效小鼠及其野生型（WT）对应小鼠的摄食量和运动活动都相当。年轻的裸小鼠和WT小鼠之间的身体组成也没有差异。正如预期的那样，随着WT小鼠年龄的增长，脂肪/瘦肉比例增加，能量消耗（EE）下降。然而，值得注意的是，与年长的WT小鼠相比，年长的Ghsr-/-小鼠表现出降低的脂肪/瘦肉比和增加的EE，从而保留了年轻的瘦肉和高EE表型;相比之下，Ghrl-/-小鼠中的EE没有显著差异。与EE数据一致，产热调节剂解偶联蛋白1（UCP 1）在Ghsr-/-小鼠的棕色脂肪组织（BAT）中显著上调，但在Ghrl-/-小鼠中没有。因此，我们的数据表明，GHS-R消融激活了BAT中的适应性产热功能并增加了EE，从而能够保持瘦型。这是第一个直接证据表明，ghrelin信号通路调节脂肪燃烧BAT，以影响衰老过程中的能量平衡。这种调节可能是通过GHS-R的一种尚未鉴定的新配体介导的。
Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin (Ghrl), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that Ghrl-/- mice have impaired thermoregulatory responses to cold and fasting stresses, while Ghsr-/- mice are adaptive. To elucidate the mechanism, we analyzed the complete metabolic profiles of younger (3–4 months) and older (10–12 months) Ghrl-/- and Ghsr-/- mice. Food intake and locomotor activity were comparable for both null mice and their wild-type (WT) counterparts, regardless of age. There was also no difference in body composition between younger null mice and their WT counterparts. As the WT mice aged, as expected, the fat/lean ratio increased and energy expenditure (EE) decreased. Remarkably, however, older Ghsr-/- mice exhibited reduced fat/lean ratio and increased EE when compared to older WT mice, thus retaining a youthful lean and high EE phenotype; in comparison, there was no significant difference with EE in Ghrl-/- mice. In line with the EE data, the thermogenic regulator, uncoupling protein 1 (UCP1), was significantly up-regulated in brown adipose tissue (BAT) of Ghsr-/- mice, but not in Ghrl-/- mice. Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R.
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