Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin.
Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin.
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DOI：
10.1210/en.2015-1745
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发表时间：
2016-01
期刊：
影响因子：
4.8
通讯作者：
Nicole H. Rogers;H. Walsh;O. Alvarez-Garcia;Seongjoon Park;B. Gaylinn;M. Thorner;Roy G. Smith
中科院分区：
文献类型：
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作者：
Nicole H. Rogers;H. Walsh;O. Alvarez-Garcia;Seongjoon Park;B. Gaylinn;M. Thorner;Roy G. Smith
衰老与生长激素释放肽信号减弱有关。在衰老过程中，慢性热量限制（CR）产生健康益处，伴随着增强的ghrelin产生。生长激素释放肽受体（生长激素促分泌素受体1a）激动剂给药到老年啮齿动物和人类恢复年轻的成年人表型，因此，我们测试的假设，CR的代谢效益是由内源性生长激素释放肽介导的。缺乏饥饿素（Ghrelin-/-）或饥饿素受体（Ghsr-/-）的三个月大雄性小鼠及其野生型（WT）同窝小鼠被随机分配到2组：随意（AL）喂食组和CR组，其中逐渐引入40%的食物限制，以使Ghrelin-/-和Ghsr-/-小鼠能够代谢适应并避免严重的低血糖。12个月后，测量血浆ghrelin、代谢参数、步行活动、下丘脑和肝脏基因表达以及身体成分。CR增加WT和Ghsr-/-小鼠血浆ghrelin和去酰基ghrelin浓度。WT、Ghsr-/-和Ghrelin-/-小鼠的CR显著改善了代谢灵活性，增强了行走活动，并减少了肥胖。Ghrelin或Ghsr的失活对AL食物摄入或食物预期行为没有影响。与人们普遍认为的内源性生长激素释放肽调节食物摄入相反，CR增加了下丘脑Agrp和Npy的表达，降低了Pomc在基因型中的表达。在AL中，消除ghrelin信号传导显著抑制肝脏脂肪变性，这与Pparγ表达减少和Irs 2表达增加相关。虽然CR和GH促分泌素受体1a激动剂的管理都有利于老化表型，我们得出结论，慢性CR的好处是增强代谢的灵活性独立于内源性生长素释放肽或去酰基生长素释放肽信号的结果。
Aging is associated with attenuated ghrelin signaling. During aging, chronic caloric restriction (CR) produces health benefits accompanied by enhanced ghrelin production. Ghrelin receptor (GH secretagogue receptor 1a) agonists administered to aging rodents and humans restore the young adult phenotype; therefore, we tested the hypothesis that the metabolic benefits of CR are mediated by endogenous ghrelin. Three month-old male mice lacking ghrelin (Ghrelin-/-) or ghrelin receptor (Ghsr-/-), and their wild-type (WT) littermates were randomly assigned to 2 groups: ad libitum (AL) fed and CR, where 40% food restriction was introduced gradually to allow Ghrelin-/- and Ghsr-/- mice to metabolically adapt and avoid severe hypoglycemia. Twelve months later, plasma ghrelin, metabolic parameters, ambulatory activity, hypothalamic and liver gene expression, as well as body composition were measured. CR increased plasma ghrelin and des-acyl ghrelin concentrations in WT and Ghsr-/- mice. CR of WT, Ghsr-/-, and Ghrelin-/- mice markedly improved metabolic flexibility, enhanced ambulatory activity, and reduced adiposity. Inactivation of Ghrelin or Ghsr had no effect on AL food intake or food anticipatory behavior. In contrast to the widely held belief that endogenous ghrelin regulates food intake, CR increased expression of hypothalamic Agrp and Npy, with reduced expression of Pomc across genotypes. In the AL context, ablation of ghrelin signaling markedly inhibited liver steatosis, which correlated with reduced Pparγ expression and enhanced Irs2 expression. Although CR and administration of GH secretagogue receptor 1a agonists both benefit the aging phenotype, we conclude the benefits of chronic CR are a consequence of enhanced metabolic flexibility independent of endogenous ghrelin or des-acyl ghrelin signaling.