Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin
Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin
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DOI：
10.1016/j.molmet.2014.10.003
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发表时间：
2015-01-01
影响因子：
8.1
通讯作者：
Bouret, Sebastien G.
中科院分区：
文献类型：
--
作者：
Collden, Gustav;Balland, Eglantine;Bouret, Sebastien G.
目的：早期营养供给过剩和体重快速增加是成年期肥胖发生的危险因素。这种代谢程序失调可能是由发育关键时期的内分泌紊乱介导的。胃饥饿素是一种由胃分泌的代谢激素，通过与下丘脑弓状核中的生长激素促分泌受体结合，起到促进摄食行为的中枢作用。在这里，我们研究了新生儿营养过剩是否会导致胃饥饿素系统的变化。方法：采用不同产仔数的小鼠模型，研究出生后过度喂养对出生后发育过程中中枢和外周胃饥饿素系统的影响。结果：小窝饲养的小鼠在哺乳期超重，成年后肥胖增加。在出生后第3周，新生儿过度营养小鼠血清中总胃饥饿素和酰基胃饥饿素水平降低，胃饥饿素mRNA表达水平降低。在营养过剩的幼崽中，正常的低饥饿素血症在改善代谢结果方面相对无效，这表明小窝幼崽可能存在饥饿素耐药性。与这一观点一致的是，出生时营养过剩的幼犬对外周饥饿素的中枢反应受损。这种胃饥饿素耐药性的机制似乎包括胃饥饿素向下丘脑的转运减少。结论：出生后早期营养过剩导致下丘脑发育重要时期对外周胃饥饿素的中枢抵抗。由于胃饥饿素信号最近被认为与新生儿的代谢程序有关，因此胃饥饿素系统的这些改变可能有助于在出生后营养过剩的小鼠中观察到的代谢缺陷。(C) 2014年作者。Elsevier GmbH出版。
Objective: Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system.Methods: We used a well-described mouse model of divergent litter sizes to study the effects of postnatal overfeeding on the central and peripheral ghrelin systems during postnatal development.Results: Mice raised in small litters became overweight during lactation and remained overweight with increased adiposity as adults. Neonatally overnourished mice showed attenuated levels of total and acyl ghrelin in serum and decreased levels of Ghrelin mRNA expression in the stomach during the third week of postnatal life. Normalization of hypoghrelinemia in overnourished pups was relatively ineffective at ameliorating metabolic outcomes, suggesting that small litter pups may present ghrelin resistance. Consistent with this idea, neonatally overnourished pups displayed an impaired central response to peripheral ghrelin. The mechanisms underlying this ghrelin resistance appear to include diminished ghrelin transport into the hypothalamus.Conclusions: Early postnatal overnutrition results in central resistance to peripheral ghrelin during important periods of hypothalamic development. Because ghrelin signaling has recently been implicated in the neonatal programming of metabolism, these alterations in the ghrelin system may contribute to the metabolic defects observed in postnatally overnourished mice. (C) 2014 The Authors. Published by Elsevier GmbH.