Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity.
Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity.
复制标题
雄性大鼠食欲和生长的发育程序会增加下丘脑血清素 (5-HT)5A 受体的表达和敏感性。
DOI：
10.1038/s41366-020-0643-2
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wargent ET
中科院分区：
文献类型：
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作者：
Wargent ET
背景虽然新生儿营养在子代终生健康中的重要作用已被公认，但其机制尚未得到很好的界定。母亲营养状况导致的出生后早期加速生长与食欲增加和体重增加有关。同样，生长缓慢与食欲下降和体重下降相关。中枢5-羟色胺(5-羟色胺，5-羟色胺)通路直接调节食物的摄取和觅食行为。为探讨低蛋白饮食对仔鼠5-羟色胺受体介导的子代摄食量的影响，采用基因芯片技术、原位杂交和激光捕获显微切割技术，对3月龄雄性低蛋白饮食大鼠下丘脑弓状核(ARC)中表达上调或下调的基因进行分析。采用第三脑室插管的方法检测雌性PLP仔鼠对5-羟色胺受体激动剂和拮抗剂的敏感性变化。结果与饲喂正常饲料的对照组仔鼠相比，3月龄以下雄性PLP仔鼠的摄食量减少，生长速度降低。与对照组相比，PLP大鼠共有97个基因上调，包括5-HT5A受体(5-HT5AR)和149个下调基因。以前的减肥药芬氟拉明和5-羟色胺受体激动剂(5-CT)显著抑制了两组大鼠的摄食量，但与对照组相比，PLP后代对d-芬氟拉明和5-CT更敏感。5-HT5AR拮抗剂SB699551可拮抗5-CT的作用。5-CT对正常大鼠和PLP大鼠的吞噬作用均有抑制作用，但对PLP仔鼠的抑制作用更明显。结论生后低蛋白饮食可通过增加下丘脑5-HT5AR的表达和敏感性，增强5-羟色胺对食欲的中枢作用。这些发现提供了对哺乳期间母体低蛋白饮食降低后代生长和食欲的可能机制的洞察。
BackgroundThough it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring.MethodsMicroarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake.ResultsMale PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5Areceptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring.ConclusionsPostnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.