5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

Though obesity is a global epidemic, the physiological mechanisms involved are little understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesized that maternal diet influences fetal 5-HT exposure, which then influences central appetite network development and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant low protein fed rat mothers exhibited elevated serum 5-HT, which was also evident in the placenta and fetal brains at E16.5. This increase was associated with reduced hypothalamic expression of 5-HT2CR - the primary 5-HT receptor influencing appetite. As expected, reduced 5-HT2CR expression was associated with impaired sensitivity to 5-HT-mediated appetite suppression. 5-HT primarily achieves effects on appetite via 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We reveal that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC and that 5-HT2AR mRNA is increased in the hypothalamus of in utero growth restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals are more sensitive to 5-HT2AR agonist-induced appetite suppression. These findings may not only reveal a 5-HT-mediated mechanism underlying programming of obesity susceptibility but also provide a promising means to correct it, via a 5-HT2AR agonist treatment.尽管肥胖已成为全球性公共卫生流行病，但相关的生理病理机制仍未得到充分阐明。近年研究进展表明，肥胖易感性可通过母体与新生儿的营养状况实现发育程序化调控。具体而言，妊娠期母体低蛋白饮食会导致胎儿宫内生长受限、出生后快速追赶生长，并增加饮食诱导性肥胖的发病风险。 鉴于神经递质5-羟色胺（5-hydroxytryptamine, 5-HT）的合成受营养调控，且5-HT本身属于神经营养因子，我们提出假说：母体饮食可影响胎儿的5-HT暴露水平，进而调控中枢食欲网络的发育，以及后续生命过程中5-HT调控能量平衡的效能。 与该假说相符的是，妊娠期喂食低蛋白饮食的大鼠母体血清5-HT水平升高，且在妊娠第16.5天（E16.5）的胎盘与胎儿脑组织中也可检测到该升高现象。该升高与下丘脑5-羟色胺2C受体（5-HT2CR）的表达下调相关，而5-HT2CR是调控食欲的主要5-HT受体亚型。如预期一致，5-HT2CR表达下调与5-HT介导的食欲抑制敏感性受损相关。 5-HT主要通过激活下丘脑弓状核（arcuate nucleus of the hypothalamus, ARC）内的前阿黑皮素（pro-opiomelanocortin, POMC）肽能神经元上的5-HT2CR来发挥食欲调控效应。我们的研究发现，5-羟色胺2A受体（5-HT2AR）在解剖结构上也可调控ARC内POMC神经元的活性；并且，经历宫内生长受限与出生后快速追赶生长的子代大鼠，其下丘脑内5-HT2AR的mRNA表达水平显著升高。此外，该类子代大鼠对5-HT2AR激动剂介导的食欲抑制作用更为敏感。 本研究结果不仅揭示了介导肥胖易感性发育程序化调控的5-HT相关机制，同时也为通过5-HT2AR激动剂治疗干预该过程提供了潜在的可行策略。