Martin-Gronert Malgorzata S, Stocker Claire J, Wargent Edward T, Cripps Roselle L, Garfield Alastair S, Jovanovic Zorica, D'Agostino Giuseppe, Yeo Giles S H, Cawthorne Michael A, Arch Jonathan R S, Heisler Lora K, Ozanne Susan E
University of Cambridge, Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
Clore Laboratory, Buckingham Institute for Translational Medicine, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK.
Dis Model Mech. 2016 Apr;9(4):401-12. doi: 10.1242/dmm.023903. Epub 2016 Jan 14.
Although obesity is a global epidemic, the physiological mechanisms involved are not well 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 an 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 hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.
尽管肥胖是一种全球性的流行病，但其涉及的生理机制尚未得到充分了解。最近的研究进展表明，肥胖易感性可能由母体和新生儿营养编程。具体而言，孕期母体低蛋白饮食会导致子宫内生长减少、出生后快速追赶生长以及饮食诱导性肥胖风险增加。鉴于神经递质5-羟色胺（5-HT）的合成受营养调节，且5-HT是一种营养因子，我们推测母体饮食会影响胎儿5-HT暴露，进而影响中枢食欲网络的发育以及5-HT在以后生活中控制能量平衡的功效。与我们的假设一致，喂食低蛋白饮食的怀孕大鼠血清5-HT水平升高，在胚胎第16.5天，胎盘和胎儿大脑中也明显升高。这种升高与胎儿、新生儿和成年下丘脑食欲的主要5-HT受体5-HT2CR水平降低有关。正如预期的那样，5-HT2CR的减少与成年期对5-HT介导的食欲抑制的敏感性受损有关。5-HT主要通过刺激下丘脑弓状核（ARC）内的阿黑皮素原（POMC）肽来实现对食欲的影响。我们发现5-HT2ARs在解剖学上也定位为影响ARC POMC神经元的活性，并且在经历出生后快速追赶生长的子宫内生长受限后代的下丘脑中，编码5-HT2AR的mRNA增加。此外，这些3个月大的动物对5-HT2AR激动剂诱导的食欲抑制更敏感。这些发现不仅揭示了肥胖易感性编程背后的5-HT介导机制，还提供了一种通过用5-HT2AR激动剂治疗来纠正它的有前景的方法。
