5-HT2Aand 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

Malgorzata S. Martin-Gronert, Claire J. Stocker, Edward T. Wargent, Roselle L. Cripps, Alastair S. Garfield, Zorica Jovanovic, Giuseppe D'Agostino, Giles S. H. Yeo, Michael A. Cawthorne, Jonathan R. S. Arch, Lora K. Heisler, Susan E. Ozanne

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Abstract

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 of in utero growth-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.

Original languageEnglish
Pages (from-to)401-412
Number of pages12
JournalDevelopment
Volume143
Issue number8
DOIs
Publication statusPublished - 15 Apr 2016

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Martin-Gronert, M. S., Stocker, C. J., Wargent, E. T., Cripps, R. L., Garfield, A. S., Jovanovic, Z., D'Agostino, G., Yeo, G. S. H., Cawthorne, M. A., Arch, J. R. S., Heisler, L. K., & Ozanne, S. E. (2016). 5-HT2Aand 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Development, 143(8), 401-412. https://doi.org/10.1242/dev.138396