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

Martin-Gronert, Malgorzata S and Stocker, Claire J. and Wargent, Edward T. and Cripps, Roselle L and Garfield, Alastair S and Jovanovic, Zorica and D'Agostino, Giuseppe and Yeo, Giles S.H. and Cawthorne, Michael A and Arch, Jonathan R.S. and Heisler, Lora K and Ozanne, Susan E (2016) 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Disease Models and Mechanisms. ISSN 1754-8411

Martin-Gronert et al, 5-HT2A and 5-HT2C ....pdf - Accepted Version
Available under License Creative Commons Attribution.

Download (1MB) | Preview
Official URL: http://dmm.biologists.org/content/dmm/early/2016/0...


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 a reduced hypothalamic expression of the primary 5-HT receptor influencing appetite, 5-HT2CR in the fetal brain as well as neonatal and adult hypothalamus. As expected, reduced 5-HT2CR expression was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 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 at 3-months of age 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.

Item Type: Article
Uncontrolled Keywords: 5-HT (Serotonin); Developmental programming; Hypothalamus; Low birth weight; Maternal diet; Protein restriction
Subjects: Q Science > QP Physiology
Divisions: School of Science > Metabolic Research
Depositing User: Julie Cakebread
Date Deposited: 04 Mar 2016 10:02
Last Modified: 03 Feb 2017 12:53
URI: http://bear.buckingham.ac.uk/id/eprint/104

Actions (login required)

View Item View Item