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.
We thank Adrian Wayman for technical assistance. Microarray hybridisation was carried out by Molecular Biology Services at the University of Warwick.
This research was supported by the Biotechnology and Biological Sciences Research Council [E007821/1 to M.S.M.-G., R.L.C. and E00797X/1; BB/K001418 /1 to L.K.H.]; the British Heart Foundation [FS/09/029/27902 to S.E.O.]; the UK Medical Research Council Metabolic Diseases Unit [MC_UU_12012/4 to S.E.O. and MC_UU_12012/1 to G.S.H.Y.]; the Wellcome Trust [WT081713 and WT098012 to L.K.H.]; the European Union [FP7-HEALTH-266408 Full4Health to G.S.H.Y.]; and the Helmholtz Alliance ICEMED to G.S.H.Y.
- Developmental programming
- Low birth weight
- Maternal diet
- Protein restriction