title: 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.
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 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.
authors.affiliation: 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 msm32@cam.ac.uk.
authors.forename: Malgorzata S
authors.initials: MS
authors.lastname: Martin-Gronert
authors.affiliation: Clore Laboratory, Buckingham Institute for Translational Medicine, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Stocker
authors.affiliation: Clore Laboratory, Buckingham Institute for Translational Medicine, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Wargent
authors.affiliation: 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.
authors.forename: Roselle L
authors.initials: RL
authors.lastname: Cripps
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Alastair S
authors.initials: AS
authors.lastname: Garfield
authors.affiliation: 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.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Jovanovic
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: 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.
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.affiliation: Clore Laboratory, Buckingham Institute for Translational Medicine, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cawthorne
authors.affiliation: Clore Laboratory, Buckingham Institute for Translational Medicine, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK.
authors.forename: Jonathan R S
authors.initials: JR
authors.lastname: Arch
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
authors.affiliation: 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.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ozanne
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004044:Dietary Proteins / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005277:Fenfluramine / Q000008:administration & dosage / Q000494:pharmacology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D048788:Growth and Development / Q000187:drug effects; D007031:Hypothalamus / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D061346:Laser Capture Microdissection; D008297:Male; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D015203:Reproducibility of Results; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism
chemical_list: D004044:Dietary Proteins; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D005277:Fenfluramine; D012701:Serotonin; D014364:Tryptophan
keywords: Developmental programming; Hypothalamus; Low birth weight; Maternal diet; Protein restriction; Serotonin