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Physiology and Biochemistry

Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity

International Journal of Obesity volume 44, pages 1946–1957 (2020)Cite this article

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Abstract

Background

Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring.

Methods

Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake.

Results

Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring.

Conclusions

Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

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Fig. 1: Growth trajectory and brain weights of Control and PLP rats.
Fig. 2: Venn diagrams of maternal protein restriction during lactation on ARC gene expression in 3-month-old male offspring according to three different analyses: GCOS, GC-RMA and RMA.
Fig. 3: RT-PCR validation of the differentially expressed genes in the ARC of Control and postnatal low protein (PLP) rats identified with microarray.
Fig. 4: PLP rats are more sensitive to the anorectic effect of d-fenfluramine.
Fig. 5: Enhanced 5-HT-induced food intake in PLP rats is 5-HT5AR-mediated.
Fig. 6: Effect of 5-HT5AR agonist 5-CT combined with NPY on food intake.

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Acknowledgements

This work was supported by the Biotechnology and Biological Sciences Research Council (Grant codes BB/E00797X/1, BB/E007821/1, BB/R01857X/1, BB/N017838/1) and Medical Research Council (MC/PC/15077). Microarray hybridization was carried out by Molecular Biology Services at the University of Warwick.

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Authors and Affiliations

  1. Buckingham Institute of Translational Medicine, University of Buckingham, Hunter Street, Buckingham, MK18 1EG, UK

    Edward T. Wargent, Jonathan R. S. Arch & Claire J. Stocker

  2. Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

    Malgorzata S. Martin-Gronert, Roselle L. Cripps, Giles S. H. Yeo & Susan E. Ozanne

  3. The Rowett, Institute, University of Aberdeen, Aberdeen, AB25 2ZD, UK

    Lora K. Heisler

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Wargent, E.T., Martin-Gronert, M.S., Cripps, R.L. et al. Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity. Int J Obes 44, 1946–1957 (2020). https://doi.org/10.1038/s41366-020-0643-2

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