Abstract
Early postnatal overnutrition in humans is associated with long-term negative outcomes including obesity, increased risk of type-II diabetes, and cardiovascular disease. Hypothalamic neurons from rodents exposed to early postnatal overnutrition show altered expression of satiety signals and receptors, and exhibit altered responses to many satiety signals, suggesting a hypothalamic link between early overnutrition and development of these sequelae. Importantly, several hypothalamic nuclei receive information regarding circulating hormones (such as insulin, leptin and ghrelin) from the subfornical organ (SFO), a forebrain sensory circumventricular organ which lacks a blood brain barrier. Previous transcriptomic studies indicate that challenges to energy balance and hydration status stimulate changes in gene expression within the SFO, including genes encoding ion channels and receptors. In order to determine if early postnatal overnutrition also causes changes in SFO gene expression which may be associated with homeostatic dysregulation, we performed whole transcriptome sequencing on SFO tissue from rats raised in small (4 pups), or control (large, 12 pups) litters. Illumina RNA sequencing was performed on SFO tissue from rats raised from small and large litters, and read sequences were aligned to the Rat Rnor_6.0 genome. Control data were further compared to previously published microarray data set for validation. We found statistically significant (p<0.05) changes in expression of 12 transcripts, three of which have likely roles in neuronal excitability, neurite outgrowth and differentiation, and food intake (Manf, Slc24a4, Cracr2b). Additionally, gene ontology analysis identified a trend among significantly altered transcripts in roles for oxidative stress response. We conclude that the SFO transcriptome is subtly altered by early postnatal overnutrition, and recommend further investigation of the effect of early postnatal overnutrition on SFO physiology and morphology.
Highlights
In humans, early postnatal overnutrition results in accelerated growth and weight gain, is predictive of childhood (Gittner et al, 2013) and adult obesity (Rzehak et al, 2017), and is correlated with increased risk of type II diabetes (Eriksson et al, 2003) and heart disease (Camhi and Katzmarzyk, 2010)
To confirm that rearing as small litters induced larger body weight, males were weighed at six weeks of age
The objective of this study was to determine if there are changes in subfornical organ (SFO) gene expression associated with early overnutrition in rat pups that may be related to the development of sequelae such obesity, type II diabetes (Eriksson et al, 2003) and heart disease (Camhi and Katzmarzyk, 2010) observed in humans and rodents (Habbout et al, 2013; Plagemann et al, 1992)
Summary
Early postnatal overnutrition results in accelerated growth and weight gain, is predictive of childhood (Gittner et al, 2013) and adult obesity (Rzehak et al, 2017), and is correlated with increased risk of type II diabetes (Eriksson et al, 2003) and heart disease (Camhi and Katzmarzyk, 2010). When fed a high fat diet, small litter rats display persistent hyperphagia and increased caloric intake (Glavas et al, 2010), suggesting early overnutrition primes rats for later weight gain. Increased densities of galanin and neuropeptide Y (NPY) neurons in the arcuate nucleus of the hypothalamus (ARC) are found in small litter rats compared to control rats, despite lower overall density of neurons (Plagemann et al, 1999b). Neurons may show altered responses to hormones following postnatal overnutrition; for example leptin and insulin resistance is seen in hypothalamic neurons (Glavas et al, 2010) in the face of increased central levels of both peptides (Glavas et al, 2010; Plagemann et al, 1999b). Altered responses to the neuropeptides cocaine and amphetamine regulated transcript (CART), NPY, and corticotropin-releasing hormones are observed in the PVN, ARC, and ventromedial nucleus of the hypothalamus (VMN) (Davidowa et al, 2003; Davidowa and Plagemann, 2004)
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