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The transcriptome of the rat subfornical organ is altered in response to early postnatal overnutrition.

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.

SUBMITTER: Peterson CS

PROVIDER: S-EPMC6095096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne proinflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating proinflammatory cytokines remain unclear. We hypothesized that proinflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of tumor necrosis factor (TNF)-? (25 ng) or interleukin (IL)-1? (25 ng) into SFO increased mean blood pressure, heart rate, and renal sympathetic nerve activity within 15 to 20 minutes, mimicking the response to systemically administered proinflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type-1 receptor blocker losartan (1 ?g), angiotensin-converting enzyme inhibitor captopril (1 ?g) or cyclooxygenase-2 inhibitor NS-398 (2 ?g) attenuated those responses. Four hours after the SFO microinjection of TNF-? (25 ng) or IL-1? (25 ng), mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, TNF-? and the p55 TNF-? receptor, IL-1? and the IL-1R receptor, and cyclooxygenase-2 had increased in SFO, and mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, and cyclooxygenase-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for the p55 TNF-? receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, colocalized with angiotensin-converting enzyme, angiotensin II type-1 receptor-like, cyclooxygenase-2, and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that proinflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation.

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The transcriptome of the rat subfornical organ is altered in response to early postnatal overnutrition.

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