Abstract
Maternal overnutrition during pregnancy leads to metabolic alterations, including obesity, hyperphagia, and inflammation in the offspring. Nutritional priming of central inflammation and its role in ghrelin sensitivity during fed and fasted states have not been analyzed. The current study aims to identify the effect of maternal programming on microglia activation and ghrelin-induced activation of hypothalamic neurons leading to food intake response. We employed a nutritional programming model exposing female Wistar rats to a cafeteria diet (CAF) from pre-pregnancy to weaning. Food intake in male offspring was determined daily after fasting and subcutaneous injection of ghrelin. Hypothalamic ghrelin sensitivity and microglia activation was evaluated using immunodetection for Iba-1 and c-Fos markers, and Western blot for TBK1 signaling. Release of TNF-alpha, IL-6, and IL-1β after stimulation with palmitic, oleic, linoleic acid, or C6 ceramide in primary microglia culture were quantified using ELISA. We found that programmed offspring by CAF diet exhibits overfeeding after fasting and peripheral ghrelin administration, which correlates with an increase in the hypothalamic Iba-1 microglia marker and c-Fos cell activation. Additionally, in contrast to oleic, linoleic, or C6 ceramide stimulation in primary microglia culture, stimulation with palmitic acid for 24 h promotes TNF-alpha, IL-6, and IL-1β release and TBK1 activation. Notably, intracerebroventricular (i.c.v.) palmitic acid or LPS inoculation for five days promotes daily increase in food intake and food consumption after ghrelin administration. Finally, we found that i.c.v. palmitic acid substantially activates hypothalamic Iba-1 microglia marker and c-Fos. Together, our results suggest that maternal nutritional programing primes ghrelin sensitivity and microglia activation, which potentially might mirror hypothalamic administration of the saturated palmitic acid.
Highlights
Maternal obesity or maternal overnutrition during pregnancy and lactation programs an adverse uterine milieu leading to defects in organ function and metabolism in offspring [1,2]
We have reported that the saturated lipid palmitic acid leads to the activation of the toll-like receptor 4 (TLR-4)-TBK1 pathway in the hypothalamus of obese murine models, which correlates with insulin resistance [20]
We found that subcutaneous ghrelin injection significantly increased Chow and cafeteria diet (CAF) diet intake in offspring programmed by maternal
Summary
Maternal obesity or maternal overnutrition during pregnancy and lactation programs an adverse uterine milieu leading to defects in organ function and metabolism in offspring [1,2]. Programing involves a new setting of peripheral and central pathways including energy expenditure and appetite regulation, which potentially increase the susceptibility for obesity and metabolic-related pathologies in adult offspring [2]. Maternal nutritional programming by cafeteria diet (CAF) in murine models sets metabolic alterations including impaired insulin sensitivity, hypertension, endothelial dysfunction, increased adiposity [3,4,5], and altered appetite regulation (hyperphagia) [2,6]. Food intake is actively regulated by ghrelin, which is the only known appetite-inducing peptide produced by endocrine cells of the gastric mucosa [7,8]. Maternal nutritional programming by overnutrition stimulates proliferation of neuroepithelial and neuronal precursor cells in the hypothalamus during the embryonic period, leading to differentiation and proliferation of orexigenic peptide-producing neurons [13]. A recent clinical study demonstrated that the maternal prenatal lipid profile was associated with the offspring’s eating behavior and energy intake [14]
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