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Female and Male C57Bl/6J Offspring Exposed to Maternal Obesogenic Diet Develop Altered Hypothalamic Energy Metabolism in Adulthood

ABSTRACT: Purpose: Study a cohort of C57Bl/6J dams, treated with a control or high-fat-high-sugar diet, and their adult offspring to explore potential hypothalamic mechanisms to explain the link between maternal and offspring obesity. Hypothalamic differential gene expression analysis was conducted following next-generation sequencing (NGS) and analyzed in Ingenuity Pathway Analysis. This methodology was supplementary to in vivo studies which characterized offspring metabolic phenotype. Methods: Total RNA was extracted from a subset of offspring hypothalamus tissue using a RNeasy Mini Kit (Qiagen, Germantown, MD). Tissues were homogenized in RLT buffer using mechanized syringe homogenization. RNA was assessed for purity and concentration using the NanoDrop (NanoDrop Technologies). Approximately 4ug of total RNA was used to generate cDNA by reverse transcription using a cDNA synthesis kit (Applied Biosystems, Carlsbad, CA). Results: There were 31,637 differentially expressed genes in adult OB offspring hypothalamus compared with control diet. Of the identified differentially expressed genes, there were 2510 differentially expressed genes that were significantly different between CON and OB offspring (Supplemental Table 3). In OB offspring, 65% of the identified differentially expressed genes were downregulated whereas 35% were upregulated. Conclusions: Collectively, data demonstrate that maternal obesity without diabetes is associated with adiposity and decreased hypothalamic energy production.

ORGANISM(S): Mus musculus

PROVIDER: GSE200611 | GEO | 2022/04/13

REPOSITORIES: GEO

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Project description:Though obesity is a global epidemic, the physiological mechanisms involved are little 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 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 hypothesized that maternal diet influences fetal 5-HT exposure, which then influences central appetite network development and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant low protein fed rat mothers exhibited elevated serum 5-HT, which was also evident in the placenta and fetal brains at E16.5. This increase was associated with reduced hypothalamic expression of 5-HT2CR - the primary 5-HT receptor influencing appetite. As expected, reduced 5-HT2CR expression was associated with impaired sensitivity to 5-HT-mediated appetite suppression. 5-HT primarily achieves effects on appetite via 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We reveal that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC and that 5-HT2AR mRNA is increased in the hypothalamus of in utero growth restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals are more sensitive to 5-HT2AR agonist-induced appetite suppression. These findings may not only reveal a 5-HT-mediated mechanism underlying programming of obesity susceptibility but also provide a promising means to correct it, via a 5-HT2AR agonist treatment. The study was carried out using male Wistar rats (Rattus norvegicus). On postnatal day 3, two experimental groups of offspring were established: controls (offspring of control dams) and recuperated (offspring of dams fed a low-protein diet (8% protein, w/v), but nursed by control dams. The animals were fed with standard chow until 3 months of age where the brains were collected for transcriptomic profiling

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Female and Male C57Bl/6J Offspring Exposed to Maternal Obesogenic Diet Develop Altered Hypothalamic Energy Metabolism in Adulthood

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