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Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring.

ABSTRACT: Purpose:Maternal obesity has emerged as an important risk factor for the development of metabolic disorders in the offspring. The hypothalamus as the center of energy homeostasis regulation is known to function based on complex neuronal networks that evolve during fetal and early postnatal development and maintain their plasticity into adulthood. Development of hypothalamic feeding networks and their functional plasticity can be modulated by various metabolic cues, especially in early stages of development. Here, we aimed at determining the underlying molecular mechanisms that contribute to disturbed hypothalamic network formation in offspring of obese mouse dams. Methods:Female mice were fed either a control diet (CO) or a high-fat diet (HFD) after weaning until mating and during pregnancy and gestation. Male offspring was sacrificed at postnatal day (P) 21. The hypothalamus was subjected to gene array analysis, quantitative PCR and western blot analysis. Results:P21 HFD offspring displayed increased body weight, circulating insulin levels, and strongly increased activation of the hypothalamic insulin signaling cascade with a concomitant increase in ionized calcium binding adapter molecule 1 (IBA1) expression. At the same time, the global gene expression profile in CO and HFD offspring differed significantly. More specifically, manifest influences on several key pathways of hypothalamic neurogenesis, axogenesis, and regulation of synaptic transmission and plasticity were detectable. Target gene expression analysis revealed significantly decreased mRNA expression of several neurotrophic factors and co-factors and their receptors, accompanied by decreased activation of their respective intracellular signal transduction. Conclusion:Taken together, these results suggest a potential role for disturbed neurotrophin signaling and thus impaired neurogenesis, axogenesis, and synaptic plasticity in the pathogenesis of the offspring's hypothalamic feeding network dysfunction due to maternal obesity.

SUBMITTER: Bae-Gartz I

PROVIDER: S-EPMC6753176 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring.

Bae-Gartz Inga I Janoschek Ruth R Breuer Saida S Schmitz Lisa L Hoffmann Thorben T Ferrari Nina N Branik Lena L Oberthuer Andre A Kloppe Cora-Sophia CS Appel Sarah S Vohlen Christina C Dötsch Jörg J Hucklenbruch-Rother Eva E

Frontiers in neuroscience 20190913

<h4>Purpose</h4>Maternal obesity has emerged as an important risk factor for the development of metabolic disorders in the offspring. The hypothalamus as the center of energy homeostasis regulation is known to function based on complex neuronal networks that evolve during fetal and early postnatal development and maintain their plasticity into adulthood. Development of hypothalamic feeding networks and their functional plasticity can be modulated by various metabolic cues, especially in early st ...[more]

PMID: 31572115

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Project description:The risk of obesity (OB) in adulthood is strongly influenced by maternal body composition. Here we examined the hypothesis that maternal OB influences white adipose tissue (WAT) transcriptome and increases propensity for adipogenesis in the offspring, prior to the development of OB, using an established model of long-term metabolic programming. Employing an overfeeding-based rat model, in which exposure to OB is limited to preconception and gestation alone, we conducted global transcriptomic profiling in WAT, and gene/protein expression analysis of lipogenic and adipogenic pathways and examined adipogenic differentiation of WAT stromal-vascular cells ex vivo. Using reduced representation bisulfite sequencing we also evaluated genome-scale changes in DNA methylation in offspring WAT. Maternal OB led to extensive changes in expression of genes (± 1.8-fold, P ? .05), revealing a distinct up-regulation of lipogenic pathways in WAT. mRNA expression of a battery of sterol regulatory element-binding protein-1-regulated genes was increased in OB-dam offspring, which were confirmed by immunoblotting. In conjunction with lipogenic gene expression, OB-dam offspring showed increased glucose transporter-4 mRNA/protein expression and greater AKT phosphorylation following acute insulin challenge, suggesting sensitization of insulin signaling in WAT. Offspring of OB dams also exhibited increased in vivo expression of adipogenic regulators (peroxisome proliferator-activated receptor-?, CCAAT enhancer binding protein ? [C/EBP-?] and C/EBP-?), associated with greater ex vivo differentiation of WAT stromal-vascular cells. These transcriptomic changes were associated with alterations in DNA methylation of CpG sites and CGI shores, proximal to developmentally important genes, including key pro-adipogenic factors (Zfp423 and C/EBP-?). Our findings strongly suggest that the maternal OB in utero alters adipocyte commitment and differentiation via epigenetic mechanisms.

Dataset Information

Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring.

Publications

Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring.

Similar Datasets

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