Abstract
PurposeMaternal 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.MethodsFemale 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.ResultsP21 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.ConclusionTaken 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.
Highlights
The rising incidence of maternal obesity is a worldwide phenomenon and the relationship between maternal obesity and the offspring’s long-term predisposition for metabolic disorders, such as obesity and type-2-diabetes, is undeniable (Howie et al, 2009; Plagemann, 2011; O’Reilly and Reynolds, 2013)
high-fat diet (HFD) offspring showed significantly increased non-fasted serum insulin and leptin concentrations at P21 compared to controls (Figures 1C,D)
HFD offspring showed increased blood glucose levels compared with CO offspring 15 min after glucose injection in the intraperitoneal Glucose tolerance tests (GTT) (Figure 1E)
Summary
The rising incidence of maternal obesity is a worldwide phenomenon and the relationship between maternal obesity and the offspring’s long-term predisposition for metabolic disorders, such as obesity and type-2-diabetes, is undeniable (Howie et al, 2009; Plagemann, 2011; O’Reilly and Reynolds, 2013). The melanocortin system of the arcuate nucleus of the hypothalamus (ARC) has been shown to convey anorexigenic and orexigenic signals in response to circulating hormones and nutrients (Elias et al, 1999; Cowley et al, 2001; Aponte et al, 2011; Krashes et al, 2011). While early studies in rodents focused on analyzing the effects of hormones or nutrients on anorexigenic or orexigenic neuropeptide gene expression in the ARC, research interest shifted toward a deeper functional understanding of acute effects of substances like insulin, leptin, ghrelin, or glucose on electrophysiological properties of neuropeptide releasing ARC producing cells (Cowley et al, 2001, 2003a,b; Jobst et al, 2004; Pinto et al, 2004; van den Top et al, 2004; Dhillon et al, 2006; Konner et al, 2007). Leptin was shown to have a major influence on synaptic organization of orexin neurons in the lateral hypothalamus (Horvath and Gao, 2005), Abbreviations: (p)AKT, (phosphorylated) RAC-alpha serine/threonine-protein kinase; (p)AMPK, (phosphorylated) 5 -adenosine monophosphate-activated protein kinase; (p)CAMKII, (phosphorylated) Ca2+/calmodulin-dependent protein kinase II; (p)ERK, (phosphorylated) extracellular-signal regulated kinases; (p)GSK3beta, (phosphorylated) glycogen synthase kinase 3 beta; (p)JNK1, (phosphorylated) c-Jun N-terminal kinase 1; (p)JNK2, (phosphorylated) c-Jun N-terminal kinase 2; (p)JNK3, (phosphorylated) c-Jun N-terminal kinase 3; (p)p38, (phosphorylated) p38 mitogen-activated protein kinase; ARC, arcuate nucleus of the hypothalamus; BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; CO, control group; DCX, doublecortin; G, gestational day; GAPDH, glycerinaldehyd-3-phosphat-dehydrogenase; GDNF, glial cell derived neurotrophic factor; GO-terms, gene ontology terms; GTT, glucose tolerance test; HFD, high fat diet; HRP, horseradish peroxidase; IBA1, ionized calcium-binding adapter molecule 1; InsR, insulin receptor; KEGG, Kyoto Encyclopedia of Genes and Genomes; LepR, leptin receptor; MAPK, mitogen activated protein kinase; NENF, neuron-derived neurotrophic factor; NGF, nerve growth factor; NPY, neuropeptide Y; NT3, neurotrophin 3; NT4/5, neurotrophin 4/5; P, postnatal day; p75NTR, p75 neurotrophin receptor; PCLgamma, phospholipase C gamma; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol 3 kinase; POMC, propriomelanocortin; PVN, paraventricular nucleus; TrkA, tropomyosin receptor kinase A; TrkB, tropomyosin receptor kinase B; TrkC, Tropomyosin receptor kinase C; vGAT, vesicular gamma-aminobutyric acid (GABA) transportervGlut Vesicular glutamate transporter 2
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