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Sexual dimorphism in offspring glucose-sensitive hypothalamic gene expression and physiological responses to maternal high-fat diet feeding.

ABSTRACT: A wealth of animal and human studies demonstrate that early life environment significantly influences adult metabolic balance, however the etiology for offspring metabolic misprogramming remains incompletely understood. Here, we determine the effect of maternal diet per se on offspring sex-specific outcomes in metabolic health and hypothalamic transcriptome regulation in mice. Furthermore, to define developmental periods of maternal diet misprogramming aspects of offspring metabolic balance, we investigated offspring physiological and transcriptomic consequences of maternal high-fat/high-sugar diet feeding during pregnancy and/or lactation. We demonstrate that female offspring of high-fat/high-sugar diet-fed dams are particularly vulnerable to metabolic perturbation with body weight increases due to postnatal processes, whereas in utero effects of the diet ultimately lead to glucose homeostasis dysregulation. Furthermore, glucose- and maternal-diet sensitive gene expression modulation in the paraventricular hypothalamus is strikingly sexually dimorphic. In summary, we uncover female-specific, maternal diet-mediated in utero misprogramming of offspring glucose homeostasis and a striking sexual dimorphism in glucose- and maternal diet-sensitive paraventricular hypothalamus gene expression adjustment. Notably, female offspring metabolic vulnerability to maternal high-fat/high-sugar diet propagates a vicious cycle of obesity and type 2 diabetes in subsequent generations.

SUBMITTER: Dearden L

PROVIDER: S-EPMC4183922 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Sexual dimorphism in offspring glucose-sensitive hypothalamic gene expression and physiological responses to maternal high-fat diet feeding.

Dearden Laura L Balthasar Nina N

Endocrinology 20140331 6

A wealth of animal and human studies demonstrate that early life environment significantly influences adult metabolic balance, however the etiology for offspring metabolic misprogramming remains incompletely understood. Here, we determine the effect of maternal diet per se on offspring sex-specific outcomes in metabolic health and hypothalamic transcriptome regulation in mice. Furthermore, to define developmental periods of maternal diet misprogramming aspects of offspring metabolic balance, we ...[more]

PMID: 24684305

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Project description:Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = -0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.

Project description:ObjectiveAmylin was found to regulate glucose and lipid metabolism by acting on the arcuate nucleus of the hypothalamus (ARC). Maternal high-fat diet (HFD) induces sex-specific metabolic diseases mediated by the ARC in offspring. This study was performed to explore 1) the effect of maternal HFD-induced alterations in amylin on the differentiation of hypothalamic neurons and metabolic disorders in male offspring and 2) the specific molecular mechanism underlying the regulation of amylin and its receptor in response to maternal HFD.MethodsMaternal HFD and gestational hyper-amylin mice models were established to explore the role of hypothalamic amylin and receptor activity-modifying protein 3 (Ramp3) in regulating offspring metabolism. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and RNA decay assays were performed to investigate the mechanism underlying the influence of maternal HFD on Ramp3 deficiency in the fetal hypothalamus.ResultsMale offspring with maternal HFD grew heavier and developed metabolic disorders, whereas female offspring with maternal HFD showed a slight increase in body weight and did not develop metabolic disorders compared to those exposed to maternal normal chow diet (NCD). Male offspring exposed to a maternal HFD had hyperamylinemia from birth until adulthood, which was inconsistent with offspring exposed to maternal NCD. Hyperamylinemia in the maternal HFD-exposed male offspring might be attributed to amylin accumulation following Ramp3 deficiency in the fetal hypothalamus. After Ramp3 knockdown in hypothalamic neural stem cells (htNSCs), amylin was found to fail to promote the differentiation of anorexigenic alpha-melanocyte-stimulating hormone-proopiomelanocortin (?-MSH-POMC) neurons but not orexigenic agouti-related protein-neuropeptide Y (AgRP-Npy) neurons. An investigation of the mechanism involved showed that IGF2BP1 could specifically bind to Ramp3 in htNSCs and maintain its mRNA stability. Downregulation of IGF2BP1 in htNSCs in the HFD group could decrease Ramp3 expression and lead to an impairment of ?-MSH-POMC neuron differentiation.ConclusionsThese findings suggest that gestational exposure to HFD decreases the expression of IGF2BP1 in the hypothalami of male offspring and destabilizes Ramp3 mRNA, which leads to amylin resistance. The subsequent impairment of POMC neuron differentiation induces sex-specific metabolic disorders in adulthood.

Project description:ObjectiveA sexual dimorphism exists in body fat distribution; females deposit relatively more fat in subcutaneous/inguinal depots whereas males deposit more fat in the intra-abdominal/gonadal depot. Our objective was to systematically document depot- and sex-related differences in the accumulation of adipose tissue and gene expression, comparing differentially expressed genes in diet-induced obese mice with mice maintained on a chow diet.Research design and methodsWe used a microarray approach to determine whether there are sexual dimorphisms in gene expression in age-matched male, female or ovariectomized female (OVX) C57/BL6 mice maintained on a high-fat (HF) diet. We then compared expression of validated genes between the sexes on a chow diet.ResultsAfter exposure to a high fat diet for 12 weeks, females gained less weight than males. The microarray analyses indicate in intra-abdominal/gonadal adipose tissue in females 1642 genes differ by at least twofold between the depots, whereas 706 genes differ in subcutaneous/inguinal adipose tissue when compared with males. Only 138 genes are commonly regulated in both sexes and adipose tissue depots. Inflammatory genes (cytokine-cytokine receptor interactions and acute-phase protein synthesis) are upregulated in males when compared with females, and there is a partial reversal after OVX, where OVX adipose tissue gene expression is more 'male-like'. This pattern is not observed in mice maintained on chow. Histology of male gonadal white adipose tissue (GWAT) shows more crown-like structures than females, indicative of inflammation and adipose tissue remodeling. In addition, genes related to insulin signaling and lipid synthesis are higher in females than males, regardless of dietary exposure.ConclusionsThese data suggest that male and female adipose tissue differ between the sexes regardless of diet. Moreover, HF diet exposure elicits a much greater inflammatory response in males when compared with females. This data set underscores the importance of analyzing depot-, sex- and steroid-dependent regulation of adipose tissue distribution and function.

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Sexual dimorphism in offspring glucose-sensitive hypothalamic gene expression and physiological responses to maternal high-fat diet feeding.

Publications

Sexual dimorphism in offspring glucose-sensitive hypothalamic gene expression and physiological responses to maternal high-fat diet feeding.

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