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Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation.

ABSTRACT: Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood.To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring.Time-pregnant mice were exposed to LG-SF or sleep control during LG (LG-SC) conditions during the last 6 days of gestation. At 24 weeks of age, lipid profiles and metabolic parameters were assessed in the offspring. We performed large-scale DNA methylation analyses using methylated DNA immunoprecipitation (MeDIP) coupled with microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice per group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks.We detected significant increases in body weight (31.7 vs 28.8?g; P=0.001), visceral (642.1 vs 497.0?mg; P=0.002) and subcutaneous (293.1 vs 250.1?mg; P=0.001) fat mass, plasma cholesterol (110.6 vs 87.6?mg?dl(-1); P=0.001), triglycerides (87.3 vs 84.1?mg?dl(-1); P=0.003) and homeostatic model assessment-insulin resistance values (8.1 vs 6.1; P=0.007) in the LG-SF group. MeDIP analyses revealed that 2148 DMRs (LG-SF vs LG-SC; P<0.0001, model-based analysis of tilling-arrays algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome, such as Cartpt, Akt2, Apoe, Insr1 and so on. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response.Our findings show a major role for epigenomic regulation of pathways associated with the metabolic processes and inflammatory responses in VWAT. LG-SF-induced epigenetic alterations may underlie increases in the susceptibility to obesity and metabolic syndrome in the offspring.

SUBMITTER: Cortese R

PROVIDER: S-EPMC4496299 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation.

Cortese R R Khalyfa A A Bao R R Andrade J J Gozal D D

International journal of obesity (2005) 20150324 7

<h4>Background</h4>Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood.<h4>Objectives</h4>To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring.<h4>Methods</h ...[more]

PMID: 25801690

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Project description:BACKGROUND: Epigenetic processes enable the environment to modulate gene transcription during fetal development, ultimately leading to stable phenotypic changes throughout the lifespan. There is a relatively high prevalence of altered sleep patterns during late gestation, especially obstructive sleep apnea (OSA). Intermittent hypoxia (IH) is a hallmark of OSA caused by periodic obstructions of the upper airway, which occurs along with sleep fragmentation (SF). We have previously shown that adult offspring of late gestational SF (LG-SF) mothers exhibited metabolic alterations via epigenomic alterations. The aims of this study were to investigate the effects of LG-IH on metabolic features in offspring and to determine the effects of LG-IH on the epigenome of visceral white adipose tissue (VWAT) in the offspring. METHODS: Time-pregnant mice were exposed to LG-IH or room air (RA) paradigms conditions during the last 6 days of gestation (LG-IH and LG-RA groups, respectively). Offspring were weaned at 21 days and fed with normal chow diet. At 24 weeks, lipid profiles and metabolic parameters were assessed. We performed large scale DNA methylation analysis using MeDIP coupled to microarrays (MeDIP-chip) in offspring VWAT (n=8 mice per group). Regions exhibiting differential DNA methylation (DMRs) between the groups were mapped to their corresponding genes and tested for potential overlaps with biological processes and pathways using Ingenuity Pathway Analysis. RESULTS: We detected 1520 DMRs between the LG-IH and LG-RA groups (p< 0.0001, two-way ANOVA), associated with 693 genes. A significant portion of these genes (n=162) were also associated with previously identified DMRs in LG-SF offspring (p=1.35 x 10-97, hypergeometric test). Pathway analyses showed that genes affected by LG-IH and LG-SF, were mainly associated with molecular processes related to metabolic regulation and inflammatory response. In particular for LG-IH, biochemical pathways related to energy production through amino acid and fatty acid metabolism (i.e. methionine, choline and 2-oxobutanoate degradation pathways, methylmalonyl pathway, cysteine biosynthesis, etc.). CONCLUSIONS: Our findings suggest a major role for epigenomic alterations in the metabolic dysfunction of adult offspring born to LG-IH and LH-SF mothers. Furthermore, whereas LG-IH may concomitantly act upon metabolic pathways also affected by LG-SF, LG-IH also affects biochemical processes underlying energy production in VWAT of the offspring.

Project description:Epidemiological and animal studies have reported that prenatal nicotine exposure (PNE) leads to obesity and type-2 diabetes in offspring. Central leptin-melanocortin signaling via hypothalamic arcuate proopiomelanocortin (POMC) neurons is crucial for the regulation of energy and glucose balance. Furthermore, hypothalamic POMC neurons were recently found to mediate the anorectic effects of nicotine through activation of acetylcholine receptors. Here, we hypothesized that PNE impairs leptin-melanocortinergic regulation of energy balance in first-generation offspring by altering expression of long non-coding RNAs (lncRNAs) putatively regulating development and/or function of hypothalamic POMC neurons.C57BL/6J females were exposed ad libitum to nicotine through drinking water and crossed with C57BL/6J males. Nicotine exposure was sustained during pregnancy and discontinued at parturition. Offspring development was monitored from birth into adulthood. From the age of 8 weeks, central leptin-melanocortin signaling, diabetes, and obesity susceptibility were assessed in male offspring fed a low-fat or high-fat diet for 16 weeks. Nicotine-exposed and non-exposed C57BL/6J females were also crossed with C57BL/6J males expressing the enhanced green fluorescent protein specifically in POMC neurons. Transgenic male offspring were subjected to laser microdissections and RNA sequencing (RNA-seq) analysis of POMC neurons for determination of nicotine-induced gene expression changes and regulatory lncRNA/protein-coding gene interactions.Contrary to expectation based on previous studies, PNE did not impair but rather enhanced leptin-melanocortinergic regulation of energy and glucose balance via POMC neurons in offspring. RNA-seq of laser microdissected POMC neurons revealed only one consistent change, upregulation of Gm15851, a lncRNA of yet unidentified function, in nicotine-exposed offspring. RNA-seq further suggested 82 cis-regulatory lncRNA/protein-coding gene interactions, 19 of which involved coding genes regulating neural development and/or function, and revealed expression of several previously unidentified metabolic, neuroendocrine, and neurodevelopment pathways in POMC neurons.PNE does not result in obesity and type 2 diabetes but instead enhances leptin-melanocortinergic feeding and body weight regulation via POMC neurons in adult offspring. PNE leads to selective upregulation of Gm15851, a lncRNA, in adult offspring POMC neurons. POMC neurons express several lncRNAs and pathways possibly regulating POMC neuronal development and/or function.

Project description:Housing of laboratory mice at room temperature (22°C) might be considered a constant cold stress, which induces a thermogenic program in brown adipose tissue (BAT). However, the early adaptive response of white adipose tissue (WAT), the fat storage organ of the body, to a change from thermoneutrality to room temperature is not known. This was investigated here for various WAT depots, focusing on epididymal WAT (eWAT), widely used as reference depot. Male adult diet-induced obese (DIO) C57BL/6JOlaHsd mice housed at thermoneutrality (29°C), were for 5 days either switched to room temperature (22°C) or remained at thermoneutrality. Energy metabolism was continuously measured using indirect calorimetry. At the end of the study, serum metabolomics and WAT transcriptomics were performed. We confirmed activation of the thermogenic program in 22°C housed mice. Body weight and total fat mass were reduced. Whole body energy expenditure (EE) was increased, with a higher fatty acid to carbohydrate oxidation ratio and increased serum acylcarnitine levels, while energy intake was not significantly different between the two groups. Transcriptome analysis of eWAT identified tissue remodeling and inflammation as the most affected processes. Expression of pro-inflammatory M1 macrophage-related genes, and M1 over M2 macrophage ratio were decreased, which might be linked to an increased insulin sensitivity. Markers of thermogenesis were not altered in eWAT. Decreased expression of tryptophan hydroxylase 2 (Tph2) and cholecystokinin (Cck) might represent altered neuroendocrine signaling. eWAT itself does not show increased fatty acid oxidation. The three measured WATs, epididymal, mesenteric, and retroperitoneal, showed mainly similar responses; reduced inflammation (s100a8), decreased carbohydrate oxidation, and no or small differences in fatty acid oxidation. However, Ucp1 was only expressed and increased in rWAT in 22°C housed mice. Cck expression was decreased in the three WATs, significantly in eWAT and rWAT, in contrast to Tph2, which was decreased in eWAT while not expressed in mWAT and rWAT. Our data show that tissue remodeling, inflammation and neuroendocrine signaling are early responses in WAT to a moderate decrease in environmental temperature.

Project description:BackgroundExcessive maternal weight gain during pregnancy impacts on offspring health. This study focused on the timing of maternal gestational weight gain, using a porcine model with mothers of normal pre-pregnancy weight.MethodsTrial design ensured the trajectory of maternal gestational weight gain differed across treatments in early, mid and late gestation. Diet composition did not differ. On day 25 gestation, sows were assigned to one of five treatments: Control sows received a standard gestation diet of 2.3 kg/day (30 MJ DE/day) from early to late gestation (day 25-110 gestation). E sows received 4.6 kg food/day in early gestation (day 25-50 gestation). M sows doubled their food intake in mid gestation (day 50-80 gestation). EM sows doubled their food intake during both early and mid gestation (day 25-80 gestation). L sows consumed 3.5 kg food/day in late gestation (day 80-110 gestation). Offspring body weight and food intake levels were measured from birth to adolescence. Markers of lipid metabolism, hypertrophy and inflammation were investigated in subcutaneous adipose tissue of adolescent offspring.ResultsThe trajectory of gestational weight gain differed across treatments. However total gestational weight gain did not differ except for EM sows who were the heaviest and fattest mothers at parturition. Offspring birth weight did not differ across treatments. Subcutaneous adipose tissue from EM offspring differed significantly from controls, with elevated mRNA levels of lipogenic (CD36, ACACB and LPL), nutrient transporters (FABP4 and GLUT4), lipolysis (HSL and ATGL), adipocyte size (MEST) and inflammation (PAI-1) indicators. The subcutaneous adipose depot from L offspring exhibited elevated levels of CD36, ACACB, LPL, GLUT4 and FABP4 mRNA transcripts compared to control offspring.ConclusionsIncreasing gestational weight gain in early gestation had the greatest impact on offspring postnatal growth rate. Increasing maternal food allowance in late gestation appeared to shift the offspring adipocyte focus towards accumulation of fat. Mothers who gained the most weight during gestation (EM mothers) gave birth to offspring whose subcutaneous adipose tissue, at adolescence, appeared hyperactive compared to controls. This study concluded that mothers, who gained more than the recommended weight gain in mid and late gestation, put their offspring adipose tissue at risk of dysfunction.

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Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation.

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Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation.

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