White Adipose Tissue Of Offspring Research Articles

Maternal Metformin Intervention during Obese Glucose-Intolerant Pregnancy Affects Adiposity in Young Adult Mouse Offspring in a Sex-Specific Manner.

Background: Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white adipose tissue (WAT) of 8-week-old male and female mouse offspring. Methods: C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR. Results: Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (p < 0.05), exaggerated adipocyte hyperplasia (p < 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (p < 0.05) and the mRNA expression of F4/80 (p < 0.05). These changes were not observed in female Ob-Met offspring. Conclusions: Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT.

Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner

We previously demonstrated that exposing mouse dams to metformin during gestation results in increased beta-cell mass at birth and increased beta-cell insulin secretion in adult male offspring. Given these favorable changes after a gestational maternal metformin exposure, we wanted to understand the long-term metabolic impact on offspring after exposing dams to metformin during the postnatal window. The newborn period provides a feasible clinical window for intervention and is important for beta-cell proliferation and metabolic tissue development. Using a C57BL/6 model, we administered metformin to dams from the day of birth to postnatal day 21. We monitored maternal health and offspring growth during the lactation window, as well as adult glucose homeostasis through in vivo testing. At necropsy we assessed pancreas and adipocyte morphology using histological and immunofluorescent staining techniques. We found that metformin exposure programmed male and female offspring to be leaner with a higher proportion of small adipocytes in the gonadal white adipose tissue (GWAT). Male, but not female, offspring had an improvement in glucose tolerance as young adults concordant with a mild increase in insulin secretion in response to glucose in vivo. These data demonstrate long-term metabolic programming of offspring associated with maternal exposure to metformin during lactation.

Maternal high fat diet consumption reduces liver alpha7 nicotinic cholinergic receptor expression and impairs insulin signalling in the offspring

The activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to anti-inflammatory response in macrophages. High-fat diet (HFD) consumption during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in liver and white adipose tissue of offspring. In order to evaluate the relationship between damage in the cholinergic anti-inflammatory pathway and insulin resistance (IR) development, the liver of offspring of obese dams was investigated. Additionally, the capacity of α7nAChR activation to reduce IR induced by saturated fatty acid was investigated in hepatoma cell line. Initially, female mice were subjected to either standard chow (SC) or HFD during pregnancy and lactation period. After weaning, only male offspring from HFD dams (HFD-O) and SC dams (SC-O) were fed with the SC diet. Hepatic α7nAChR expression was downregulated, and hepatic TNF-α, IL-1β, and pIKK level, but not pJNK, were elevated in the HFD-O compared to SC-O mice. Besides, hepatic expression of TNF-α in response to lipopolysaccharide (LPS) was higher in HFD-O than SC-O mice. Insulin-stimulated phosphorylation of the AKT was lower in HFD-O compared to SC-O. Additionally, insulin-stimulated phosphorylation of the AKT in KOα7Alb-Cre mice fed HFD was lower than WT mice fed HFD. In hepatoma cell line, palmitate increased IL-6 and TNF-α expressions and pJNK level. These effects were accompanied by reduced capacity of insulin to stimulate AKT phosphorylation. PNU or nicotine reduced cytokine expression and JNK activation, but improved insulin resistance induced by palmitate. Our results suggest that maternal obesity impairs hepatic α7nAChR expression and AKT phosphorylation in the offspring. In vitro studies suggest that α7nAChR activation has potential to reduce deleterious effect of saturated fatty acids on insulin signalling.

RNA-Sequencing Analysis of Paternal Low-Protein Diet-Induced Gene Expression Change in Mouse Offspring Adipocytes

Increasing evidence indicates that parental diet affects the metabolism and health of offspring. It is reported that paternal low-protein diet (pLPD) induces glucose intolerance and the expression of genes involved in cholesterol biosynthesis in mouse offspring liver. The aim of the present study was to determine the effect of a pLPD on gene expression in offspring white adipose tissue (WAT), another important tissue for the regulation of metabolism. RNA-seq analysis indicated that pLPD up- and down-regulated 54 and 274 genes, respectively, in offspring WAT. The mRNA expression of many genes involved in lipogenesis was down-regulated by pLPD feeding, which may contribute to metabolic disorder. The expression of carbohydrate response element-binding protein β (ChREBP-β), an important lipogenic transcription factor, was also significantly lower in the WAT of pLPD offspring, which may have mediated the down-regulation of the lipogenic genes. By contrast, the LPD did not affect the expression of lipogenic genes in the WAT of the male progenitor, but increased the expression of lipid oxidation genes, suggesting that a LPD may reduce lipogenesis using different mechanisms in parents and offspring. These findings add to our understanding of how paternal diet can regulate metabolism in their offspring.

Resveratrol supplementation of high-fat diet-fed pregnant mice promotes brown and beige adipocyte development and prevents obesity in male offspring.

Maternal high-fat diet impairs brown adipocyte function and correlates with obesity in offspring. Maternal resveratrol administration recovers metabolic activity of offspring brown adipose tissue. Maternal resveratrol promotes beige adipocyte development in offspring white adipose tissue. Maternal resveratrol intervention protects offspring against high-fat diet-induced obesity. Promoting beige/brite adipogenesis and thermogenic activity is considered as a promising therapeutic approach to reduce obesity and metabolic syndrome. Maternal obesity impairs offspring brown adipocyte function and correlates with obesity in offspring. We previously found that dietary resveratrol (RES) induces beige adipocyte formation in adult mice. Here, we evaluated further the effect of resveratrol supplementation of pregnant mice on offspring thermogenesis and energy expenditure. Female C57BL/6J mice were fed a control diet (CON) or a high-fat diet (HFD) with or without 0.2% (w/w) RES during pregnancy and lactation. Male offspring were weaned onto a HFD and maintained on this diet for 11 weeks. The offspring thermogenesis and related regulatory factors in adipose tissue were evaluated. At weaning, HFD offspring had lower thermogenesis in brown and white adipose tissues compared with CON offspring, which was recovered by maternal RES supplementation, along with the appearance of multilocular brown/beige adipocytes and elevated thermogenic gene expression. Adult offspring of RES-treated mothers showed increased energy expenditure and insulin sensitivity when on an obesogenic diet compared with HFD offspring. The elevated metabolic activity was correlated with enhanced brown adipose function and white adipose tissue browning in HFD+RES compared with HFD offspring. In conclusion, RES supplementation of HFD-fed dams during pregnancy and lactation promoted white adipose browning and thermogenesis in offspring at weaning accompanied by persistent beneficial effects in protecting against HFD-induced obesity and metabolic disorders.

Maternal undernutrition programs the apelinergic system of adipose tissue in adult male rat offspring.

Based on the Developmental Origin of Health and Disease concept, maternal undernutrition has been shown to sensitize adult offspring to metabolic pathologies such as obesity. Using a model of maternal 70% food restriction in pregnant female rats throughout gestation (called FR30), we previously reported that obesity-prone adult male rat offspring displayed hyperleptinemia with modifications in leptin and leptin receptor messenger RNA (mRNA) levels in white adipose tissue (WAT). Apelin is a member of the adipokine family that regulates various aspects of energy metabolism and WAT functionality. We investigated whether apelin and its receptor APJ could be a target of maternal undernutrition. Adult male rat offspring from FR30 dams showed increased plasma apelin levels and apelin gene expression in WAT. Post-weaning high-fat diet led to marked increase in APJ mRNA and protein levels in offspring's WAT. We demonstrate that maternal undernutrition and post-weaning diet have long-term consequences on the apelinergic system of adult male rat offspring.

Dietary intervention in obese dams protects male offspring from WAT induction of TRPV4, adiposity, and hyperinsulinemia.

One major risk factor for childhood overweight is maternal obesity. The underlying molecular mechanisms are ill-defined, and effective prevention strategies are missing. Diet-induced obese mouse dams were changed to standard chow during pregnancy and lactation as an intervention against predisposition for obesity and metabolic sequelea in the offspring. Expression of adipokines and TRPV4, a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis, in offspring's white adipose tissue (WAT) was assessed. Pathological effects on offspring's body weight, fat content, and serum insulin were fully reversed in intervention offspring on postnatal day 21. In WAT, a sixfold increase of Trpv4 mRNA expression in offspring consuming high-fat-containing diet was found, which was completely blunted in the intervention group. Simultaneously, WAT adipokine, interleukin-6, and peroxisome proliferator-activated receptor-γ mRNA and UCP1 protein expression were largely returned to control levels in intervention offspring. Improvement of maternal nutrition offers a powerful strategy to improve offspring's metabolic health. Targeting TRPV4-linked aspects of WAT metabolic function during early development might be a promising approach to prevent long-term adverse metabolic effects of maternal high-fat nutrition.

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

BackgroundSleep 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.ObjectivesTo 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.MethodsTime-pregnant mice were exposed to LG-SF or control sleep (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 MeDIP coupled to microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice/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.ResultsWe 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; p=0.001), triglycerides (87.3 vs. 84.1 mg/dL; p=0.003) and HOMA-IR 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, MAT 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, etc. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response.ConclusionsOur findings show a major role for epigenomic regulation of pathways associated with metabolic processes and inflammatory response in VWAT. LG-SF-induced epigenetic alterations may underlies increases in the susceptibility to obesity and metabolic syndrome in offspring.

Maternal Obesity Enhances White Adipose Tissue Differentiation and Alters Genome-Scale DNA Methylation in Male Rat Offspring

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-γ, CCAAT enhancer binding protein α [C/EBP-α] and C/EBP-β), 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-β). Our findings strongly suggest that the maternal OB in utero alters adipocyte commitment and differentiation via epigenetic mechanisms.

High Dietary Fat Intake during Lactation Promotes Development of Diet-Induced Obesity in Male Offspring of Mice

The maternal nutritional status during pregnancy and lactation influences the risk of obesity in offspring, but the details of this phenomenon are unclear. In particular, there is little information on the influence on the offspring of the maternal nutritional status during lactation only. Therefore, in this study, we examined the influence of high dietary fat intake in dams during lactation on the risk of obesity in offspring, using C57BL/6J mice. The mice were fed a control diet (CD) during pregnancy. After birth, dams were fed a CD or a high-fat diet (HD) during lactation (3 wk). Fat and energy were significantly increased in milk from dams fed a HD during lactation. Male offspring were weaned at 3 wk old and fed a CD for 4 wk, which resulted in no significant difference in their physique. Four weeks after weaning, the offspring (7 wk old) were fed a CD or HD for 4 wk to induce obesity. High dietary fat intake in dams and offspring promoted lipid accumulation in white adipose tissue and adipocyte hypertrophy in male offspring. The underlying mechanism may involve an increase in expression of Lpl and a decrease in expression of Hsl in white adipose tissue of offspring. In conclusion, our results show that high dietary fat intake during lactation promotes development of diet-induced obesity in male offspring.

Hydrogenated fat diet intake during pregnancy and lactation modifies the PAI-1 gene expression in white adipose tissue of offspring in adult life

We examine whether feeding pregnant and lactating rats hydrogenated fats rich in trans fatty acids modifies the plasma lipid profiles and the expression of adipokines involved with insulin resistance and cardiovascular disease in their 90-day-old offspring. Pregnant and lactating Wistar rats were fed with either a control diet (C group) or one enriched with hydrogenated vegetable fat (T group). Upon weaning, the male pups were sorted into four groups: CC, mothers were receiving C and pups were kept on C; CT, mothers were receiving C and pups were fed with T; TT, mothers were receiving T and pups were kept on T; TC, mothers were receiving T and pups were fed with C. Pups' food intake and body weight were quantified weekly and the pups were killed at day 90 of life by decapitation. Blood and carcass as well as retroperitoneal, epididymal, and subcutaneous white adipose tissues were collected. Food intake and body weight were lower in TC and TT, and metabolic efficiency was reduced in TT. Offspring of TT and TC rats had increased white adipose tissue PAI-1 gene expression. Insulin receptor was higher in TT than other groups. Ingestion of hydrogenated vegetable fat by the mother during gestation and lactation could promote deleterious consequences, even after the withdrawal of the causal factor.

Long-term effects of trans fatty acid intake during pregnancy and lactation: does it have deleterious consequences?

Evaluation of: Pisani LP, Oller do Nascimento CM, Bueno AA et al.: Hydrogenated fat diet intake during pregnancy and lactation modifies the PAI-1 gene expression in white adipose tissue of offspring in adult life. Lipids Health Dis. 7, 13 (2008). Placental transfer of lipid moieties is relatively low compared with other nutrients, but alterations of lipid components at the maternal site during pregnancy and/or lactation may have negative long-term consequences in the offspring. Industrial hydrogenation of edible oils produces trans fatty acids (TFAs). TFAs enhance inflammatory markers and insulin resistance, cross the placenta and interfere in the conversion of essential fatty acids into their long-chain derivatives, which are critical in perinatal development. Pisani et al. have described that adult offspring of rats fed a TFA-rich diet during pregnancy and lactation, and exposed to the same diet after weaning, have increased serum insulin and adiponectin, body fat and adipose tissue PAI-1 mRNA. The expe...