High-fat Diet Offspring Research Articles

Maternal Gestational Diabetes Mellitus and High-Fat Diet Influenced Hepatic Polyunsaturated Fatty Acids Profile in the Offspring of C57BL/6J Mice.

This research examines the effects of maternal high-fat (HF) diet and gestational diabetes mellitus (GDM) on offspring lipid metabolism and polyunsaturated fatty acids (PUFA) profile. GDM is induced using the insulin receptor antagonist S961. Weaning offspring are categorized into HF-GDM, HF-CON, NC-GDM, and NC-CON groups based on maternal diet or GDM. Adult offspring are then grouped into NC-CON-NC, NC-CON-HF, NC-GDM-NC, NC-GDM-HF, HF-CON-NC, HF-CON-HF, HF-GDM-NC, and HF-GDM-HF according to dietary patterns. Gas chromatography determines PUFA composition. Western blot assesses PI3K/Akt signaling pathway-related protein expression. Feeding a normal chow diet until adulthood improves the distribution of hepatic PUFA during weaning across the four groups. PI3K expression is upregulated during weaning in HF-CON and HF-GDM, particularly in HF-CON-NC and HF-GDM-NC, compared to NC-CON-NC during adulthood. Akt expression increases in NC-GDM-NC after weaning with a normal diet. The hepatic PUFA profile in HF-CON-HF significantly distinguishes among the maternal generation health groups. Maternal HF diet exacerbates the combined impact of maternal GDM and offspring HF diet on hepatic PUFA and PI3K/Akt signaling pathway-related proteins during adulthood. Early exposure to HF diets and GDM affects hepatic PUFA profiles and PI3K/Akt signaling pathway protein expression in male offspring during weaning and adulthood.

Maternal undernutrition results in transcript changes in male offspring that may promote resistance to high fat diet induced weight gain.

Maternal nutrition during embryonic development and lactation influences multiple aspects of offspring health. Using mice, this study investigates the effects of maternal caloric restriction (CR) during mid-gestation and lactation on offspring neonatal development and on adult metabolic function when challenged by a high fat diet (HFD). The CR maternal model produced male and female offspring that were significantly smaller, in terms of weight and length, and females had delayed puberty. Adult offspring born to CR dams had a sexually dimorphic response to the high fat diet. Compared to offspring of maternal control dams, adult female, but not male, CR offspring gained more weight in response to high fat diet at 10 weeks. In adipose tissue of male HFD offspring, maternal undernutrition resulted in blunted expression of genes associated with weight gain and increased expression of genes that protect against weight gain. Regardless of maternal nutrition status, HFD male offspring showed increased expression of genes associated with progression toward nonalcoholic fatty liver disease (NAFLD). Furthermore, we observed significant, sexually dimorphic differences in serum TSH. These data reveal tissue- and sex-specific changes in gene and hormone regulation following mild maternal undernutrition, which may offer protection against diet induced weight gain in adult male offspring.

Maternal consumption of a high-fat diet modulates the inflammatory response in their offspring, mediated by the M1 muscarinic receptor.

High-fat diet (HFD) consumption is associated with various metabolic disorders and diseases. Both pre-pregnancy and maternal obesity can have long-term consequences on offspring health. Furthermore, consuming an HFD in adulthood significantly increases the risk of obesity and metabolic disorders. However, an intriguing phenomenon known as the obesity paradox suggests that obesity may confer a protective effect on mortality outcomes in sepsis. In sepsis, activation of the cholinergic anti-inflammatory pathway (CAP) can help mitigate systemic inflammation. We employed a metabolic programming model to explore the relationship between maternal HFD consumption and offspring response to sepsis. We fed female mice either a standard diet (SC) or an HFD during the pre-pregnancy, pregnancy, and lactation periods. Subsequently, we evaluated 28-day-old male offspring. Notably, we discovered that offspring from HFD-fed dams (HFD-O) exhibited a higher survival rate compared with offspring from SC-fed dams (SC-O). Importantly, inhibition of the m1 muscarinic acetylcholine receptor (m1mAChR), involved in the CAP, in the hypothalamus abolished this protection. The expression of m1mAChR in the hypothalamus was higher in HFD-O at different ages, peaking on day 28. Treatment with an m1mAChR agonist could modulate the inflammatory response in peripheral tissues. Specifically, CAP activation was greater in the liver of HFD-O following agonist treatment. Interestingly, lipopolysaccharide (LPS) challenge failed to induce a more inflammatory state in HFD-O, in contrast to SC-O, and agonist treatment had no additional effect. Analysis of spleen immune cells revealed a distinct phenotype in HFD-O, characterized by elevated levels of CD4+ lymphocytes rather than CD8+ lymphocytes. Moreover, basal Il17 messenger RNA (mRNA) levels were lower while Il22 mRNA levels were higher in HFD-O, and we observed the same pattern after LPS challenge. Further examination of myeloid cells isolated from bone marrow and allowed to differentiate showed that HFD-O macrophages displayed an anti-inflammatory phenotype. Additionally, treatment with the m1mAChR agonist contributed to reducing inflammatory marker levels in both groups. In summary, our findings demonstrate that HFD-O are protected against LPS-induced sepsis, and this protection is mediated by the central m1mAChR. Moreover, the inflammatory response in the liver, spleen, and bone marrow-differentiated macrophages is diminished. However, more extensive analysis is necessary to elucidate the specific mechanisms by which m1mAChR modulates the immune response during sepsis.

Prenatal caffeine exposure induces autism-like behaviors in offspring under a high-fat diet via the gut microbiota-IL-17A-brain axis

Prenatal caffeine exposure (PCE) is a significant contributor to intrauterine growth retardation (IUGR) in offspring, which has been linked to an increased susceptibility to autism spectrum disorder (ASD) later in life. Additionally, a high-fat diet (HFD) has been shown to exacerbate ASD-like behaviors, but the underlying mechanisms remain unclear. In this study, we first noted in the rat model of IUGR induced by PCE that male PCE offspring exhibited typical ASD-like behaviors post-birth, in contrast to their female counterparts. The female PCE offspring demonstrated only reduced abilities in free exploration and spatial memory. Importantly, both male and female PCE offspring displayed ASD-like behaviors when exposed to HFD. We further observed that PCE + HFD offspring exhibited damaged intestinal mucus barriers and disturbed gut microbiota, resulting in an increased abundance of Escherichia coli (E. coli). The induced differentiation of colonic Th17 cells by E. coli led to an increased secretion of IL-17A, which entered the hippocampus through peripheral circulation and caused synaptic damage in hippocampal neurons, ultimately resulting in ASD development. Our strain transplantation experiment suggested that E. coli-mediated increase of IL-17A may be the core mechanism of ASD with a fetal origin. In conclusion, PCE and HFD are potential risk factors for ASD, and E. coli-mediated IL-17A may play a crucial role in fetal-originated ASD through the gut-brain axis.

Effect of a High-Fat Diet and Probiotic Supplementation on the Gut Microbiota of Maternal Mice at Term Pregnancy and Offspring at Three-Week Postpartum.

The effects of probiotics on the gut microbiota in maternal mice-fed high-fat diet (HFD) during pregnancy and offspring are still unknown. We aimed to evaluate the effect of high-fat diet and probiotic supplementation on the gut microbiota of maternal mice at term pregnancy and offspring at three-week postpartum. Female pregnant Kunming mice were randomly divided into four groups: mice on a control diet (MC), mice on HFD (MHF), mice on a control diet and probiotics (MCP), and mice on HFD and probiotics (MHFP). The result showed that MHF had significantly reduced Bacteroidetes and Muribaculaceae (P < 0.05) and increased Firmicutes/Bacteroidetes ratio vs. MC. Lachnospiraceae_NK4A136_group and Alistipes reduced (P < 0.05), and Firmicutes/Bacteroidetes ratio significantly increased in MCP vs. MC. There was no significant difference between MHF and MHFP. Higher levels of Prevotella, Prevotellaceae, and Streptococcaceae were found in mice offspring on HFD (OHF) vs. mice offspring on a control diet (OC) (P < 0.05, respectively). Bacteroidia, Bacteroidota, Bacteroidales, and Muribaculaceae decreased markedly in mice offspring on a control diet and probiotics (OCP) vs. OC (P < 0.05, respectively), while Firmicutes, Lactobacillales, Lactobacillaceae, and Lactobacillus significantly increased in OCP (P < 0.05, respectively). There was no significant difference between the OHF and mice offspring on HFD and probiotics (OHFP). The findings suggest that the gut microbial composition of pregnant mice and offspring were altered to some extent due to HFD or probiotic intervention. Further, maternal mice on HFD and offspring were less affected by probiotic supplementation.

OR12-05-23 The Impact of Maternal Protein Restriction and High-Fat Diet in Offspring on the Outcomes of Growth Hormone Treatment in Mice

OR12-05-23 The Impact of Maternal Protein Restriction and High-Fat Diet in Offspring on the Outcomes of Growth Hormone Treatment in Mice

Estrogen normalizes maternal HFD-induced vascular dysfunction in offspring by regulating ATR.

Previous studies have shown that female offspring are resistant to fetal high-fat diet (HFD)-induced programming of heightened vascular contraction; however, the underlying mechanisms remain unclear. The present study tested the hypothesis that estrogen plays a key role in protecting females from fetal programming of increased vascular contraction induced by maternal HFD exposure. Pregnant rats were fed a normal diet (ND) or HFD (60% kcal from fat). Ovariectomy (OVX) and 17β-estradiol (E2) replacement were performed on 8-week-old female offspring. Aortas were isolated from adult female offspring. Maternal HFD exposure increased angiotensin II (Ang II)-induced contractions of the aorta in adult OVX offspring, which was abrogated by E2 replacement. The AT1 receptor (AT1R) antagonist losartan (10 μM), but not the AT2 receptor (AT2R) antagonist PD123319 (10 μM), completely blocked Ang II-induced contractions in both ND and HFD offspring. In addition, HFD exposure caused a decrease in endothelium-dependent relaxations induced by acetylcholine (ACh) in adult OVX but not OVX-E2 offspring. However, it had no effect on sodium nitroprusside (SNP)-induced endothelium-independent aorta relaxation in any of the six groups. Maternal HFD feeding increased AT1R, but not AT2R, leading to an increased AT1R/AT2R ratio in HFD-exposed OVX offspring, associated with selective decreases in DNA methylation at the AT1aR promoter, which was ameliorated by E2 replacement. Our results indicated that estrogen play a key role in sex differences of maternal HFD-induced vascular dysfunction and development of hypertensive phenotype in adulthood by differently regulating vascular AT1R and AT2R gene expression through a DNA methylation mechanism.

P-558 Childhood exposure to high-fat diets changes sperm small RNA content up to two unexposed generations of mice

Abstract Study question Is the adoption of high-fat diet from childhood associated with sperm small RNA content in mice? Are those changes inherited by the offspring and grand-offspring? Summary answer The adoption of high-fat diet during childhood changes sperm small RNA content up to the grand-offspring even after dietary correction. What is known already The prevalence of childhood obesity is increasing worldwide. The adoption of high-fat diet (HFD) from early age is a major factor for this trend. However, the long-lasting health effects of childhood obesity associated to HFD is unknown, particularly after dietary reversion. Multiple studies demonstrated that sperm small non-coding RNA (sncRNA) content changes in response to acute and chronic dietary factors. Also, sperm sncRNAs can transmit acquired traits such as metabolic syndrome. However, it is not known how the HFD-related sperm sncRNA fingerprints varies across generations, and how it relates with the phenotypes of the progeny. Study design, size, duration At weaning, 36 C57BL/6 mice were randomly divided into three groups (n = 12) feeding on 1) standard chow (CTRL) for 200 days, 2) HFD for 200 days, or 3) HFD for 60 days reverted to chow for 140 days (childhood HFD, CHFD). Subsequent generations (36 mice/generation, all fed on chow) were obtained by mating F0 and F1 males with same-age normoponderal females 120 days post-weaning and were assigned to the same experimental group as the progenitor. Participants/materials, setting, methods Mice were euthanized 200 days after weaning and tissues collected. Epidydimal sperm was collected, and concentration, viability, motility, and morphology were evaluated. Sperm RNA were extracted using the tri-reagent protocol, and sncRNAs sequenced by NGS RNA-seq. Sequences were annotated using SPORTS 1.1 and differential expression analysis performed using DESeq2. Targets of differently expressed sequences were estimated and Gene Ontology (GO) analysis of biological function performed using topGO. Main results and the role of chance HFD consumption during childhood is associated with poorer sperm parameters, even after dietary correction. No changes in sperm parameters were found between the offspring of HFD, CHFD and CTRL but, the grand-offspring of HFD and HFDt mice had lower sperm counts than the grand-offspring of CTRL. Regarding sperm sncRNA content, no changes were found between HFD and CTRL, but several mitochondrial transcription initiation RNAs (tiRNA) and repeat-derived RNAs (repRNAs) were differently expressed comparing to CTRL. Sperm sncRNA content of the offspring of HFD (piwi-interacting RNAs and repRNA) and CHFD (tRNA-derived fragments and repRNAs) displayed several differently expressed sequences comparing to CTRL. Only microRNAs (miRNAs) were differently expressed in the grandoffspring (CTRL vs. CHFD). GO analysis of biological function based on the targets of differently expressed sncRNAs showed a potential impact of childhood obesity in pathways related to sperm motility, chemotaxis and membrane integrity. These results suggest that sperm sncRNA content is altered due to childhood obesity even after two generations. This signature is not preserved across the male germline, but may influence the sperm sncRNA content of the progeny. This long-lasting, transgenerational signature of childhood obesity may explain the inheritance of the poor sperm quality phenotype from grand-sire to grand-offspring. Limitations, reasons for caution This model does not evaluate the impact of earlier dietary intervention, before sexual maturation. Also, it is not clear if the reported effects are exclusively due to childhood obesity or to excessive caloric intake. The estimates of biological impact using GO analysis of sperm sncRNA targets require further experimental evidence. Wider implications of the findings Our findings evidence the long-lasting effects of childhood obesity to sperm parameters, even after dietary reversion, and the potential transgenerational effects to the health of the progeny. Our results raise awareness about the impact of childhood obesity to reproductive health of future fathers and their progeny. Trial registration number 0421/000/000/2016

Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs.

Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.

Maternal high-fat diet aggravates fructose-induced mitochondrial damage in skeletal muscles and causes differentiated adaptive responses on lipid metabolism in adult male offspring

Maternal high-fat diet (HFD) is associated with metabolic disturbances in the offspring. Fructose is a highly consumed lipogenic sugar; however, it is unknown whether skeletal muscle of maternal HFD offspring respond differentially to a fructose overload. Female Wistar rats received standard diet (STD: 9% fat) or isocaloric high-fat diet (HFD: 29% fat) during 8 weeks before mating until weaning. After weaning, male offspring received STD and, from 120 to 150 days-old, they drank water or 15% fructose in water (STD-F and HFD-F). At 150th day, we collected the oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles. Fructose-treated groups exhibited hypertriglyceridemia, regardless of maternal diet. Soleus of maternal HFD offspring showed increased triglycerides and monounsaturated fatty acid content, independent of fructose, with increased fatty acid transporters and lipogenesis markers. The EDL exhibited unaltered triglycerides content, with an apparent equilibrium between lipogenesis and lipid oxidation markers in HFD, and higher lipid uptake (fatty acid-binding protein 4) accompanied by enhanced monounsaturated fatty acid in fructose-treated groups. Mitochondrial complexes proteins and Tfam mRNA were increased in the soleus of HFD, while uncoupling protein 3 was decreased markedly in HFD-F. In EDL, maternal HFD increased ATP synthase, while fructose decreased Tfam predominantly in STD offspring. Maternal HFD and fructose induced mitochondria ultrastructural damage, intensified in HFD-F in both muscles. Thus, alterations in molecular markers of lipid metabolism and mitochondrial function in response to fructose are modified by an isocaloric and moderate maternal HFD and are fiber-type specific, representing adaptation/maladaptation mechanisms associated with higher skeletal muscle fructose-induced mitochondria injury in adult offspring.

Synergism between maternal and offspring high fat diet feeding in the non-human primate neuroactive metabolome

The microbiome produces small molecules, including neuroactive metabolites crucial for normal lifelong behavior. In a non-human primate (NHP) model, offspring exposed to maternal high fat diet (mHFD) display physiological changes compared to offspring exposed to maternal control diet (mCTR). To investigate the relationship between maternal diet and offspring post-weaning diet, we hypothesized that mHFD exposure plus a post-weaning high fat diet (HFD) will produce a persistently altered gut metabolome profile in vivo compared to mCTR exposure.

Maternal Metformin Treatment during Gestation and Lactation Improves Skeletal Muscle Development in Offspring of Rat Dams Fed High-Fat Diet.

Maternal high-fat (HF) diet is associated with offspring metabolic disorder. This study intended to determine whether maternal metformin (MT) administration during gestation and lactation prevents the effect of maternal HF diet on offspring’s skeletal muscle (SM) development and metabolism. Pregnant Sprague-Dawley rats were divided into four groups according to maternal diet {CHOW (11.8% fat) or HF (60% fat)} and MT administration {control (CT) or MT (300 mg/kg/day)} during gestation and lactation: CH-CT, CH-MT, HF-CT, HF-MT. All offspring were weaned on CHOW diet. SM was collected at weaning and 18 weeks in offspring. Maternal metformin reduced plasma insulin, leptin, triglyceride and cholesterol levels in male and female offspring. Maternal metformin increased MyoD expression but decreased Ppargc1a, Drp1 and Mfn2 expression in SM of adult male and female offspring. Decreased MRF4 expression in SM, muscle dysfunction and mitochondrial vacuolization were observed in weaned HF-CT males, while maternal metformin normalized them. Maternal metformin increased AMPK phosphorylation and decreased 4E-BP1 phosphorylation in SM of male and female offspring. Our data demonstrate that maternal metformin during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in offspring, by altering their myogenesis, mitochondrial biogenesis and dynamics through AMPK/mTOR pathways in SM.

A Maternal High Fat Diet Leads to Sex-Specific Programming of Mechanical Properties in Supraspinatus Tendons of Adult Rat Offspring.

Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however there is a paucity of evidence examining its effects on tendon. Alterations in the early life environment during critical periods of tendon growth therefore have the potential to influence tendon health that cross the lifespan. We hypothesised that a maternal HFD would alter biomechanical, morphological and gene expression profiles of adult offspring rotator cuff tendon.Materials and Methods: Female Sprague-Dawley rats were randomly assigned to either: control diet (CD; 10% kcal or 43 mg/g from fat) or HFD (45% kcal or 235 mg/g from fat) 14 days prior to mating and throughout pregnancy and lactation. Eight female and male offspring from each maternal diet group were weaned onto a standard chow diet and then culled at postnatal day 100 for tissue collection. Supraspinatus tendons were used for mechanical testing and histological assessment (cellularity, fibre organisation, nuclei shape) and tail tendons were collected for gene expression analysis.Results: A maternal HFD increased the elasticity (Young's Modulus) in the supraspinatus tendon of male offspring. Female offspring tendon biomechanical properties were not affected by maternal HFD. Gene expression of SCX and COL1A1 were reduced in male and female offspring of maternal HFD, respectively. Despite this, tendon histological organisation were similar between maternal diet groups in both sexes.Conclusion: An obesogenic diet during pregnancy increased tendon elasticity in male, but not female, offspring. This is the first study to demonstrate that maternal diet can modulate the biomechanical properties of offspring tendon. A maternal HFD may be an important factor in regulating adult offspring tendon homeostasis that may predispose offspring to developing tendinopathies and adverse tendon outcomes in later life.

Maternal high-fat diet increases anhedonic behavior and modulates hippocampal Mash1 and BDNF expression in adult offspring

BackgroundThe consumption of a high-fat diet (HFD) during pregnancy and perinatal periods can lead to long-term effects in the offspring central nervous system, affecting pathways related to neurogenesis and behavior, and increasing predispositions to depressive and anxiety-like behaviors. Thus, this study aimed to investigate the effects of a maternal HFD on the hippocampi of adult offspring and behaviors related to anxiety and depression. MethodsThe protein and mRNA expression of the brain-derived neurotrophic factor (BDNF), Mash1, Notch1, Hes5, serotonin transporter (SERT), 5-HT1A serotonergic receptor (5-HT1A), tryptophan hydroxylase 2 (TPH2, key enzyme of serotonin synthesis), JNK and pJNK were analyzed in the hippocampi of male Swiss mice. Hippocampal serotonin levels were measured using ELISA. The lipid peroxidation, total oxidant status, total antioxidant status, and GSH/GSSG were evaluated as oxidative stress measures. For the behavioral analysis, the open field, elevated plus maze, and sucrose preference tests were used. ResultsMaternal HFD led to increased body weight in dams and their offspring, as well as altered body composition and LDL levels in the offspring. There were no alterations in oxidative stress or JNK phosphorylation. Hippocampal Mash1 and BDNF expression were altered in HFD offspring. The HFD offspring exhibited anhedonic behavior. ConclusionThese findings suggest that maternal HFD leads to long-term alterations in the offspring's neurotrophic systems, impairing their behavior.

Estrogen normalizes maternal HFD-induced cardiac hypertrophy in offspring by regulating AT2R.

Our previous study has demonstrated maternal high-fat diet (HFD) caused sex-dependent cardiac hypertrophy in adult male, but not female offspring. The present study tested the hypothesis that estrogen normalizes maternal HFD-induced cardiac hypertrophy by regulating angiotensin II receptor (ATR) expression in adult female offspring. Pregnant rats were divided into the normal diet (ND) and HFD (60% kcal fat) groups. Ovariectomy (OVX) and 17β-estradiol (E2) replacement were performed on 8-week-old female offspring. Maternal HFD had no effect on left ventricular (LV) wall thickness, cardiac function and molecular markers of cardiac hypertrophy function in sham groups. However, maternal HFD caused cardiac hypertrophy of offspring in OVX groups, which was abrogated by E2 replacement. In addition, maternal HFD had no effect on ERα and ERβ in sham groups. In contrast, HFD significantly decreased ERα, but not ERβ in OVX groups. In sham groups, there was no difference in the cardiac ATR type 1 (AT1R) and ATR type 2 (AT2R) between ND and HFD offspring. HFD significantly increased AT2R, but not AT1R in OVX groups. Furthermore, maternal HFD resulted in decreased glucocorticoid receptors (GRs) binding to the glucocorticoid response elements at the AT2R promoter, which was due to decreased GRs in hearts from OVX offspring. These HFD-induced changes in OVX groups were abrogated by E2 replacement. These results support a key role of estrogen in the sex difference of maternal HFD-induced cardiac hypertrophy in offspring, and suggest that estrogen protects female offspring from cardiac hypertrophy in adulthood by regulating AT2R.

Milk Polar Lipids Supplementation to Obese Rats During Pregnancy and Lactation Benefited Skeletal Outcomes of Male Offspring.

Dietary intervention to obese dams during pregnancy and lactation period provides avenues for improving metabolic profiles of the offspring. In the current study, the effects of polar lipids-enriched milk fat globule membrane (MFGM-PL) supplementation to obese dams during pregnancy and lactation on the skeletal outcomes of male offspring are investigated. MFGM-PL is supplemented to obese rats induced by high-fat diet during pregnancy and lactation at a dose of 400mg kg-1 body weight. Results show that maternal MFGM-PL supplementation significantly ameliorates the stunted skeletal growth of male offspring at weaning. In adulthood offspring, maternal MFGM-PL supplementation protects against high-fat diet (HFD)-induced bone microstructure degeneration and bone marrow adipocyte accumulation. Further investigation shows that maternal supplementation of MFGM-PL significantly ameliorates insulin resistance and increases the mRNA expression of growth hormone releasing hormone (GHRH) in the hypothalamus of HFD offspring. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis is subsequently enhanced in MFGM-PL + HFD offspring, contributing to the beneficial skeletal outcomes. The findings suggest that maternal MFGM-PL supplementation of HFD dam during pregnancy and lactation shows desirable effects on fetal skeletal development, with lasting beneficial programming impacts on skeletal outcomes of offspring.

Rodents on a High-Fat Diet Born to Mothers with Gestational Diabetes Exhibited Sex- Specific Lipidomic Changes in Reproductive Organs, Hormonal Imbalances and Insulin Resistance

Background: Maternal gestational diabetes mellitus (GDM) and offspring high-fat diet (HFD) have shown to have sex-specific detrimental effects on the health of offspring. Methods: A maternal GDM mice model was established by feeding maternal C57BL/6 mice HFD and then their offspring were exposed to either HFD or low-fat diet. Testes, ovaries, liver and gonadal adipose tissue were collected from offspring at 20 weeks, and their reproductive lipidomic profiles were characterized using gas chromatography-mass spectrometry. Findings: Male offspring following HFD had a substantially elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers had decreased testes weights and testosterone levels, while female offspring from GDM mothers had increased ovary weights and estrogen levels. AKT pathway were increased in the offspring liver and gonadal adipose tissue of those fed with HFD. The fatty acid profiling showed that testes were prone to the effect of maternal GDM, whereas ovarian metabolite profiles were upregulated in maternal GDM and downregulated in offspring following HFD. Eicosapentaenoic acid were attenuated in both maternal serum and offspring testes under the impact of maternal GDM and in offspring following HFD. Interpretation: Maternal GDM and offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in offspring such as obesity. Funding: the National Natural Science Foundation of China, The 111 Project, The National Key Research and Development Program of Reproductive Health & Major Birth Defects Control and Prevention, Chongqing Health Commission, Kuanren Talents Programs, and Chongqing Science & Technology Commission. Declaration of Interest: Andi Wang, Xinyang Yu, Zhu Chen, Yinyin Xia, Chang Chen, Hongbo Qi, Philip N. Baker, Richard Saffery, Ting-Li Han and Hua Zhang declare that they have no conflict of interest. Ethical Approval: All WT C57BL/6 mice in this study were purchased from the Model Animal Research Center of Nanjing University. All animal experiments complied with the ARRIVE guidelines and approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (Batch number: 2020-41).

99-OR: Effects of Early Time-Restricted Feeding during Gestation on Offspring Glucose Homeostasis in Mice

Time-Restricted Feeding (TRF) is an increasingly common diet that may improve insulin sensitivity. This practice merits study in the setting of pregnancy, as the diet is common, pregnancy represents a critical period for the health of both mother and offspring, and the effects of TRF during pregnancy on maternal gestational health and long-term offspring consequences remain unexamined. To test these effects, female mice were randomized to 6 hours of food availability in the dark cycle (early-time restricted feeding, eTRF), or given 24-hour ad libitum (AL) food access. After one week of acclimatization, females were mated. Food intake and body composition were measured weekly throughout gestation; insulin sensitivity was assessed at day 16 of pregnancy. Offspring birth rate, survival, birthweight, and gestational age were assessed. Body composition and food intake were assessed weekly. After 70 days on a normal diet, all offspring were switched to a 45% high-fat diet (HFD) with continued weekly monitoring. Glucose tolerance and insulin tolerance tests were conducted before and after 10 weeks of HFD feeding. Our data suggests that maternal eTRF does not affect birth weight or gestational age, but does reduce litter size (7.7 pups vs. 6.0 pups) and 3-day pup survival (95% vs. 58%) compared to AL. eTRF offspring had similar insulin and glucose tolerance compared to AL counterparts until adulthood (70 days of age). After 12 weeks of high-fat diet feeding, eTRF males develop concomitant glucose intolerance (auc, p&amp;lt;0.0001) and insulin sensitivity (auc, p=0.006), which was absent in females. These metabolic changes were present despite eTRF males having similar fat mass, body weight, and food intake when compared to AL males. Taken together, these data suggest that eTRF during pregnancy followed by offspring HFD feeding results in male-specific impaired glucose metabolism. Further work planned will evaluate the role of pancreatic islet insulin secretion in vivo and in vitro in future cohorts. Disclosure M. E. Carter: None. N. El habbal: None. D. S. Snyder: None. J. R. Redd: None. B. Gregg: None. D. Bridges: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107535); University of Michigan

Effects of Maternal Hyperglycemia Associated with Snack Intake on Male and Female Offspring High-Fat Diet Preference on Infancy

Effects of Maternal Hyperglycemia Associated with Snack Intake on Male and Female Offspring High-Fat Diet Preference on Infancy

Maternal and offspring high-fat diet leads to platelet hyperactivation in male mice offspring

Maternal over-nutrition increases the risk of diabetes and cardiovascular events in offspring. While prominent effects on cardiovascular health are observed, the impact on platelet physiology has not been studied. Here, we examined whether maternal high-fat diet (HF) ingestion affects the platelet function in lean and obese offspring. C57BL6/N mice dams were given a HF or control (C) diet for 8 weeks before and during pregnancy. Male and female offspring received C or HF diets for 26 weeks. Experimental groups were: C/C, dam and offspring fed standard laboratory diet; C/HF dam fed standard laboratory diet and offspring fed HF diet; HF/C and HF/HF. Phenotypic and metabolic tests were performed and blood collected for platelet studies. Compared to C/C, offspring HF groups were obese, with fat accumulation, hyperglycaemia and insulin resistance. Female offspring did not present platelet hyperactivity, hence we focused on male offspring. Platelets from HF/HF mice were larger, hyperactive and presented oxidative stress when compared to C/C. Maternal and offspring HF diet results in platelet hyperactivation in male mouse offspring, suggesting a novel ‘double-hit’ effect.