Maternal High-fat Diet Exposure Research Articles

Maternal High-Fat Diet Multigenerationally Programs HPA Function and Behaviors in Male Rat Offspring.

Maternal environmental factors have been demonstrated to exert significant influences on the health of offspring. The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine stress system that can be influenced by early life challenges. Our previous research has revealed that the consumption of a high-fat diet (HFD) by pregnant and lactating rats leads to the programming of HPA axis activity in male offspring of the first generation (referred to as F1HFD/C). The present study aimed to investigate whether the observed remodeling of the HPA axis could be inherited by second-generation male offspring (referred to as F2HFD/C), following maternal HFD exposure. The results showed that F2HFD/C rats exhibited enhanced basal HPA axis activity, similar to their F1HFD/C ancestors. Moreover, F2HFD/C rats displayed exacerbated corticosterone responses to restraint and lipopolysaccharide-induced stress, but not to insulin-induced hypoglycemia stress. Furthermore, maternal HFD exposure significantly aggravated depression-like behavior in the F2 generation subjected to chronic unpredictable mild stress. To investigate the role of central calcitonin gene-related peptide (CGRP) signaling in maternal diet-induced programming of the HPA axis across generations, we conducted central infusion of αCGRP8-37, a CGRP receptor antagonist, in F2HFD/C rats. The results demonstrated that αCGRP8-37 attenuated depression-like behaviors and reduced the hyperresponsiveness of the HPA axis to restraint stress in these rats. Therefore, central CGRP signaling may contribute to maternal diet-induced programming of HPA axis across generations. In conclusion, our study provides evidence that maternal HFD consumption can lead to multigenerational programming of the HPA axis and behaviors in adult male descendants.

Perinatal high-fat diet exposure alters oxytocin and corticotropin releasing factor inputs onto vagal neurocircuits controlling gastric motility.

Perinatal high-fat diet (pHFD) exposure alters the development of vagal neurocircuits that control gastrointestinal (GI) motility and reduce stress resiliency in offspring. Descending oxytocin (OXT; prototypical anti-stress peptide) and corticotropin releasing factor (CRF; prototypical stress peptide) inputs from the paraventricular nucleus (PVN) of the hypothalamus to the dorsal motor nucleus of the vagus (DMV) modulate the GI stress response. How these descending inputs, and their associated changes to GI motility and stress responses, are altered following pHFD exposure are, however, unknown. The present study used retrograde neuronal tracing experiments, cerebrospinal fluid extraction, in vivo recordings of gastric tone, motility and gastric emptying rates, and in vitro electrophysiological recordings from brainstem slice preparations to investigate the hypothesis that pHFD alters descending PVN-DMV inputs and dysregulates vagal brain-gut responses to stress. Compared to controls, rats exposed to pHFD had slower gastric emptying rates and did not respond to acute stress with the expected delay in gastric emptying. Neuronal tracing experiments demonstrated that pHFD reduced the number of PVNOXT neurons that project to the DMV, but increased PVNCRF neurons. Both in vitro electrophysiology recordings of DMV neurons and in vivo recordings of gastric motility and tone demonstrated that, following pHFD, PVNCRF -DMV projections were tonically active, and that pharmacological antagonism of brainstem CRF1 receptors restored the appropriate gastric response to brainstem OXT application. These results suggest that pHFD exposure disrupts descending PVN-DMV inputs, leading to a dysregulated vagal brain-gut response to stress. KEY POINTS: Maternal high-fat diet exposure is associated with gastric dysregulation and stress sensitivity in offspring. The present study demonstrates that perinatal high-fat diet exposure downregulates hypothalamic-vagal oxytocin (OXT) inputs but upregulates hypothalamic-vagal corticotropin releasing factor (CRF) inputs. Both in vitro and in vivo studies demonstrated that, following perinatal high-fat diet, CRF receptors were tonically active at NTS-DMV synapses, and that pharmacological antagonism of these receptors restored the appropriate gastric response to OXT. The current study suggests that perinatal high-fat diet exposure disrupts descending PVN-DMV inputs, leading to a dysregulated vagal brain-gut response to stress.

Maternal high fat diet exposure results in MyD88 dependent alteration in placental and offspring intestinal fatty acid transporters.

Abstract Introduction: We know that offspring born to parents with obesity are more likely to be obese. We hypothesized that the maternal high fat diet (mHFD) exposure may increase placental and offspring small intestinal transport of fatty acids. We hypothesized both these processes would be dependent on the presence of MyD88. Methods: Wild-type (WT) and MyD88 deficient mice on either 60% mHFD or regular diet (RD) were profiled. The baseline expression of fatty acid transport proteins FATP1 and FATP4, fatty acid binding proteins FABP1, FABP4, and CD36 were profiled by qRT-PCR from placenta after C-section at E20, and offspring small intestine 2-weeks after birth. Serum from 0-day old RD and HFD WT mice were collected and analyzed using high-throughput, non-targeted mass spectroscopy based metabolic analysis. Results: In WT mice, we found FATP1 was increased 32-fold and FABP was increased 7-fold in the mHFD placenta. FATP2 was decreased 2-fold and FATP4 was decreased 2.5-fold in the mHFD offspring small intestine. In MyD88 KO mice, we found no difference in any of the above fatty acid transporters. Serum of neonatal pups showed unique clustering of metabolites by PCA analysis in HFD and RD mice, with increased butanoate and propanoate metabolites in mHFD offspring. Conclusion: Fatty acid transport regulators in the placenta and offspring small intestine were modified by exposure mHFD. In both the placenta and small intestine, this outcome was dependent on the presence of MyD88. Fatty acid metabolites were increased in the serum of neonatal pups exposed to mHFD. These findings suggest that mHFD exposure can modulate fetal metabolism and may be an opportunity for future development of therapeutics that target placental and intestinal transporters.

Maternal high fat diet exposure results in maternal microbiome dependent increase in inflammatory cytokines and decrease in neurons in offspring brain.

Abstract Introduction: We hypothesized that maternal high fat diet (mHFD) exposure will result in a microbiota dependent increase in inflammation and inhibition of axonal development in offspring brain. Methods: Conventional and germ-free murine dams were exposed to 60% high fat diet (HFD) or regular diet (RD) prior to mating. Offspring brains were collected at 2-weeks of life and analyzed for inflammatory (TNF-α, IL-6, IL-17A, IL1β and TGF-β) and regulatory markers of neuronal development (Nurr1) by quantitative RT-PCR. RNA seq was performed on whole brain in conventional mice. We quantified differences in regional neurons by histology (Nissl and H&E). Behavioral studies on mHFD and RD offspring are ongoing. Results: mHFD offspring had a significant increase in the inflammatory cytokines IL-17A and IL-6 when compared to controls. Nurr1 was increased 50-fold in mHFD offspring. In germ-free mHFD offspring, there was no difference. Quantification of neurons by Nissl staining demonstrated a decrease in neuron cell count in the cortex (20% decrease), and in hippocampal regions (22% in CA2 and 32% in CA3). Preliminary RNAseq analysis showed upregulation of specific genes involved in immunoregulation, neuron development and migration, and apoptosis in mHFD offspring. Conclusion: mHFD exposure resulted in increased inflammatory cytokines and reduced neurogenesis in the offspring brain. This change was ameliorated in germ free mice, demonstrating a microbiome dependent diet effect. RNAseq findings demonstrate changes in specific immunoregulatory pathways which warrant further exploration. We speculate that maternal diet interacts with the maternal microbiome to increase immune activation in the fetal brain which affects neurogenesis. Supported by grants from NIH (R01 1K12HD068369) and Children’s Medical Center Research Grant

509 - Maternal high fat diet exposure results in differential inflammatory gene expression, diminished hippocampal neurons and reduced sensitivity to stimuli in offspring, dependent on the maternal microbiome.

509 - Maternal high fat diet exposure results in differential inflammatory gene expression, diminished hippocampal neurons and reduced sensitivity to stimuli in offspring, dependent on the maternal microbiome.

Serotonin/tryptophan pathway disruption by maternal high fat diet exposure in non-human primate offspring gut

Serotonin/tryptophan pathway disruption by maternal high fat diet exposure in non-human primate offspring gut

Fetal liver epigenetic and transcriptomic alterations by a maternal high-fat diet exposure in Japanese macaques

Fetal liver epigenetic and transcriptomic alterations by a maternal high-fat diet exposure in Japanese macaques

Maternal Metformin Treatment Reprograms Maternal High-Fat Diet-Induced Hepatic Steatosis in Offspring Associated with Placental Glucose Transporter Modifications.

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.

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.

Milk fat globule membrane supplementation to obese rats during pregnancy and lactation promotes neurodevelopment in offspring via modulating gut microbiota.

Pre-pregnancy obesity and high-fat diet (HFD) during pregnancy and lactation are associated with neurodevelopmental delay in offspring. This study aimed to investigate whether milk fat globule membrane (MFGM) supplementation in obese dams could promote neurodevelopment in offspring. Obese female rats induced by HFD were supplemented with MFGM during pregnancy and lactation. Maternal HFD exposure significantly delayed the maturation of neurological reflexes and inhibited neurogenesis in offspring, which were significantly recovered by maternal MFGM supplementation. Gut microbiota analysis revealed that MFGM supplementation modulated the diversity and composition of gut microbiota in offspring. The abundance of pro-inflammatory bacteria such as Escherichia shigella and Enterococcus were down-regulated, and the abundance of bacteria with anti-inflammatory and anti-obesity functions, such as Akkermansia and Lactobacillus were up-regulated. Furthermore, MFGM alleviated neuroinflammation by decreasing the levels of lipopolysaccharides (LPS) and pro-inflammatory cytokines in the circulation and brain, as well as inhibiting the activation of microglia. Spearman’s correlation analysis suggested that there existed a correlation between gut microbiota and inflammation-related indexes. In conclusion, maternal MFGM supplementation promotes neurodevelopment partly via modulating gut microbiota in offspring.

High Maternal Total Cholesterol Is Associated With No-Catch-up Growth in Full-Term SGA Infants: The Japan Environment and Children's Study.

ObjectivesInfants born small for gestational age (SGA) with no catch-up growth (No-CU) are at high risk of intellectual and developmental disabilities. However, factors leading to No-CU among SGA infants are unclear. This study aimed to examine the association between maternal total cholesterol (TC) in mid-pregnancy and No-CU at 3 years among full-term SGA infants.Study DesignThe Japan Environment and Children’s Study (JECS) is a nationwide prospective birth cohort study. We extracted a total of 2,222 mothers and full-term SGA infants (length and/or weight <‐2 standard deviation [SD]) without congenital abnormalities from the original JECS cohort comprising a total of 104,062 fetal records. According to the distribution of maternal TC in the entire cohort, participants were classified into nine groups per each fifth percentile with the 20th–79th percentiles (204–260 mg/dl) as the reference group. No-CU was defined by a Z-score of height at 3 years <‐2 SD according to the growth standard charts for Japanese children. Multivariable-adjusted logistic regression models were carried out using multiple imputations. Additionally, a multiple-adjusted restricted cubic spline model was performed in the complete dataset.ResultsA total of 362 (16.3%) children were No-CU at 3 years. After adjusting for the Z-score of birth weight, age of mother, smoking status, weight gain during pregnancy, breastfeeding and meal frequency at 2 years, and parents’ heights, the odds ratio (95% confidence intervals) of No-CU was 2.95 (1.28–6.80) for children whose maternal TC levels were in the highest category (≥294 mg/dl), compared to the reference group. A multiple-adjusted restricted cubic spline model showed a non-linear trend of the significant association between high maternal TC and No-CU (p for linear trend = 0.05, p for quadratic trend <0.05).ConclusionHigh maternal TC at mid-pregnancy was associated with No-CU among SGA infants. Such infants should be carefully followed up to introduce appropriate growth hormonal treatment. The findings may support previous animal experimental studies which indicated that maternal high-fat diet exposure induces impairment of growth and skeletal muscle development in the offspring. Future studies are required to elucidate the detailed mechanism.

NFB-02. Maternal high-fat diet exposure increases the proliferation and glial differentiation of the cells of origin for NF1-optic glioma

Some pediatric cancers arise in the context of tumor predisposition syndromes caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), results in the development of low-grade tumors of the optic pathway (optic pathway gliomas; OPGs) in ~15% of affected children. However, risk assessment for each individual child is difficult, as it is currently challenging to predict which children with NF1 will develop OPG. Emerging human population-based evidence has raised the possibility that patient-specific risk factors, including infant birth weight, may modulate the risk of glioma development. High-infant birth weight can be modeled in mice by maternal exposure to a high-fat high-sucrose (HFHS) diet. To address the hypothesis that maternal high-fat diet exposure will increase the risk of OPG formation through intrinsic effects on the putative tumor cell of origin, we evaluated the effect of maternal exposure to a HFHS diet on the proliferation and differentiation of these cells (neural stem cells within the third ventricular zone; TVZ NSCs). Progeny from obese dams (MatOb) exposed to HFHS diet during and preceding gestation demonstrated increased proliferation and glial differentiation of TVZ NSCs in vivo. Similar results were observed with gestational HFHS diet exposure (GE) that did not result in maternal weight gain, suggesting these effects were related to maternal diet rather than weight. These effects were not observed in NSCs from other regions of the brain, supporting the regional specificity of the effect of diet on these tumor-initiating stem cells. Finally, we found that maternal HFHS diet resulted in elevated levels of leptin and insulin, both of which increase the proliferation of TVZ NSCs. Taken together, these findings provide early experimental evidence that maternal environmental exposure affects developing neural stem cells relevant to the risk of glioma formation.

Amniotic fluid metabolites mediate maternal high fat diet expansion of group 3 innate lymphoid cells in offspring.

Abstract Introduction Previously, we demonstrated that maternal high fat diet (mHFD) exposure results in a unique pattern of microbial colonization in offspring, expansion of IL-17 producing group 3 innate lymphoid cells (ILC3) and increased susceptibility to a model of necrotizing enterocolitis (NEC). We hypothesized that amniotic fluid (AF) metabolites are modified by maternal diet and partially responsible for the phenotype in offspring. Methods To assess if AF metabolites in mHFD were unique from regular diet (RD) AF, we collected AF from E15 dams and performed non-targeted global mass spectroscopy. To determine if the mHFD AF is responsible for expansion of ILC3, we gavaged 5-day-old RD germ-free pups with mHFD and RD AF (from conventional dams) every other day and examined them at 2 weeks by flow cytometry for ILC3. mHFD mothers were supplemented with metabolites that were decreased in the mHFD AF and offspring examined for expansion of ILC3 and susceptibility to the LPS/PAF model of NEC. Results We identified 1069 metabolites in HFD and RD AF. Principal component analysis revealed that mHFD AF was uniquely clustered from RD AF. We specifically found decreases in indole, short chain fatty acid and furoic acid metabolites in HFD AF compared to RD AF. Gavage of germ-free neonatal pups with mHFD AF resulted in expansion of IL-17 producing ILC3 compared to RD AF at 2 weeks. Supplementation of mHFD dams prenatally with metabolites diminished in HFD AF resulted in decreased expansion of ILC3 and resistance to LPS/PAF model of NEC. Conclusion mHFD modifies metabolites present in AF and can expand ILC3 in germ-free offspring. Supplementation of deficient dietary metabolites in mHFD pregnant dams rescues offspring from susceptibility to NEC. Supported by NIH R01 1K12HD068369

Maternal high fat diet exposure persistently alters the non-human primate neurometabolome independent of offspring diet

Our microbiome produces metabolites required for lifelong health. In a non-human primate (NHP) model, we have shown that offspring exposed to maternal high fat diet (mHFD) display persistent anxiety and a persistently altered gut microbiome, even when weaned onto a control diet for 2.5 years. Since the gut and its microbes influence behavior/neuroactivity, we hypothesized that mHFD exposure influences offspring behavior years after birth via a persistently altered gut metabolome in vivo.

Maternal High-Fat Diet Exposure During Gestation and Lactation Affects Intestinal Development in Suckling Rats.

Maternal health and diet influence metabolic status and play a crucial role in the development of metabolic function in offspring and their susceptibility to metabolic diseases in adulthood. The pathogenesis of various metabolic disorders is often associated with impairment in intestinal structure and function. Thus, the aim of the current study was to determine the effects of maternal exposure to a high fat diet (HFD), during gestation and lactation, on small intestinal growth and maturation in rat pups at 21 days old. Female, Wistar Han rats were fed either a breeding diet (BD) or high fat diet (HFD), from mating until the 21st day of lactation. Maternal HFD exposure increased body weight, BMI and adiposity. Compared to the maternal BD, HFD exposure influenced small intestine histomorphometry in a segment-dependent manner, changed the activity of brush border enzymes and had an impact on intestinal contractility via changes in cholinergic signaling. Moreover, offspring from the maternal HFD group had upregulated mRNA expression of cyclooxygenase (COX)-2, which plays a role in the inflammatory process. These results suggest that maternal HFD exposure, during gestation and lactation, programs the intestinal development of the offspring in a direction toward obesity as observed changes are also commonly reported in models of diet-induced obesity. The results also highlight the importance of maternal diet preferences in the process of developmental programming of metabolic diseases.

Maternal high fat diet interacts with the maternal microbiome to expand IL-17 producing type 3 innate lymphoid cells in offspring.

Abstract Introduction: Previously, we demonstrated that maternal high fat diet (mHFD) exposure results in a unique pattern of microbial colonization in offspring and subsequent expansion of IL-17 producing type 3 innate lymphoid cells (ILC3). We hypothesized that in utero mechanisms involving the maternal microbiome were responsible for the phenotype in offspring. Methods: To assess if the maternal microbiome was responsible for altering the mHFD offspring phenotype, we delivered mHFD and regular diet (RD)-exposed pups at birth by C-section (CS) and exposed mHFD mothers to broad-spectrum antibiotics (ABX) throughout pregnancy. We cross-fostered the offspring to RD mothers at birth. Microbial colonization in 2-week-old offspring was determined by 16s-based rRNA analysis, intestinal cytokines were quantified by qRT-PCR and lamina propria cells (LP) were profiled by flow cytometry. To determine if innate immunity is altered prenatally by maternal diet, we delivered mHFD and RD offspring by CS and examined the small intestine (SI) at birth for cytokine expression, TLR signaling and LP profiling. Global MyD88 KO mice on mHFD or RD were also examined for the same endpoints. Results: mHFD offspring at 2-weeks showed an expansion of Firmicutes and IL-17 producing ILC3, independent of the mode of delivery. ABX in mHFD mothers ameliorated the mHFD offspring phenotype, with microbial colonization and ILC3 similar to controls. mHFD offspring had altered TLR signaling at birth in SI. ILC3 were expanded at birth in mHFD offspring (14.2% vs 9.5%). MyD88−/− offspring exposed to mHFD did not have an expansion of ILC3. Conclusion: mHFD prenatally alters the offspring microbiome and ILC3 and this effect is dependent on the maternal microbiome and TLR signaling.

Maternal High-Fat Diet Induces Long-Lasting Defects in Bone Structure in Rat Offspring Through Enhanced Osteoclastogenesis

Maternal stressors during the prenatal and perinatal periods are associated with increased susceptibility for and severity of chronic disease phenotypes in adult offspring. In this study, we used a rat model of maternal high-fat diet (HFD) exposure during pregnancy and lactation to investigate the impact on skeletal homeostasis in offspring. In the distal femur, young male and female offspring (up to 3 weeks of age) from dams fed a HFD exhibited marked increases in trabecular bone volume relative to offspring from dams fed a chow diet, but this was followed by sustained bone loss. By 15 weeks of age, male offspring of HFD fed dams exhibited a 33% reduction in trabecular bone volume fraction that histomorphometric analyses revealed was due to a nearly threefold increase in the abundance of bone-resorbing osteoclasts, while there were no differences between female control and HFD offspring by 15 weeks of age. The osteoblastic differentiation of male offspring-derived bone marrow stromal cells was not affected by maternal diet. However, osteoclastic precursors isolated from the male offspring of HFD fed dams exhibited enhanced differentiation in vitro, forming larger osteoclasts with higher expression of the fusion marker DC-STAMP. This effect appears to be mediated by a cell autonomous increase in the sensitivity of precursors to RANKL. Taken together, these results suggest that maternal stressors like HFD exposure have persistent consequences for the skeletal health of offspring that may ultimately lead to a predisposition for osteopenia/osteoporosis.

Maternal High-Fat Diet Multigenerationally Impairs Hippocampal Synaptic Plasticity and Memory in Male Rat Offspring.

As advances are made in the field of developmental origins of health and disease, there is an emphasis on long-term influence of maternal environmental factors on offspring health. Maternal high-fat diet (HFD) consumption has been suggested to exert detrimental effects on cognitive function in offspring, but whether HFD-dependent brain remodeling can be transmitted to the next generations is still unclear. This study tested the hypothesis that HFD consumption during rat pregnancy and lactation multigenerationally influences male offspring hippocampal synaptic plasticity and cognitive function. We observed that hippocampus-dependent learning and memory was impaired in 3 generations from HFD-fed maternal ancestors (referred as F1-F3), as assessed by novel object recognition and Morris water maze tests. Moreover, maternal HFD exposure also affected electrophysiological and ultrastructure measures of hippocampal synaptic plasticity across generations. We observed that intranasal insulin replacement partially rescued hippocampal synaptic plasticity and cognitive deficits in F3 rats, suggesting central insulin resistance may play an important role in maternal diet-induced neuroplasticity impairment. Furthermore, maternal HFD exposure enhanced the palmitoylation of GluA1 critically involved in long-term potentiation induction, while palmitoylation inhibitor 2-bromopalmitate counteracts GluA1 hyperpalmitoylation and partially abolishes the detrimental effects of maternal diet on learning and memory in F3 offspring. Importantly, maternal HFD-dependent GluA1 hyperpalmitoylation was reversed by insulin replacement. Taken together, our data suggest that maternal HFD exposure multigenerationally influences adult male offspring hippocampal synaptic plasticity and cognitive performance, and central insulin resistance may serve as the cross-talk between maternal diet and cognitive impairment across generations.

Interleukin 1 Receptor 1 Knockout and Maternal High Fat Diet Exposure Induces Sex-Specific Effects on Adipose Tissue Adipogenic and Inflammatory Gene Expression in Adult Mouse Offspring.

Background: The global incidence of obesity continues to rise, increasing the prevalence of metabolic diseases such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus. Low-grade chronic inflammation, associated with the obese state, also contributes to the development of these metabolic comorbidities. Interleukin-1-receptor-1 (IL-1R1), a pro-inflammatory mediator, bridges the metabolic and inflammatory systems. In young male mice, deficiency of IL-1R1 (IL-1R1−/−) paired with a high-fat diet (HFD) offered beneficial metabolic effects, however in female mice, the same pairing led to metabolic dysfunction. Therefore, we examined the contribution of maternal HFD in combination with IL1R1−/− to metabolic health in adult offspring.Methods: Female C57BL/6 and IL-1R1−/− mice were randomly assigned to a control diet (10% kcal from fat) or HFD (45% kcal from fat) 10 days prior to mating and throughout gestation and lactation. Male and female offspring were housed in same-sex pairs post-weaning and maintained on control diets until 16 weeks old. At 15 weeks, an oral glucose tolerance test (OGTT) was performed to assess glucose tolerance. Histological analysis was carried out to assess adipocyte size and gene expression of adipogenic and inflammatory markers were examined.Results: IL-1R1−/− contributed to increased body weight in male and female adult offspring, irrespective of maternal diet. IL-1R1−/− and maternal HFD increased adipocyte size in the gonadal fat depot of female, but not male offspring. In female offspring, there was reduced expression of genes involved in adipogenesis and lipid metabolism in response to IL1R1−/− and maternal HFD. While there was an increase in inflammatory gene expression in response to maternal HFD, this appeared to be reversed in IL1R1−/− female offspring. In male offspring, there was no significant impact on adipogenic or lipid metabolism pathways. There was an increase in inflammatory gene expression in IL1R1−/− male offspring from HFD-fed mothers.Conclusion: This study suggests that IL-1R1 plays a complex and important role in the metabolic health of offspring, impacting adipogenesis, lipogenesis, and inflammation in a sex-specific manner.

Indole metabolites are altered in maternal high fat diet exposed offspring and can modulate type 3 innate lymphoid cell function

Abstract Background We have shown that maternal high fat diet exposure (mHFD) results in a microbiota-dependent expansion of IL-17 producing type 3 innate lymphoid cells (ILC3) in offspring. We hypothesized that the unique mHFD microbiome in offspring would result in an altered metabolite profile that could potentiate Ahr signaling and ILC3 function. Methods Murine offspring exposed to 60% mHFD were examined at 2-weeks old. Stool was examined by high-throughput, non-targeted mass spectroscopy-based metabolic analysis. Microbial colonization was examined by next generation sequencing. 2-week-old small intestine (SI) from regular diet (RD) offspring was exposed to selected indole metabolites for 24 hours and supernatant examined by ELISA. For in vivo experiments, bacteria was gavaged to RD offspring beginning at 5 days old. Flow cytometry of SI lamina propria cells was used to examine ILC3. Results mHFD offspring had a differential pattern of colonization and metabolite composition. mHFD offspring had a consistent expansion of Lactobacillus murinus. In vivo exposure to L. murinus resulted in a 30% increase in IL-17 producing ILC3 not seen with exposure to L. rhamnosus. Metabolomics of stool from mHFD offspring showed a decrease in indole-3-acetate and 3-methyldiozyindole (p&amp;lt;0.00001). SI stimulated with indole metabolites showed a 50% decrease in production of IL-17 (p&amp;lt;0.05) and IL-22 (p&amp;lt;0.05). Conclusion L. murinus is specifically expanded in mHFD offspring and can increase IL-17 producing ILC3. L. murinus may expand ILC3 by differential metabolism of indole metabolites. Metabolism of indole metabolites by L. murinus and their role on Ahr signaling need to be further examined as a mechanism of modulating ILC3 response in offspring.