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Sex Differences in Early Programming by Maternal High Fat Diet Induced-Obesity and Fish Oil Supplementation in Mice.

ABSTRACT: Pre-pregnancy obesity is a contributing factor for impairments in offspring metabolic health. Interventional strategies during pregnancy are a potential approach to alleviate and/or prevent obesity and obesity related metabolic alterations in the offspring. Fish oil (FO), rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) exerts metabolic health benefits. However, the role of FO in early life remains still unknown. Hence, this study objective was to determine the effect of FO supplementation in mice from pre-pregnancy through lactation, and to study the post-natal metabolic health effects in gonadal fat and liver of offspring fed high fat (HF) diet with or without FO. Female C57BL6J mice aged 4-5 weeks were fed a HF (45% fat) diet supplemented with or without FO (30 g/kg of diet) and low fat (LF; 10% fat) pre-pregnancy through lactation. After weaning, offspring (male and female) from HF or FO dams either continued the same diet (HF-HF and FO-FO) or switched to the other diet (HF-FO and FO-HF) for 13 weeks, creating four groups of treatment, and LF-LF was used as a control group. Serum, gonadal fat and liver tissue were collected at termination for metabolic analyses. Offspring of both sexes fed HF with or without fish oil gained (p < 0.05) more weight post weaning, compared to LF-LF-fed mice. All the female offspring groups supplemented with FO had reduced body weight compared to the respective male groups. Further, FO-FO supplementation in both sexes (p < 0.05) improved glucose clearance and insulin sensitivity compared to HF-HF. All FO-FO fed mice had significantly reduced adipocyte size compared to HF-HF group in both male and females. Inflammation, measured by mRNA levels of monocyte chemoattractant protein 1 (Mcp1), was reduced (p < 0.05) with FO supplementation in both sexes in gonadal fat and in the liver. Markers of fatty acid synthesis, fatty acid synthase (Fasn) showed no sex specific differences in gonadal fat and liver of mice supplemented with HF. Female mice had lower liver triglycerides than male counterparts. Supplementation of FO in mice improved metabolic health of offspring by lowering markers of lipid synthesis and inflammation.

SUBMITTER: Ramalingam L

PROVIDER: S-EPMC8625698 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Children are prescribed second-generation antipsychotic (SGA) medications, such as olanzapine (OLZ) for FDA-approved and "off-label" indications. The long-term impact of early-life SGA medication exposure is unclear. Olanzapine and other SGA medications are known to cause excessive weight gain in young and adult patients, suggesting the possibility of long-term complications associated with the use of these drugs, such as obesity, diabetes, and heart disease. Further, the weight gain effects of OLZ have previously been shown to depend on the presence of gut bacteria and treatment with OLZ, which shifts gut bacteria toward an "obesogenic" profile. The purpose of the current study was to evaluate changes in gut bacteria in adult mice following early life treatment with OLZ and being fed either a high-fat diet or a high-fat diet supplemented with fish oil, which has previously been shown to counteract gut dysbiosis, weight gain, and inflammation produced by a high-fat diet. Female and male C57Bl/6J mice were fed a high fat diet without (HF) or with the supplementation of fish oil (HF-FO) and treated with OLZ from postnatal day (PND) 37-65 resulting in four groups of mice: mice fed a HF diet and treated with OLZ (HF-OLZ), mice fed a HF diet and treated with vehicle (HF), mice fed a HF-FO diet and treated with OLZ (HF-FO-OLZ), and mice fed a HF-FO diet and treated with vehicle (HF-FO). Following euthanasia at approximately 164 days of age, we determined changes in gut bacteria populations and serum LPS binding protein, an established marker of gut inflammation and dysbiosis. Our results showed that male HF-FO and HF-FO-OLZ mice had lower body weights, at sacrifice, compared to the HF group, with a comparable body weight across groups in female mice. HF-FO and HF-FO-OLZ male groups also exhibited lower serum LPS binding protein levels compared to the HF group, with no differences across groups in female mice. Gut microbiota profiles were also different among the four groups; the Bacteroidetes-to-Firmicutes (B/F) ratio had the lowest value of 0.51 in the HF group compared to 0.6 in HF-OLZ, 0.9 in HF-FO, and 1.1 in HF-FO-OLZ, with no differences in female mice. In conclusion, FO reduced dietary obesity and its associated inflammation and increased the B/F ratio in male mice but did not benefit the female mice. Although the weight lowering effects of OLZ were unexpected, FO effects persisted in the presence of olanzapine, demonstrating its potential protective effects in male subjects using antipsychotic drugs.

Project description:OBJECTIVE:Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. METHODS:We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. RESULTS:Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. CONCLUSIONS:Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment.

Project description:Objective Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. Methods We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. Results Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. Conclusions Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment. Examination of differentially expressed genes between gestational day 15 (+/- 0.5 days) C57BL/6 mouse fetal livers from diet-induced (60% fat diet) obese or control female mice.

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Sex Differences in Early Programming by Maternal High Fat Diet Induced-Obesity and Fish Oil Supplementation in Mice.

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