Developmentally programmed obesity: Is there a role for anti-inflammatory nutritional strategies?

Pregnancy represents a period of immense maternal physiological adaptation, with progressive increases in lipid storage potential and insulin resistance to support fetal/placental growth. This requires significant change in the adipose tissue. Women living with obesity/overweight are more susceptible to these changes causing complications such as gestational diabetes. This is particularly worrying as up to 60% of European women are living with overweight/obesity at the onset of pregnancy. Furthermore, less than 1% meet all nutrition guidelines. There is now evidence that these deep metabolic changes can result in a predisposition to metabolic disease in both the mother and child in later life. Health and nutrition status during this period therefore represents a window to future health. This period offers a valuable opportunity for intervention to prevent the negative consequences of poor in utero environments and increases the long-term quality of life for mother and offspring. This review will examine a range of in utero factors which determine adipose tissue development, the impact of these factors on later-life obesity and metabolic health and the therapeutic value of dietary anti-inflammatory nutritional interventions during pregnancy and early life. When it comes to early life nutrition, a 'one size fits all' approach is not always appropriate. Understanding the mechanisms of adipose tissue development in response to differing nutritional strategies may be important in the context of complicated or adverse in utero environments and represents a substantial step towards a more personalised nutritional approach for the prevention of obesity, metabolic syndrome and related non-communicable diseases in future generations.

Toxicity of oxidized fish oil in pregnancy: a dose-response study in rats.

Fish oil (FO) supplements are consumed during pregnancy to increase dietary omega-3. However, FO is often oxidized past recommended limits. In rats, a large dose of highly oxidized FO substantially increased newborn mortality, but the effects of human-relevant doses of less oxidized oil are unknown. A dose-response study in rats was conducted to estimate the safe level of oxidation during pregnancy. Sprague-Dawley rat dams were mated, then individually housed and provided with a gel treatment on each day of pregnancy. Treatment groups differed only in the FO content of the gel; control (no oil), PV5, PV10, and PV40 [0.05 mL of FO oxidized to a peroxide value (PV) of 5, 10, or 40 meq/kg], or PV40(1 mL) (1 mL of PV40). A subset of dams was culled on gestational day 20 to enable sampling, and the remainder were allowed to give birth. Newborn mortality was recorded. Offspring were sampled on postnatal days 2 and 21, and dams on day 21. There were no signs of unwellness during pregnancy. However, there was markedly increased neonatal mortality affecting the PV40(1 mL) (12.8%) and PV40 (6.3%) groups, but not the control, PV5, or PV10 groups (1%-1.4%). Dietary-oxidized FO altered the expression of placental genes involved in antioxidant pathways and the production of free radicals. Highly oxidized FO was toxic in rat pregnancy leading to a marked increase in mortality even at a human-relevant dose. We observed no toxic effects of FOs with PV ≤10 meq/kg, suggesting that this is an appropriate maximum limit.

Preterm human milk: associations between perinatal factors and hormone concentrations throughout lactation.

BACKGROUND: Infants born moderate to late preterm constitute the majority of preterm births, yet guidelines for their nutritional care are unclear. Maternal milk is the most appropriate nutrition for these infants; however, its composition can be influenced by environmental factors. The present study therefore investigated perinatal predictors of human milk composition in a preterm cohort. METHODS: Milk was collected during the DIAMOND trial (DIfferent Approaches to Moderate and late preterm Nutrition: Determinants of feed tolerance, body composition and development) from 169 mothers of 191 infants at three time-points (5 and 10 days post partum and 4 months' corrected age). Leptin, adiponectin and insulin-like growth factor-1 (IGF-1) were analysed by enzyme-linked immunosorbent assay. Generalised mixed models were used to evaluate associations between milk composition and maternal/infant/perinatal factors. RESULTS: Most findings were independent of collection time-point. Gestational diabetes was associated with lower adiponectin. Higher adiponectin and lower leptin were associated with higher socioeconomic status, higher maternal education and ability to fully breastfeed at discharge from hospital. Higher leptin was associated with high perceived stress during hospital admission. Milk IGF-1 displayed sex-specific patterns in association with maternal social deprivation. CONCLUSION: Maternal, infant and environmental factors during the perinatal period were associated with milk compositional profiles throughout lactation. Further clinical trials should investigate the impact of such changes in terms of long-term infant outcomes. IMPACT: Human milk is the best nutrition for the infant. However, its composition may be susceptible to alterations determined by pathological conditions mother and infant may face throughout pregnancy and in the perinatal period. This study found that perinatal factors are associated with human milk composition from early to late lactation. If human milk composition throughout lactation is "programmed" during pregnancy or early lactation, infants who were exposed in utero to environmental insults may still be exposed to them during lactation. The impact of human milk compositional alteration on infant growth following perinatal pathological events requires further investigation.

Consumption of the Artificial Sweetener Acesulfame Potassium throughout Pregnancy Induces Glucose Intolerance and Adipose Tissue Dysfunction in Mice.

BACKGROUND: Sugar-sweetened beverage consumption is associated with metabolic dysfunction. Artificially sweetened beverages (ASBs) are often promoted as an alternative. However, evidence for the safety of ASB consumption during pregnancy is lacking. OBJECTIVES: The effects of sugar-sweetened beverage and ASB consumption during pregnancy in mice were examined, and we hypothesized that both sugar-sweetened beverages and ASBs would impair maternal metabolic function. METHODS: Pregnant female C57BL/6J mice received control drinking water (CD), high-fructose corn syrup (Fr; 20% kcal intake; 335 mM), or the artificial sweetener acesulfame potassium (AS; 12.5 mM) in their drinking water, from gestational day (GD) 0.5 (n = 8/group). Body weights and food and water intakes were assessed every second day, an oral-glucose-tolerance test (OGTT) was performed at GD 16.5, and mice were culled at GD 18.5. RT-PCR was carried out on adipose tissue, liver, and gut. Adipose tissue morphology was assessed using histological methods. In a separate cohort of animals, pregnancy length was assessed. Repeated-measures ANOVA was performed for the OGTT and weight gain data. All other data were analyzed by 1-way ANOVA. RESULTS: Fr and AS significantly impaired glucose tolerance, as demonstrated by OGTT (21% and 24% increase in AUC, respectively; P = 0.0006). Fr and AS reduced expression of insulin receptor (39.5% and 33% reduction, respectively; P = 0.02) and peroxisome proliferator-activated receptor γ (45.2% and 47%, respectively; P = 0.039), whereas Fr alone reduced expression of protein kinase B (36.9% reduction; P = 0.048) and resulted in an increase in adipocyte size and leptin concentrations (40% increase; P = 0.03). AS, but not Fr, reduced male fetal weight (16.5% reduction; P = 0.04) and female fetal fasting blood glucose concentration at cull (20% reduction; P = 0.02) compared with CD. AS significantly reduced the length of pregnancy compared with the CD and Fr groups (1.25 d shorter; P = 0.02). CONCLUSIONS: Fr and AS consumption were associated with maternal metabolic dysfunction in mice. AS was also associated with reduced fetal growth and fetal hypoglycemia. Therefore, ASBs may not be a beneficial alternative to sugar-sweetened beverages during pregnancy.

Cyclic glycine-proline normalizes systolic blood pressure in high-fat diet-induced obese male rats.

BACKGROUND AND AIMS: Insulin-like growth factor (IGF)-1 deficiency is associated with a range of metabolic disorders. Cyclic glycine-proline (cGP) is a natural nutrient and regulates the amount of active IGF-1 in plasma. Plasma cGP decreases in hypertensive women whereas increases in obese women, suggesting its involvement in cardio-metabolic function. We therefore examined the effects of cGP on metabolic profiles and blood pressure in high-fat diet (HFD)-induced obese male rats. METHODS: Male rats were fed either a HFD or a standard chow diet (STD) ad-libitum from 3 to 15 weeks of age. Rats were administered either saline or cGP from 11 to 15 weeks of age. At 14 weeks of age, systolic-blood pressure (SBP) was measured by tail-cuff plethysmography and body composition quantified by DEXA. Blood and retroperitoneal fat tissues were collected. Plasma concentrations of insulin, IGF-1, IGF binding protein (IGFBP)-3 and cGP were evaluated using ELISA and HPLC-MS respectively. RESULTS: Compared to STD, HFD feeding increased SBP, total fat mass and fat/lean ratio, retroperitoneal fat weight, fasting plasma insulin and cGP concentrations whereas decreased plasma IGF-1 and IGFBP-3 concentrations. Administration of cGP reduced SBP and retroperitoneal fat weight, but had no effect on body composition and plasma insulin concentrations. CONCLUSION: HFD-associated decreases in IGFBP-3 and increases in cGP represent an autocrine response to normalize IGF-1 function through improving the amount of bioavailable IGF-1 in the circulation of obese male rats. The beneficial effects of cGP on SBP and retroperitoneal fat mass may suggest a therapeutic potential for cGP in HFD-associated cardio-metabolic complications.

Nutritional Supplementation for the Prevention and/or Treatment of Gestational Diabetes Mellitus.

PURPOSE OF REVIEW: Gestational diabetes mellitus (GDM) is a common pregnancy complication that has short- and long-term health implications for both the mother and child. While lifestyle modifications, insulin therapy, and oral agents such as metformin are effective, they can be difficult to adhere to, and there remain concerns over long-term effects of oral agents on the infant. Further, GDM has no proven preventive strategies, which could be more effective than treatment postdiagnosis. Nutritional supplements are an appealing, potentially safer, and better tolerated alternative to pharmaceuticals to treat and/or prevent GDM. Here, we review the existing evidence for nutritional supplementation for treatment and prevention of GDM. RECENT FINDINGS: There is limited evidence that myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics might be beneficial for the prevention or treatment of GDM. There are very few studies for each nutrient, and the existing studies tend to have few participants. Where multiple studies of a nutrient exist, often those studies were conducted within the same country, limiting the generalizability of the findings, or alternatively there was no consensus across findings. There is limited evidence that nutritional supplementation of myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics could improve glycemic control or prevent GDM. Our understanding is constrained by the small number of studies, small sample sizes in most studies, and by lack of consistency across findings. Further large, high-quality, randomized controlled trials are required to determine the efficacy of nutritional supplements to treat or prevent GDM.

Preclinical Models of Altered Early Life Nutrition and Development of Reproductive Disorders in Female Offspring.

Early epidemiology studies in humans have and continue to offer valuable insight into the Developmental Origins of Health and Disease (DOHaD) hypothesis, which emphasises the importance of early-life nutritional and environmental changes on the increased risk of metabolic and reproductive disease in later life. Human studies are limited and constrained by a range of factors which do not apply to preclinical research. Animal models therefore offer a unique opportunity to fully investigate the mechanisms associated with developmental programming, helping to elucidate the developmental processes which influence reproductive diseases, and highlight potential biomarkers which can be translated back to the human condition. This review covers the use and limitations of a number of animal models frequently utilised in developmental programming investigations, with an emphasis on dietary manipulations which can lead to reproductive dysfunction in offspring.

The Pathophysiology of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic ß-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist-including insulin and lifestyle interventions-there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.

Manipulation of the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) Axis: A Treatment Strategy to Reverse the Effects of Early Life Developmental Programming.

Evidence from human clinical, epidemiological, and experimental animal models has clearly highlighted a link between the early life environment and an increased risk for a range of cardiometabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and overnutrition, spanning exposure windows that cover the period from preconception through to early infancy, clearly highlight an increased risk for a range of disorders in offspring in later life. This process, preferentially termed "developmental programming" as part of the developmental origins of health and disease (DOHaD) framework, leads to phenotypic outcomes in offspring that closely resemble those of individuals with untreated growth hormone (GH) deficiency, including increased adiposity and cardiovascular disorders. As such, the use of GH as a potential intervention strategy to mitigate the effects of developmental malprogramming has received some attention in the DOHaD field. In particular, experimental animal models have shown that early GH treatment in the setting of poor maternal nutrition can partially rescue the programmed phenotype, albeit in a sex-specific manner. Although the mechanisms remain poorly defined, they include changes to endothelial function, an altered inflammasome, changes in adipogenesis and cardiovascular function, neuroendocrine effects, and changes in the epigenetic regulation of gene expression. Similarly, GH treatment to adult offspring, where an adverse metabolic phenotype is already manifest, has shown efficacy in reversing some of the metabolic disorders arising from a poor early life environment. Components of the GH-insulin-like growth factor (IGF)-IGF binding protein (GH-IGF-IGFBP) system, including insulin-like growth factor 1 (IGF-1), have also shown promise in ameliorating programmed metabolic disorders, potentially acting via epigenetic processes including changes in miRNA profiles and altered DNA methylation. However, as with the use of GH in the clinical setting of short stature and GH-deficiency, the benefits of treatment are also, in some cases, associated with potential unwanted side effects that need to be taken into account before effective translation as an intervention modality in the DOHaD context can be undertaken.

Oxidized fish oil in rat pregnancy causes high newborn mortality and increases maternal insulin resistance.

Fish oil is commonly taken by pregnant women, and supplements sold at retail are often oxidized. Using a rat model, we aimed to assess the effects of supplementation with oxidized fish oil during pregnancy in mothers and offspring, focusing on newborn viability and maternal insulin sensitivity. Female rats were allocated to a control or high-fat diet and then mated. These rats were subsequently randomized to receive a daily gavage treatment of 1 ml of unoxidized fish oil, a highly oxidized fish oil, or control (water) throughout pregnancy. At birth, the gavage treatment was stopped, but the same maternal diets were fed ad libitum throughout lactation. Supplementation with oxidized fish oil during pregnancy had a marked adverse effect on newborn survival at day 2, leading to much greater odds of mortality than in the control (odds ratio 8.26) and unoxidized fish oil (odds ratio 13.70) groups. In addition, maternal intake of oxidized fish oil during pregnancy led to increased insulin resistance at the time of weaning (3 wks after exposure) compared with control dams (HOMA-IR 2.64 vs. 1.42; P = 0.044). These data show that the consumption of oxidized fish oil is harmful in rat pregnancy, with deleterious effects in both mothers and offspring.

Conjugated linoleic Acid supplementation during pregnancy and lactation reduces maternal high-fat-diet-induced programming of early-onset puberty and hyperlipidemia in female rat offspring.

A maternal high-fat (HF) diet during pregnancy and lactation can result in adverse metabolic and reproductive outcomes in female offspring independent of postnatal diet. Interventions during critical windows of developmental plasticity may prevent developmental programming in offspring. The effects of maternal supplementation with the anti-inflammatory lipid conjugated linoleic acid (CLA) on early-onset puberty, metabolic dysfunction, and estrous cycle dysfunction was assessed. Sprague-Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA). Diets were fed ad libitum for 10 days prior to time mating and throughout gestation and lactation. Offspring plasma/tissues were taken at Day 24 (prepubertal) or Day 150 (adult). Puberty was assessed from Day 26 and estrous cycle from Day 128. Female offspring from HF mothers had lower birth weights but by Postnatal Day 24 had exhibited catch-up growth concomitant with increased fat mass, hyperleptinemia, and dyslipidemia. Maternal CLA supplementation reversed these effects. Early-onset puberty was only observed in HF offspring; this was reversed in HFCLA offspring. In adulthood, despite no evidence of glucose intolerance or altered insulin sensitivity, HF offspring displayed increased fat mass, dyslipidemia, disrupted estrous cyclicity. and hyperleptinemia; this was reversed by maternal CLA supplementation. Data presented in this study demonstrate the importance of diet in women of reproductive age and during pregnancy on reproductive and metabolic parameters in their offspring and that supplementation with CLA during critical windows of development may represent a therapeutic strategy in the prevention of early-life programming of metabolic and reproductive dysfunction.

The impact of non-nutritive sweeteners on fertility, maternal and child health outcomes: a review of human and animal studies.

There is significant evidence that an unhealthy diet greatly increases the risk of complications during pregnancy and predisposes offspring to metabolic dysfunction and obesity. While fat intake is typically associated with the onset of obesity and its comorbidities, there is increasing evidence linking sugar, particularly high fructose corn syrup, to the global rise in obesity rates. Furthermore, the detrimental effects of added sugar intake during pregnancy on mother and child have been clearly outlined. Guidelines advising pregnant women to avoid food and beverages with high fat and sugar have led to an increase in consumption of 'diet' or 'light' options. Examination of some human birth cohort studies shows that heavy consumption (at least one beverage a day) of non-nutritive sweetener (NNS) containing beverages has been associated with increased risk of preterm birth and increased weight/BMI in male offspring independent of maternal weight, which appears to be offset by breastfeeding for 6 months. Rodent models have shown that NNS exposure during pregnancy can impact maternal metabolic health, adipose tissue function, gut microbiome profiles and taste preference. However, the mechanisms underlying these effects are multifaceted and further research, particularly in a translational setting is required to fully understand the effects of NNS on maternal and infant health during pregnancy. Therefore, this review examines maternal sweetener intakes and their influence on fertility, maternal health outcomes and offspring outcomes in human cohort studies and rodent models.

Long-term exposure to a high-fat diet results in the development of glucose intolerance and insulin resistance in interleukin-1 receptor I-deficient mice.

Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1ß production and inflammasome-mediated IL-1ß activation is critical in obesity-associated insulin resistance (IR). Nonetheless, IL-1 receptor I-deficient (IL-1RI(-/-)) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL-1RI(-/-) mice were protected against long-term (6 mo) high-fat diet (HFD)-induced IR. Male wild-type and IL-1RI(-/-) mice were fed LFD or HFD for 3 or 6 mo, and glucose and insulin tolerance tests were performed. Adipose insulin sensitivity, cytokine profiles, and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. IL-1RI(-/-) mice developed glucose intolerance and IR after 6 mo HFD compared with 3 mo HFD, coincident with enhanced weight gain, hyperinsulinemia, and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI(-/-) preadipocytes after 6 mo HFD compared with 3 mo HFD. Obese LFD-IL-1RI(-/-) mice exhibited preserved metabolic health. IL-1RI(-/-) mice develop glucose intolerance and IR after 6 mo HFD intervention. While mature-onset obesity is evident in LFD-IL-1RI(-/-) mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health.

Maternal Intake of Either Fructose or the Artificial Sweetener Acesulfame-K Results in Differential and Sex-Specific Alterations in Markers of Skin Inflammation and Wound Healing Responsiveness in Mouse Offspring: A Pilot Study.

Growing evidence has demonstrated that maternal artificial sweetener (AS) consumption may not be a beneficial alternative when compared to sugar-sweetened beverages and potentially leads to metabolic dysfunction in adult offspring. Compromised skin integrity and wound healing associated with type 2 diabetes can lead to complications such as diabetic pressure injury (PI). In this context, the skin plays an important role in the maintenance of metabolic homeostasis, yet there is limited information on the influence of sugar- or AS-sweetened beverages during pregnancy on developmental programming and offspring skin homeostasis. This study examined the impact of maternal fructose or acesulfame-k consumption on offspring wound healing. Female C57Bl/6 mice received a chow diet ad libitum with either water (CD), fructose (FR; 34.7 mM fructose), or AS (AS; 12.5 mM Acesulfame-K) throughout pregnancy and lactation. PIs were induced in offspring at 9 weeks of age (n = 6/sex/diet). PIs and healthy skin biopsies were collected for later analysis. Maternal AS intake increased skin inflammatory markers in healthy biopsies while an FR diet increased Tgfb expression, and both diets induced subtle changes in inflammatory markers post-wound inducement in a sex-specific manner. Furthermore, a maternal FR diet had a significant effect on pressure wound severity and early wound healing delay, while AS maternal diet had a sex-specific effect on the course of the healing process. This study demonstrates the need for a better understanding of developmental programming as a mediator of later-life skin integrity and wound responsiveness.

Inter-organ proteomic analysis reveals insights into the molecular mechanisms underlying the anti-diabetic effects of cis-9, trans-11-conjugated linoleic acid in ob/ob mice.

cis-9, trans-11-Conjugated linoleic acid (c9 t11 CLA) exerts anti-diabetic effects by improving systemic insulin sensitivity and inflammation. Levels of CLA in beef can be increased by feeding cattle on pasture. This study aimed to explore the efficacy of a CLA-rich diet (0.6% w/w c9 t11 CLA), presented as beef enriched with CLA or beef supplemented with synthetic CLA (c9 t11 CLA), for 28 days on molecular biomarkers of the metabolic syndrome, and adipose, hepatic, and skeletal muscle proteome in male ob/ob mice. Despite equal weight gain, CLA-fed mice had lower plasma glucose, insulin, non-esterified fatty acid, triacylglycerol and interleukin-6, and higher adiponectin concentrations than controls. c9 t11 CLA induced differential regulation of redox status across all tissues, and decreased hepatic and muscle endoplasmic reticulum stress. CLA also modulated mechanistic links between the actin cytoskeleton, insulin signalling, glucose transport and inflammation in the adipose tissue. In the liver and muscle, c9 t11 CLA improved metabolic flexibility through co-ordination between carbohydrate and energy metabolism. c9 t11 CLA may ameliorate systemic insulin sensitivity in obesity-induced diabetes by altering cellular stress and redox status, and modulating nutrient handling in key insulin-sensitive tissues through complex biochemical interplay among representative proteomic signatures.

The Impact of Non-caloric Sweeteners on Male Fertility: A Systematic Review and Narrative Synthesis in Rodent Models.

Understanding the factors which influence fertility is essential for developing appropriate nutritional recommendations for couples trying to conceive. Non-caloric sweeteners (NCS) are increasing in the food chain and despite being no/low calorie, several adverse metabolic consequences have been attributed to their consumption. Their effects on reproduction have been relatively under-researched, particularly in males. This review aims to systematically review the literature for evidence of the effect of NCS on male fertility in rodents, with sperm parameters (sperm quantity and quality) assessed as primary outcomes. Given the lack of information available in humans this review has been carried out using evidence from rodent models. Risk of bias assessment was carried out using the Syrcle risk of bias tool. Nine studies met the inclusion criteria. Forty-four percent showed a negative effect of NCS on male reproductive parameters compared with controls. The effects of NCS on fertility have been conflicting and selected studies have been heterogeneous in relation to study design. It is unclear if NCS has an impact on male reproductive function. There is a need for randomized controlled trials using a standardized protocol for analysis, to formulate a clear message in terms of male fertility.

Maternal intake of fructose or artificial sweetener during pregnancy and lactation has persistent effects on metabolic and reproductive health of dams post-weaning.

As rates of obesity, diabetes, and related comorbidities have increased, the consumption of artificial sweeteners (ASs) as sugar substitutes has also risen in popularity as they are perceived as a healthier alternative to sugar sweetened products. However, there is conflicting evidence regarding the impact of AS intake on metabolic and reproductive health. Glucose intolerance during pregnancy due to intake of sugar sweetened foods can result in an increased risk for the development of type 2 diabetes post-pregnancy. However, limited information exists on the impact of AS intake during pregnancy and lactation on the mother's health in later life. We hypothesised both AS and fructose would impair metabolic health post-partum (PP) following maternal consumption during pregnancy and lactation. Female C57Bl/6 mice received a standard control diet ad libitum with either water (CD), fructose (Fr; 34.7 mm intake), or AS (AS;12.5 mm Acesulfame-K) throughout pregnancy and lactation. Post-weaning, AS and Fr dams were fed the CD diet for the remainder of the experiment. Oral glucose tolerance tests were undertaken 8 weeks PP and dams were humanely killed at 9 weeks PP, with adipose tissue and ovaries collected for analysis. Experimental diets did not influence maternal bodyweight. At 8 weeks PP, increased glucose intolerance was evident in both AS and Fr dams. Adipocyte size was significantly increased in both the AS and Fr groups PP. Further, in the ovary, AS increased expression of genes associated with follicular development and ovulation. Therefore, ASs may not represent beneficial substitutes to fructose during pregnancy, with the potential to increase the risk of T2DM in later life in mothers.

Fish oil supplementation of rats fed a high fat diet during pregnancy improves offspring insulin sensitivity.

Introduction: In rats, a maternal high-fat diet (HFD) leads to adverse metabolic changes in the adult offspring, similar to the children of mothers with obesity during pregnancy. Supplementation with a high dose of fish oil (FO) to pregnant rats fed a HFD has been shown to prevent the development of insulin resistance in adult offspring. However, the effects of supplementation at a translationally relevant dose remain unknown. Aim: To determine whether supplementation with a human-relevant dose of FO to pregnant rats can prevent the long-term adverse metabolic and cardiovascular effects of a maternal HFD on adult offspring. Methods: Female rats (N = 100, 90 days of age) were assigned to HFD (45% kcal from fat) or control diet (CD) for 14 days prior to mating and throughout pregnancy and lactation. Following mating, dams received a gel containing 0.05 ml of FO (human equivalent 2-3 ml) or a control gel on each day of pregnancy. This produced 4 groups, CD with control gel, CD with FO gel, HFD with control gel and HFD with FO gel. Plasma and tissue samples were collected at day 20 of pregnancy and postnatal day 2, 21, and 100. Adult offspring were assessed for insulin sensitivity, blood pressure, DXA scan, and 2D echocardiography. Results: There was an interaction between maternal diet and FO supplementation on insulin sensitivity (p = 0.005) and cardiac function (p < 0.01). A maternal HFD resulted in impaired insulin sensitivity in the adult offspring (p = 0.005 males, p = 0.001 females). FO supplementation in the context of a maternal HFD prevented the reduction in insulin sensitivity in offspring (p = 0.05 males, p = 0.0001 females). However, in dams consuming CD, FO supplementation led to impaired insulin sensitivity (p = 0.02 males, p = 0.001 females), greater body weight and reduced cardiac ejection fraction. Conclusion: The effects of a human-relevant dose of maternal FO on offspring outcomes were dependent on the maternal diet, so that FO was beneficial to the offspring if the mother consumed a HFD, but deleterious if the mother consumed a control diet. This study suggests that supplementation with FO should be targeted to women expected to have abnormalities of metabolism such as those with overweight and obesity.

Interleukin-1 Receptor-1 Deficiency Impairs Metabolic Function in Pregnant and Non-Pregnant Female Mice.

SCOPE: Glucose intolerance during pregnancy is associated with short- and long-term maternal and offspring health consequences. In young male mice, knockout of the major pro-inflammatory mediator interleukin-1-receptor-1 (IL1R1) protects against high-fat diet (HFD)-induced glucose intolerance and metabolic dysfunction. This phenotype has not been examined during pregnancy. The hypothesis that IL1R1 depletion will protect females against HFD-induced glucose intolerance and metabolic dysfunction before, during, and post pregnancy is tested. METHODS AND RESULTS: C57BL/6J control and IL1R1 knockout (IL1R1-/- ) mice are randomized to either a control diet (10% kcal from fat) or HFD (45% kcal from fat), and three distinct cohorts are established: nulliparous, pregnant, and postpartum females. Contrary to the authors' hypothesis, it is found that IL1R1-/- does not protect against glucose intolerance in nulliparous or pregnant females, and while control HFD animals see a resolution of glucose tolerance postpartum, IL-1R1-/- mice remain impaired. These effects are accompanied by adipocyte hypertrophy, hyperleptinemia, and increased adipose tissue inflammatory gene expression. Maternal genotype differentially affects fetal growth in male and female fetuses, demonstrating sexual dimorphism in this genotype prior to birth. CONCLUSIONS: These findings suggest that IL1R1 signaling is important for normal metabolic functioning in females, during and outside of pregnancy.