Insulin Sensitivity In Offspring Research Articles

Feasibility and efficacy of pemafibrate for prevention of maternal high-fat intake-induced glucose metabolic dysfunction in offspring

Given the significance of the intrauterine lipid environment in glucose metabolic homeostasis in offspring, the present study was undertaken to investigate the feasibility and efficacy of pemafibrate, a triglyceride-lowering peroxisome proliferator-activated agent, for maternal high-fat diet (HFD) intake-induced glucose metabolic dysfunction in offspring. A mouse model of HFD-induced gestational obesity was employed, and pemafibrate was orally administered from day 10 of gestation until delivery. The influences of maternal pemafibrate treatment on biological processes and toxicity were evaluated in both newborns and 12-week-old offspring. The findings of a dose-dependent decrease of β cell islet mass and of impairment of glucose tolerance and insulin sensitivity in offspring suggest that maternal pemafibrate intervention can prevent maternal HFD-intake-induced diabetes in offspring. Of particular interest in the prevention of future glucose metabolic dysfunction in offspring, low-dose maternal pemafibrate treatment (0.02 mg/kg/day) had sufficient efficacy and appeared to be safe in offspring. Therefore, pemafibrate may be a potential agent for the prevention of maternal high-fat exposure-induced diabetes in offspring.Abbreviations: CD, control diet; DEG, differentially expressed genes; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; MC, 0.5w/v% methyl cellulose 400 solution; PPAR, triglyceride-lowering peroxisome proliferator-activated receptor; RNA-seq, RNA sequencing; TC, total cholesterol; TG, triglycerides.

Increased Allergic Inflammation and Decreased Lung Insulin Sensitivity in Offspring of Obese Allergic Mothers.

Epidemiological studies demonstrate that maternal obesity and maternal allergy are major risk factors for asthma in offspring. However, the impact of maternal allergy and obesity on offspring lung insulin signaling and allergen responsiveness is not known. To evaluate this, allergic and non-allergic female mice were fed a high fat diet or low-fat diet from 7 weeks before pregnancy until weaning. Neonatal pups were allergen-sensitized and allergen-challenged and then were assessed for obesity, insulin signaling, and allergic inflammation. Compared to pups of non-obese non-allergic mothers, allergen-challenged pups of obese non-allergic mothers, non-obese allergic mothers and obese allergic mothers had bronchoalveolar lavage eosinophilia, with the pups of obese allergic mothers having the highest bronchoalveolar lavage eosinophilia. These pups also had lower insulin-induced lung AKT-phosphorylation, indicating a decrease in lung parenchymal insulin sensitivity. In cross-fostering experiments, allergen-challenged pups exposed to both pre- and post-natal obese allergic mothers had the highest level of BAL eosinophilia. Maternal obesity or allergy increased offspring serum allergen-specific IgE and IL-5 that was highest when the mother was both obese and allergic. Also, allergen-challenged pups exposed to both pre- and post-natal obese allergic mothers had the highest level of IL5. In summary, offspring born to obese allergic mothers have decreased lung insulin sensitivity and have increased lung allergic inflammation. Interestingly, our data also demonstrates that there is both a pregnancy and post-pregnancy aspect of maternal allergy and obesity that enhance allergen responsiveness in offspring.

Estrogen promotes fetal skeletal muscle mitochondrial distribution and ATP synthase activity important for insulin sensitivity in offspring

PurposeWe previously showed that offspring delivered to baboons in which levels of estradiol (E2) were suppressed during the second half of gestation exhibit insulin resistance. Mitochondria are essential for the production of ATP as the main source of energy for intracellular metabolic pathways, and skeletal muscle of type 2 diabetics exhibit mitochondrial abnormalities. Mitochondria express estrogen receptor β and E2 enhances mitochondrial function in adults. Therefore, the current study ascertained whether exposure of the fetus to E2 is essential for mitochondrial development.MethodsLevels of ATP synthase and citrate synthase and the morphology of mitochondria were determined in fetal skeletal muscle obtained near term from baboons untreated or treated daily with the aromatase inhibitor letrozole or letrozole plus E2.ResultsSpecific activity and amount of ATP synthase were 2-fold lower (P < 0.05) in mitochondria from skeletal muscle of E2 suppressed letrozole-treated fetuses and restored to normal by treatment with letrozole plus E2. Immunocytochemistry showed that in contrast to the punctate formation of mitochondria in myocytes of untreated and letrozole plus E2 treated animals, mitochondria appeared to be diffuse in myocytes of estrogen-suppressed fetuses. However, citrate synthase activity and levels of proteins that control mitochondrial fission/fusion were similar in estrogen replete and suppressed animals.ConclusionWe suggest that estrogen is essential for fetal skeletal muscle mitochondrial development and thus glucose homeostasis in adulthood.

Maternal dexamethasone exposure does not affect glucose tolerance but alters renal haemodynamics in F1 rats in a sex-dependent manner.

Prenatal programming with dexamethasone increases the risk of the development of hyperglycaemia and insulin resistance, leading to diabetes in adulthood. Dexamethasone also causes a decline in renal glomerular filtration in the adult offspring. Sodium-glucose cotransporter-2 (SGLT2) plays a significant role in regulating blood glucose and renal haemodynamics in diabetic patients. However, the role of SGLT2 in dexamethasone-induced programming and the putative sex-dependent effects on the changes named earlier is unknown. Therefore, this study aimed to investigate the impact of maternal dexamethasone treatment on glucose tolerance, insulin sensitivity, renal perfusion and renal function in adult male and female offspring and the possible contribution of SGLT2 to these changes. Pregnant Sprague Dawley rats (F0 ) were treated with either vehicle or dexamethasone (0.2 mg/kg ip) from gestation Day 15 to 20. F1 males and F1 females were randomly selected from each mother at 4 months of age. There was no change in serum Na+ , Na+ excretion rate, glucose tolerance or insulin sensitivity in F1 male or female rats. However, dexamethasone caused significant glomerular hypertrophy and decreases in CSinistrin and CPAH indicating decreased glomerular filtration rate and renal plasma flow, respectively, in dexamethasone-treated F1 male but not female rats. Dexamethasone did not affect SGLT2 mRNA or protein expression in F1 males or females. We conclude that dexamethasone-mediated prenatal programming of glomerular volume, renal function and haemodynamics is sex-dependent, occurring only in adult male offspring.

Like father, like daughter:Paternal cadmium exposure causes hepatic glucose metabolic disorder and phospholipids accumulation in adult female offspring

Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases.

178-LB: Association of Pregnancy Oral Glucose Tolerance Test (OGTT) Glucose Response with Metabolic Profile in Mother and Child—Hyperglycemia and Adverse Pregnancy Outcomes Follow-up Study (HAPO-FUS)

The glucose response shape during an OGTT, monophasic or biphasic, can characterize physiologically distinct groups with differences in insulin secretion and sensitivity. Biphasic response (glucose rebound after nadir ≥ 0.025 mmol/L) has been associated with higher insulin sensitivity and β-cell function. We aimed to identify the association of the pregnancy OGTT response shape with follow-up maternal and offspring metabolic profiles. Method: Using HAPO-FUS study data from the NIH-NIDDK repository, monophasic glucose response was defined as 2-hr glucose - 1-hr glucose &amp;lt; 0. Multiple linear regression assessed the relationship of glucose response shape with maternal profile at 10-year follow-up and offspring metabolic profile at 10-12 years of age. Maternal covariates include age, gestational age, field center and BMI. Child covariates include age, sex, pubertal stage, and family history of diabetes. Results: 4,605 mothers (83.7% monophasic) and 3792 children were included. Mothers with monophasic shape were older (30.7 vs 29.8 years, p=.002), had higher BMI (26.7 vs 26.0 kg/m2, p=.003), HbA1c (4.80 vs 4.70 %, p &amp;lt;.001), 1-hour c-peptide level (9.60 vs 7.75 ug/dL, p &amp;lt;.001) and gestational diabetes (14 vs 9.5%, p &amp;lt;.001). At 10-year follow-up, pregnancy monophasic response was associated with higher fasting glucose level (0.06 [0.01, 0.11], p =.01) and log HOMA-IR (0.06 [0.02, 0.10], p=.007) in mothers at follow-up. Offspring had higher cord c-peptide (0.12 [0.04, 0.21], p=.005) and body fat percent (1.35 [0.50-2.21], p =.002). Offspring insulin sensitivity (-0.17 [-0.04, -0.3], p=.01) and Matsuda index (-0.46 [-0.15, -0.76], p=.003) were lower with monophasic response. Conclusion: Maternal glucose response profiles during pregnancy determined by both insulin secretion and whole-body insulin resistance are associated with long-term maternal and offspring metabolic profile. Disclosure V. V. Thaker: None. C. A. Leduc: None. R. Salem: Other Relationship; Travere Inc. Funding National Institutes of Health (K23DK110539)

1741-P: Placental Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Regulate Offspring Glucose Homeostasis and Insulin Sensitivity

Maternal hyperinsulinemia, often underlying pregnancies complicated by obesity and gestational diabetes, is associated with impaired placental insulin signaling, yet the consequences of altered placental insulin action on the metabolic health trajectory of the offspring remains unclear. Insulin binds to the insulin receptor (IR) and to the insulin-like growth factor receptor 1 (IGF1R). We reported that IR ablation in placental trophoblast cells mildly improved glucose homeostasis in adult male offspring when metabolically challenged by a high-fat diet. The current study examines metabolic phenotypes of offspring that experienced placental IGF1R knockout (IGF1RKO) or double IGF1R/IR knockout (DKO) in utero. We report that male IGF1RKO offspring have a decrease in body weight at embryonic day 17.5 but no differences in placenta weight. After weaning and throughout adulthood, no body weight differences were observed in male or female offspring. At 16 weeks of normal chow diet (NCD), random blood glucose was decreased in female IGF1RKO offspring but increased in male IGF1RKO offspring compared to respective littermate controls. Interestingly, these opposite changes in glycemia corresponded with reciprocal pancreas weights, prompting our investigation of beta-cell and alpha-cell mass and function. Glucose tolerance tests revealed improved glucose tolerance in IGF1RKO male offspring at 20 weeks NCD. Insulin tolerance tests have demonstrated comparable insulin sensitivity in IGF1RKO offspring of both sexes. In contrast, DKO offspring display reduced body weights at post-natal days 7 and 21. At 12 weeks of NCD, DKO females were significantly more insulin sensitive than littermate controls but had comparable glucose tolerance and body weights across adulthood. DKO males did not display glucose or insulin intolerance. Together, findings from these models suggest a need for further investigation of insulin action during pregnancy. Disclosure M.Beetch: None. E.Alejandro: None. Funding National Institutes of Health (T32DK007203, T32DK083250)

Maternal High-Fat Diet Results in Long-Term Sex-Specific Alterations to Metabolic and Gut Microbial Diurnal Oscillations in Adult Offspring.

Circadian rhythms profoundly impact metabolism and the gut microbiota. A maternal high-fat diet (HFD) exerts effects on the metabolic syndrome of adult offspring in a sex-specific manner, the underlying mechanisms, however, remain unclear. Female mice are fed an HFD and raise their offspring on a standard chow diet until 24 weeks. The glucose tolerance, insulin sensitivity, and diurnal rhythms of serum metabolic profiles are assessed in male and female adult offspring. Simultaneously, 16S rRNA is applied to characterize gut microbiota diurnal rhythms. The study finds that maternal HFD tends to deteriorate glucose tolerance and impairs insulin sensitivity in male offspring, but not female offspring, which can be associated with the circadian alterations of serum metabolic profiles in male offspring. As expected, maternal HFD sex-specifically alters diurnal rhythms of the gut microbiota, which exhibits putative associations with metabolic profiles in males. The presentstudy identifies the critical role of gut microbiota diurnal rhythms in triggering sex-biased metabolic diurnal rhythms in response to maternal HFD, at least in part. As early life may be a critical window for preventing metabolic diseases, these findings provide the basis for developing chronobiology applications targeting the gut microbiota to combat early metabolic alterations, especially in males.

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

IntroductionIn 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.AimTo 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.MethodsFemale 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.ResultsThere 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.ConclusionThe 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.

Estrogen promotes fetal skeletal muscle myofiber development important for insulin sensitivity in offspring.

Using our nonhuman primate baboon model, we showed that offspring born to mothers deprived of estrogen during the second half of gestation exhibited insulin resistance and a deficit in first phase insulin release. Although insulin resistance was not due to an impairment of fetal or offspring growth, nor to an alteration in adipose or hepatic sensitivity to insulin, skeletal muscle microvacularization critical for delivery of nutrients/insulin was significantly reduced in fetuses and offspring deprived of estrogen in utero. Skeletal muscle myofiber maturation occurs in utero and estrogen modulates myofiber growth in adults. Therefore, the current study determined whether fetal skeletal muscle development was altered in baboons in which estradiol levels were suppressed/restored during the second half of gestation by maternal treatment with letrozole ± estradiol benzoate. In estrogen-suppressed animals, fetal skeletal muscle fascicles were structurally less organized, smaller, and comprised of slow type I and fast type II fibers, the size, but not the number of which were smaller than in untreated baboons. Moreover, the proportion of non-muscle fiber tissue was greater and that of muscle fibers lower in estrogen-deprived fetuses. Thus, the maintenance of fetal body weight in estrogen-deprived animals was maintained at the expense of muscle fibers and likely reflected increased deposition of non-muscle proteins. Importantly, fetal skeletal muscle development, including fascicle organization, myofiber size and composition was normal in baboons treated with letrozole and estradiol benzoate. Collectively, these and our previous findings support our proposal that exposure of the fetus to estrogen is important for fetal skeletal muscle development and glucose homeostasis in adulthood.

Maternal Exercise May Improve Metabolic Outcomes in Offspring in Mice

ObjectiveIt is well recognized in both human epidemiological and animal studies that the maternal in utero environment has significant effects on development of offspring. This includes sedentary lifestyle, which has been linked to developmental programming of metabolic dysfunction. The aim of this study is to investigate metabolic outcomes in offspring of sedentary mice versus mice that exercised in pregnancy.Study DesignC57BL/6J female mice were placed on a control diet and allocated to sedentary versus exercise cages at 17 weeks of age. Exercise cages included a voluntary running wheel, with daily exercise measured via activity trackers. Mice were allowed to exercise for 2 weeks prior to breeding and throughout weaning. Offspring underwent body composition measurement and insulin and glucose tolerance tests at 6 weeks of age. At 14‐16 weeks of age, body composition was reassessed and mice were euthanized for tissue collection. Outcomes were analyzed between sedentary (SED) and exercise (EX) offspring using an unpaired t‐test, with p&lt;0.05 considered significant.ResultsWe studied metabolic function in 10 SED and 9 EX offspring. Insulin sensitivity, measured as the area under the curve for the decrease in glucose over time in response to insulin, tended to be improved in EX versus SED offspring (‐188 vs. 2991; p=0.062), with no difference in fasting glucose levels or glucose tolerance. While body mass was similar at end of study (23.4 EX vs. 23.1 SED; p=0.83), the percentage of subcutaneous white adipose tissue tended to be lower (0.94 EX vs. 1.67 SED; p=0.054) and brown adipose tissue was higher (0.57 EX vs. vs 0.30 SED; p&lt;0.001) in EX offspring.ConclusionsThese data suggest that maternal exercise may improve insulin sensitivity in offspring even under normal diet conditions. Further, despite similar body mass, offspring from mice that exercised during pregnancy had a shift in adipose depot composition with lower white adipose and higher brown adipose tissue. This change in body composition may have important implications for energy metabolism and is an important area of future study.

Perinatal low-fat dietary intervention affects glucose metabolism in female adult and aging offspring.

Diabetes confers a high risk of developing poor health in later life in women. Based on the Developmental Origins of Health and Disease theory, the present study was undertaken to investigate the efficacy of perinatal fat restriction in maternal high-fat-exposed female offspring to maintain glucose homeostasis in later life between adulthood and aging. Low-fat dietary intervention during either gestation or lactation was performed using a high-fat diet-induced maternal obesity mouse model (HFD mice). Physiological metabolic parameters, including body weight and serum levels of total cholesterol and triglycerides, were monitored. Glucose tolerance test and insulin sensitivity test were performed in 12- and 70-week-old offspring. Insulin-positive islet cells were also observed using immunohistochemical staining. HFD significantly induced abnormal weight gain, hyperlipidemia and impairment of both glucose tolerance and insulin sensitivity in offspring. Standard diet intake after weaning improved weight gain, serum total cholesterol level and glucose tolerance, but not insulin sensitivity, in 70-week-old offspring. Only perinatal fat restriction during both gestation and lactation, followed by standard food intake for the rest of their life, provided adequate efficacy to restore insulin sensitivity in aging female progeny. Perinatal low-fat intervention may prevent deterioration of glucose metabolism. To improve the health status over a female's lifespan, appropriate nutritional intervention during the early developmental stage may reset the disease trajectory and prevent the onset and development of diabetes. Geriatr Gerontol Int 2022; 22: 441-448.

Estrogen Promotes Microvascularization in the Fetus and Thus Vascular Function and Insulin Sensitivity in Offspring.

We have shown that normal weight offspring born to estrogen-deprived baboons exhibited insulin resistance, although liver and adipose function and insulin receptor and glucose transporter expression were unaltered. The blood microvessels have an important role in insulin action by delivering insulin and glucose to target cells. Although little is known about the regulation of microvessel development during fetal life, estrogen promotes capillary proliferation and vascular function in the adult. Therefore, we tested the hypothesis that estrogen promotes fetal microvessel development and thus vascular function and insulin sensitivity in offspring. Capillary/myofiber ratio was decreased 75% (P < 0.05) in skeletal muscle, a major insulin target tissue, of fetal baboons in which estradiol levels were depleted by administration of aromatase inhibitor letrozole. This was sustained after birth, resulting in a 50% reduction (P < 0.01) in microvessel expansion; 65% decrease (P < 0.01) in arterial flow-mediated dilation, indicative of vascular endothelial dysfunction; and 35% increase (P < 0.01) in blood pressure in offspring from estrogen-deprived baboons, changes prevented by letrozole and estradiol administration. Along with vascular dysfunction, peak insulin and glucose levels during a glucose tolerance test were greater (P < 0.05 to P < 0.01) and the homeostasis model of insulin resistance 2-fold higher (P < 0.01) in offspring of letrozole-treated than untreated animals, indicative of insulin resistance. This study makes the novel discovery that estrogen promotes microvascularization in the fetus and thus normal vascular development and function required for eliciting insulin sensitivity in offspring and that placental hormonal secretions, independent from improper fetal growth, are an important determinant of risk of developing insulin resistance.

Disruption of O-Linked N-Acetylglucosamine Signaling in Placenta Induces Insulin Sensitivity in Female Offspring.

Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain (p = 0.02) and an improved insulin tolerance (p = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment (p = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.

PSX-21 Maternal dietary supplementation of fatty acids during late gestation on offspring’s growth, carcass characteristics and energy metabolism in sheep

Abstract Our objective was to evaluate the effect of different sources of fatty acids (FA) fed to ewes during late gestation on offspring growth, carcass characteristics (CC), and glucose and insulin metabolism [via glucose tolerance test (GTT)]. Fifty-four ewes (n = 18/treatment) were blocked by age, and BW; and within each block randomly assigned to one of three treatments fed from day 100 gestation until lambing. Treatments were: 1) no FA supplementation (CONT); or supplemented with 1% of lipid-enrich diet in 2) monounsaturated FA (MUFA); or 3) polyunsaturated FA (PUFA). At birth, all ewes and lambs were placed in a common pen and feed a common diet. At 60 days of age, lambs were weaned (d0), blocked by weight, and placed (3 lambs/pen; 6 pen/treatment; 3 pens of each sex) in a common diet until d56. Weight was measured on d0, d28, and d54; feed intake (FI) was measured daily. One lamb/pen was used on a GTT on d55, and another lamb/pen was used to determine CC (d56). Offspring data were analyzed as a randomized complete block design with a 2x2 factorial arrangement (FA*Sex; SAS 9.4). Treatments did not affect (P &amp;gt; 0.1) offspring FI, neither plasma glucose concentration (GTT). There was a FA*Sex interaction (P &amp;lt; 0. 05) for insulin. Males’ plasma insulin concentration increased as FA unsaturation degree increased during the GTT, the opposite happened with females. There was an interaction of FA*Sex*Day (P &amp;lt; 0.05) on lamb growth. On d0 MUFA females were heavier than MUFA males, but PUFA males were heavier than PUFA females; these differences disappeared at d28. Lambs born from PUFA had a heavier (P &amp;lt; 0. 05) hot carcass weight. In conclusion, dam’s FA supplementation modified offspring growth, insulin sensitivity, and HCW; these changes depended on the supplement FA unsaturation degree and offspring sex.

Maternal exercise attenuates the lower skeletal muscle glucose uptake and insulin secretion caused by paternal obesity in female adult rat offspring.

Key points Paternal obesity negatively influences metabolic outcomes in adult rat offspring.Maternal voluntary physical activity has previously been reported to improve glucose metabolism in adult rat offspring sired by healthy fathers.Here, we investigated whether a structured programme of maternal exercise training before and during gestation can attenuate the negative impacts that paternal obesity has on insulin sensitivity and secretion in female adult offspring.Exercise before and during pregnancy normalised the lower insulin sensitivity in skeletal muscle and the lower insulin secretion observed in female offspring sired by obese fathers.This paper presents a feasible, low‐cost and translatable intervention strategy that can be applied perinatally to support multifactor interventions to break the cycle of metabolic dysfunction caused by paternal obesity. We investigated whether maternal exercise before and during gestation could attenuate the negative metabolic effects of paternal high‐fat diet‐induced obesity in female adult rat offspring. Fathers consumed a normal chow or high‐fat diet before mating. Mothers exercised on a treadmill before and during gestation or remained sedentary. In adulthood, female offspring were assessed using intraperitoneal insulin and glucose tolerance tests (IPITT and IPGTT, respectively), pancreatic morphology, ex vivo skeletal muscle insulin‐stimulated glucose uptake and mitochondrial respiratory function. Paternal obesity impaired whole‐body and skeletal muscle insulin sensitivity and insulin secretion in adult offspring. Maternal exercise attenuated the lower insulin‐stimulated glucose uptake in offspring sired by obese fathers but distal insulin signalling components (p‐AKT Thr308 and Ser473, p‐TBC1D4 Thr642 and GLUT4) remained unchanged (P > 0.05). Maternal exercise increased citrate synthase activity only in offspring sired by obese fathers. Maternal exercise also reversed the lower insulin secretion in vivo observed in offspring of obese fathers, probably due to an attenuation of the decrease in pancreatic beta cell mass. In summary, maternal exercise before and during pregnancy in rats attenuated skeletal muscle insulin resistance and attenuated the decrease in pancreatic beta cell mass and insulin secretion observed in the female offspring of obese fathers.

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta-analysis.

This systematic review and meta‐analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity—following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non‐diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA‐IR]) were included in the meta‐analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA‐IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA‐IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA‐IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity.

Leprdb/+ Dams Protect Wild-type Male Offspring Bone Strength from the Detrimental Effects of a High-Fat Diet.

The prevalence of maternal obesity is increasing at an alarming rate and increases the life-long risk of developing cardiometabolic disease in adult offspring. Leptin, an adipokine, is systemically elevated in the obese milieu. We recently showed that maternal hyperleptinemia without obesity improves offspring insulin sensitivity and glucose tolerance while protecting against weight gain on a high-fat, high-sugar (HFD). Here, we investigate the effect of maternal hyperleptinemia on offspring bone by using 2 independent maternal models. First, we compared wild-type (WT) offspring from severely hyperleptinemic Leprdb/+ (DB/+) dams with those from WT dams. In the second model, WT females were implanted with miniosmotic pumps that released either saline (group SAL) or leptin (group LEP; 650ng/hour) and the WT offspring were compared. At 23 weeks of age, a subset of offspring were challenged with a HFD for 8 weeks. When the offspring were 31 weeks of age, bone geometry, strength, and material properties were investigated. The HFD increased trabecular bone volume but decreased both total breaking strength and material strength of femora from the offspring of WT dams. However, male offspring of DB/+ dams were protected from the detrimental effects of a HFD, while offspring of LEP dams were not. Further material analysis revealed a modest decrease in advanced glycation end product accumulation coupled with increased collagen crosslinking in male offspring from DB/+ dams on a HFD. These data suggest that while maternal leptin may protect bone quality from the effects of a HFD, additional factors of the maternal environment controlled by leptin receptor signaling are likely also involved.

No Association Between Maternal Dietary Protein Intake and Offspring Insulin Sensitivity Measures in the First Two Years of Life

Abstract Objectives Findings of an association between maternal dietary protein intake (1.1–1.7 g·kg−1·day−1) close to requirements for pregnant women throughout gestation (1.22–1.52 g·kg−1·day−1) and offspring insulin sensitivity are mixed, perhaps as a result of the small spread in protein intake and the large gap between measurements (∼9–40 years). Therefore, our objective was to evaluate the association between a wider spread of dietary protein intake during pregnancy and measurements of insulin sensitivity in the offspring in early life. Methods Healthy women (n = 182, mean ± SD; BMI: 26.2 ± 4.2 kg/m2) were recruited early in pregnancy (&amp;lt;10 weeks). Dietary protein intake was assessed using a 3-day food record in early (∼10 weeks, EP) and late (∼30 weeks, LP) pregnancy. Offspring blood was sampled at 12 and 24 months, and the updated homeostatic model assessment of insulin resistance (HOMA2-IR) was computed using fasting glucose and insulin. Body composition was measured using nuclear magnetic resonance. Two linear models were fitted to the data to estimate: 1) the unadjusted relationship of maternal protein intake to offspring HOMA2-IR and 2) the relationship of maternal protein intake to offspring HOMA2-IR adjusted for maternal plant protein intake and BMI, and offspring sex and body fat percentage. Values are mean ± SD. Results Habitual protein intake (average of early and late pregnancy measurements range: 0.5–1.9 g·kg−1·day−1) decreased throughout pregnancy (EP: 1.09 ± 0.36; vs. LP: 0.97 ± 0.28 g·kg−1·day−1, P = 0.0003). Offspring HOMA2-IR did not change from 12 (0.8 ± 0.8) to 24 (0.8 ± 0.9) months. Simple regression analysis: EP dietary protein intake did not associate with HOMA2-IR at 12 (β = 0.153, P = 0.429) and 24 (β = −0.349, P = 0.098) months. Similarly, LP dietary protein intake did not associate with offspring HOMA2-IR at 12 (β = 0.023, P = 0.916) and 24 (β = −0.442, P = 0.085) months. Results remained unchanged after multiple regression analyses were conducted. Conclusions Maternal dietary protein intake (amount or type) during pregnancy is not associated with indirect measurements of insulin sensitivity in offspring during the first two years of life. Funding Sources United States Department of Agriculture Agricultural Research Service Project 6026-51,000-012-06S, and NIH/NIDDK R01 DK107516.

Dietary Protein Intake during Pregnancy Is Not Associated with Offspring Insulin Sensitivity during the First Two Years of Life

Literature describing a relationship between dietary protein intake during pregnancy and offspring insulin resistance are equivocal perhaps because of the lapse between maternal and offspring measurements (~9–40 years). Thus, we evaluated protein intake in healthy women [n = 182, mean ± SD; body mass index (BMI): 26.2 ± 4.2 kg/m2] in early pregnancy (8.4 ± 1.6 weeks, EP), late pregnancy (30.1 ± 0.4 weeks, LP), and averaged throughout pregnancy, and determined the relationship between protein intake and offspring homeostatic model assessment of insulin resistance (HOMA2-IR) at 12 (12mo) and 24 (24mo) months. EP protein (g·kg−1·day−1) did not associate with HOMA2-IR at 12mo (β = 0.153, p = 0.429) or 24mo (β = −0.349, p = 0.098). LP protein did not associate with HOMA2-IR at 12mo (β = 0.023, p = 0.916) or 24mo (β = −0.442, p = 0.085). Finally, average protein did not associate with HOMA2-IR at 12mo (β = 0.711, p = 0.05) or 24mo (β = −0.445, p = 0.294). Results remained unchanged after adjusting for plant protein intake quartiles during pregnancy, maternal BMI, and offspring sex and body fat percentage. Additionally, these relationships did not change after quartile analysis of average protein intake, even after considering offspring fasting time and HOMA2-IR outliers, and maternal under-reporters of energy intake. Protein intake during pregnancy is not associated with indirect measurements of insulin sensitivity in offspring during the first two years of life.