Insulin Resistance In Later Life Research Articles

Comparison of hyperoxia or normoxia resolution of intermittent hypoxia and intermittent hyperoxia episodes on liver histopathology, IGF-1, IGFBP-3, and GHBP in neonatal rats

ObjectiveExtremely low gestational age neonates requiring oxygen therapy for chronic lung disease experience repeated fluctuations in arterial oxygen saturation, or intermittent hypoxia (IH), during the first few weeks of life. These events are associated with a high risk for reduced growth, hypertension, and insulin resistance in later life. This study tested the hypothesis that IH, or intermittent hyperoxia have similar negative effects on the liver; somatic growth; and liver insulin-like growth factor (IGF)-I, IGF binding protein (BP)-3, and growth hormone binding protein (GHBP), regardless of resolution in normoxia or hyperoxia between episodes. DesignNewborn rats on the first day of life (P0) were exposed to two IH paradigms: 1) hyperoxia (50% O2) with brief hypoxia (12% O2); or 2) normoxia (21% O2) with hypoxia (12% O2); intermittent hypoxia (50% O2/21% O2); hyperoxia only (50% O2); or room air (RA, 21% O2). Pups were euthanized on P14 or placed in RA until P21. Controls remained in RA from P0-P21. Growth, liver histopathology, apoptosis, IGFI, IGFBP-3, and GHBP were assessed. ResultsPathological findings of the liver hepatocytes, including cellular swelling, steatosis, apoptosis, necrosis and focal sinusoid congestion were seen in the IH and intermittent hyperoxia groups, and were particularly severe in the 21–12% O2 group during exposure (P14) with no significant improvements during recovery/reoxygenation (P21). These effects were associated with induction of HIF1α, and reductions in liver IGFI, IGFBP-3, and GHBP. ConclusionsExposure to IH or intermittent hyperoxia during the first few weeks of life regardless of resolution in RA or hyperoxia is detrimental to the immature liver. These findings may suggest that interventions to prevent frequent fluctuations in oxygen saturation during early neonatal life remain a high priority.

Mother with Obesity Induced by High‐Fat Diet Impaired Autophagic Process and Induced Renal Lipid Accumulation in the Offspring

IntroductionThe prevalence of obesity has increased worldwide, and more women are entering obese pregnancy. The offspring born to maternal obesity have an increased risk of obesity and insulin resistance in later life and could affect offspring’s kidney injury. The abnormal renal lipid metabolism leads to renal lipid accumulation and these suggested to be the importance mechanism to develop and progress of chronic kidney disease (CKD). Lipophagy is the autophagic process to hydrolyze lipid droplet into free fatty acid for preserve energy and prevent an excess of lipid accumulation. The defect in lipophagy regulation is associated with renal lipid accumulation and contribute to kidney injury. Therefore, we hypothesized that maternal obesity induced by high‐fat diet programmed to increase offspring renal lipid accumulation via dysregulation of autophagic process and abnormal renal lipid metabolism leading to offspring’s kidney injury.MethodsFemale C57BL/6 mice were divided into two groups, control lean mother and maternal obesity groups, fed with standard and high‐fat diet, respectively, for 8 weeks. After that, female mice were mated with normal male mice and were housed and maintain each diet throughout gestation and lactation periods. After weaning, male offspring from each mother were sacrificed and blood samples and kidney were collected to evaluate autophagic and lipid metabolism.ResultsMaternal obesity was significantly increased body weight, fat weight, blood glucose and HOMA‐IR in the offspring. The increasing in renal cholesterol and triglyceride together with upregulated FAS, Srebp1, ADFP and CD36 protein expression indicating increased renal lipid synthesis and renal lipid uptake were observed in the offspring born to maternal obesity. Meanwhile, maternal obesity affected to downregulated PPARα and CPT1A demonstrating decreased renal lipolysis leading to exacerbated renal lipid accumulation in the offspring born to maternal obesity. The significant increase in mTOR, decrease in AMPK, Beclin‐1, LC3B and LAMP2 protein expression were shown in offspring’s kidney born to maternal obesity. These represented the inhibition of autophagic process, impaired autophagosome formation along with aberrant lysosome formation.ConclusionMaternal obesity affected to program offspring obese‐insulin resistance and increased the risk of kidney injury. The stimulation of renal lipogenesis and the suppression of renal lipolysis led to increased renal lipid accumulation. Moreover, maternal obesity induced impaired autophagic process by decreasing autophagosome formation and impaired lysosome formation. These alterations reduced the hydrolyzation of lipid droplet in the offspring’s kidney leading to more severity of renal lipid accumulation and resulting in offspring’s kidney injury.

Enhanced sensitivity to 4-hydroxynonenal and impaired redox signaling in human endothelial cells in gestational diabetes

Fetal exposure to gestational diabetes (GDM) in utero is strongly associated with a higher risk of cardiovascular disease and insulin resistance in later life, and accumulating evidence suggests this may be a consequence of fetal programming potentially involving epigenetic influences.1 Notably, offspring of mothers with GDM exhibit elevated blood pressure and reduced endothelium-dependent reactivity. We previously reported abnormal nitric oxide production, insulin resistance and reduced cell proliferation in fetal umbilical vein endothelial cells (HUVEC) from GDM pregnancies,2,3 and in parallel studies with endothelial cells from pre-eclamptic pregnancies, associated with in utero oxidative stress, identified abnormalities in NO production and regulation of [Ca2+]i.4,5 These phenotypic changes are maintained during culture, highlighting the involvement of fetal programming and epigenetics. As placental oxidative stress is propagated to the maternal and fetal vasculature via circulating lipid peroxides and H2O2 in GDM, we hypothesised that sustained oxidative stress in the fetal vasculature in utero may impair endogenous antioxidant defences. We established that activation of the redox sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)6 and its downstream target antioxidant enzymes is markedly inhibited in HUVEC from GDM pregnancies. Fetal endothelial cells exhibited marked deficits in glutathione synthesis, increased basal mitochondrial superoxide production, reduced nuclear translocation of Nrf2, and diminished adaptive increases in the expression of the Nrf2 target genes heme oxygenase-1 (HO-1) and/or NAD(P)H quinone oxidoreductase 1 (NQO1) in response to the lipid peroxidation product 4-hydroxynonenal (4-HNE). A proteomic analysis of normal and GDM HUVEC confirmed the altered GDM phenotype, characterised by markers of increased oxidative stress, reduced antioxidant protection and reduced cell proliferation.7 More recently, we have confirmed increased 4-HNE induced damage and attenuated Nrf2-regulated gene expression in umbilical artery smooth muscle cells from GDM mothers. The altered phenotype of fetal venous endothelial and arterial smooth muscle cells derived from GDM pregnancies may underlie an increased risk of developing type 2 diabetes and cardiovascular disease in childhood and early adulthood.8-12

Maternal and neonatal omentin-1 levels in gestational diabetes

PurposeTo evaluate the effect of gestational diabetes on omentin-1 in maternal and cord plasma. As a potent mediator of insulin resistance, Omentin-1, an adipokine derived from human adipose and placental tissue, may be an important player in the pathophysiology of gestational diabetes.MethodsThis was a prospective case–control study. The study included 96 women with gestational diabetes and 96 pregnant women without. Omentin-1 was measured at the time of the oral glucose tolerance test, at 32 weeks in maternal plasma and right after delivery in umbilical cord blood by ELISA assay.ResultsOver a period of 2 years, 200 patients were enrolled. Omentin-1 levels did not significantly differ between both groups throughout the pregnancy: omentin-1 levels were 157 ± 83 ng/ml in women with gestational diabetes and 158 ± 93 ng/ml in women without gestational diabetes (p = 0.94) at time of the oral glucose tolerance test and 118 ± 77 ng/ml in women with diabetes and 150 ± 89 ng/ml in women without (p = 0.12) at 32 weeks, respectively. Both groups showed a decrease in omentin-1 levels throughout pregnancy, with a more pronounced decrease in diabetic women (13 ± 53 versus 4 ± 48 ng/ml; p = 0.5). Neonatal omentin-1 levels were significantly lower in offspring of diabetic mothers: 106 ± 61 versus 134 ± 45 ng/ml (p = 0.03).ConclusionsThere was no significant difference in omentin-1 levels between healthy and diabetic mothers throughout the pregnancy. However, we found significantly lower omentin-1 levels in offspring of diabetic mothers. This may indicate a risk for the development of insulin resistance in later life.

Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring

Substantial evidence demonstrated that maternal dietary nutrients can significantly determine the susceptibility to developing metabolic disorders in the offspring. Therefore, we aimed to investigate the later-life effects of maternal and postweaning diets interaction on epigenetic modification of the central nervous system in the offspring. We examined the effects of dams fed a high-fat, high-sucrose (FS) diet during pregnancy and lactation and weaned to FS diet continuously until 32weeks of age. Then, DNA methylation and gene expressions of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in the offspring. Offspring of FS diet had heavier body weight, impaired glucose tolerance, decreased insulin sensitivity and higher serum leptin level at 32-week age (p < 0.05). The expression of POMC and MC4R genes were significantly increased in offspring exposed to FS diet during gestation, lactation and into 32-week age (p < 0.05). Consistently, hypomethylation of POMC promoter in the hypothalamus occurred in the FS diet offspring (p < 0.05), compared with the C group. However, no methylation was detected of MC4R promoter in both the two groups. Furthermore, POMC-specific methylation (%) was negatively associated with glucose response to a glucose load (r = -0.273, p = 0.039). Maternal and post-weaning high-fat diet predisposes the offspring for obesity, glucose intolerance and insulin resistance in later life. Our findings can advance our thinking around the DNA methylation status of the promoter of the POMC and MC4R genes between long-term high-fat, high-sucrose diet and glucose homeostasis in mouse.

Maternal nutrition restriction affects carbohydrate and lipid metabolism in adult rat offspring

Maternal food restriction in early development stages may program risks for adverse health outcomes in the adult offspring.We evaluated if the moderate caloric restriction (30%) in dams during gestation and/or lactation impairs the glucose and lipid metabolism of male adult offspring rats (16-week-old). No effect of maternal caloric restriction (CR) during gestation and lactation was observed in blood glucose and insulin levels and hepatic glycogen content of offspring. However, the area under the curve for the glucose tolerance test was greater (P= 0.044) in rats born to caloric restricted dams during gestation or lactation, that is suggestive of impaired glucose tolerance in these animals. Rats born to nutritional-restricted dams during gestation and lactation showed higher (P< 0.05)GLUT4 mRNA abundance in the epididymal adipose tissue than rats born to dams that were food-restricted only in the gestation. The CR during gestation and lactation resulted in slight but not significant reduction in the GLUT4 mRNA abundance (p=0.069) in the soleus muscle. The hepatic lipids content increased, whereas the adiposity index at 16 weeks of age decreased (P< 0.05) in rats born to dams that were nutritional-restricted during gestation and lactation. These data show that the moderate caloric restriction in gestation and lactation affects the glucose and lipid metabolism of the offspring, and may become it more susceptible to chronic diseases such as insulin resistance in later life. Research supported by FAPESP (2011/22011-9)

Early postnatal alteration of body composition in preterm and small-for-gestational-age infants: implications of catch-up fat

The concept of the developmental origins of health and disease is based on studies by Barker et al. They proposed a hypothesis that undernutrition in utero permanently changes the body's structure, function, and metabolism in ways that lead to atherosclerosis and insulin resistance in later life. In addition, profound effects on the extent of body fatness and insulin sensitivity are demonstrated, if there is a "mismatch" between prenatal and postnatal environments. In previous studies, undernutrition in utero has been evaluated simply by birth weight itself or birth weight for gestational age, and the degree of mismatch has been estimated by postnatal rapid weight gain. Recently, we investigated subcutaneous fat accumulation in small-for-gestational-age infants and found that a rapid catch-up in skinfold thickness developed prior to the body weight catch-up. Furthermore, insulin-like growth factor-I and lipoprotein lipase mass concentrations also demonstrate rapid increase during the neonatal period with fat accumulation. Investigating the precise mechanisms of developmental origins of health and disease including mediating metabolic and hormonal factors may provide a new approach to prevent atherosclerosis and insulin resistance. Better management of undernutrition during gestation and neonatal growth during the early postnatal period is an important theme for future health.

Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications.

Metformin is an effective oral anti-hyperglycaemic drug used as first-line medical treatment for type 2 diabetes. It improves systemic hyperglycaemia by reducing hepatic glucose production and enhancing peripheral insulin sensitivity. It also stimulates fat oxidation and reduces fat synthesis and storage. The molecular mechanism of this drug is thought to be secondary to its actions on the mitochondrial respiratory chain. This paper reviews the relevant literature (research articles up to October 2013) on the use of metformin in infertility, polycystic ovary syndrome (PCOS), pregnancy and gynaecological cancers. We present a comprehensive discussion of the evidence supporting the efficacy of metformin in these clinical conditions. Metformin is used clinically off-label in the management of hirsutism, acne and insulin resistance in PCOS, although the evidence for anti-androgenic effects is inconsistent. Metformin is also used to improve ovulation in women with PCOS both alone and in combination with clomiphene citrate. Trial findings are conflicting but metformin treatment in IVF/ICSI cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates. Metformin also appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight and obese women. Studies have shown that metformin is safe in pregnancy and women with GDM treated with metformin have less weight gain during pregnancy than those treated with insulin. One study with a 2-year follow-up demonstrated that babies born to women treated with metformin also developed less visceral fat, making them less prone to insulin resistance in later life. These findings have sparked interest in the use of metformin for pregnant, obese, non-diabetic women. On-going clinical trials are underway to determine if women treated prophylactically with metformin have a reduced incidence of GDM and demonstrate less weight gain during pregnancy. The hypothesis in these studies is that babies born to obese women on prophylactic metformin will also have better outcomes. Epidemiological studies have linked metformin exposure to a decreased risk of cancer. Pre-clinical experiments report that metformin has a growth-static effect on several cancers, including endometrial cancer, which may be partly due to the effect of metformin on the PI3K/AKT/mTOR signal transduction pathway. A number of on-going early phase clinical trials aim to explore the anti-cancer effects of metformin and investigate its potential as a chemopreventative or adjuvant treatment. Obesity is on the rise in developing countries and is strongly linked to several reproductive health problems, including PCOS, GDM and endometrial cancer. Traditional lifestyle measures aimed at weight reduction are challenging to implement and maintain. Metformin may be a valuable alternative to, or adjunct for, modifying the toxic effects of obesity in these populations. This review will appraise the evidence for the use of metformin for the prevention and treatment of adverse health outcomes in obstetrics and gynaecology.

The development and validation of a fast and robust dried blood spot based lipid profiling method to study infant metabolism.

Early life exposures and metabolic programming are associated with later disease risk. In particular lipid metabolism is thought to play a key role in the development of the metabolic syndrome and insulin resistance in later life. Investigative studies of metabolic programming are limited by the ethics and practicalities of sample collection in small infants. Dried blood spots on filter paper, derived from heel pricks are considered as the most suitable option for this age group. We validated a novel lipid profiling method, based on high resolution mass spectrometry to successfully determine the lipid composition of infants using dried blood spots. The spotting and air drying of blood on paper has noticeable effects on many of the lipids, leading to lipid oxidation and hydrolysis, which demand careful interpretation of the obtained data. We compared the lipid profiles from plasma or whole blood samples and the results from dried blood spots to determine if these revealed the same inter-subject differences. The results from dried blood spots were no less reproducible than other lipid profiling methods which required comparatively larger sample volumes. Therefore, lipid profiles obtained from dried blood spots can be successfully used to monitor infancy lipid metabolism and we show significant differences in the lipid metabolism of infants at age 3 versus 12 months.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-014-0628-z) contains supplementary material, which is available to authorized users.

Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms.

We determined the effects of maternal diet-induced obesity on offspring adipose tissue insulin signalling and miRNA expression in the aetiology of insulin resistance in later life. Although body composition and glucose tolerance of 8-week-old male offspring of obese dams were not dysregulated, serum insulin was significantly (p<0.05) elevated. Key insulin signalling proteins in adipose tissue were down-regulated, including the insulin receptor, catalytic (p110β) and regulatory (p85α) subunits of PI3K as well as AKT1 and 2 (all p<0.05). The largest reduction observed was in IRS-1 protein (p<0.001), which was regulated post-transcriptionally. Concurrently, miR-126, which targets IRS-1, was up-regulated (p<0.05). These two features were maintained in isolated primary pre-adipocytes and differentiated adipocytes in-vitro. We have therefore established that maternal diet-induced obesity programs adipose tissue insulin resistance. We hypothesise that maintenance of the phenotype in-vitro strongly suggests that this mechanism is cell autonomous and may drive insulin resistance in later life.

Effect of bisphenol A exposure during early development on glucose metabolism and adipokine expression in adolescent female rats

Accumulating evidences indicate that bisphenol A (BPA) exposure during early development increases the risk of obesity and insulin resistance in later life. Despite growing public concern, it is not totally clear about the mechanism of BPA. This study aimed to evaluate the effect of perinatal exposure to BPA on body weight, glucose metabolism and adipokine expression in adolescent female offspring rats. Pregnant rats were exposed to BPA in water at levels of either 1 μg/mL (LBPA) or 10 μg/mL (HBPA) from gestation day 6 to the end of lactation. Body weight, the levels of fasting serum glucose, insulin and adiponectin (ADP), and Zinc-alpha2-glycoprotein (ZAG) and ADP mRNA and protein expression from adipose tissue in 7 weeks old female offspring were measured. There were high birth weight and high body weight at age of 7 weeks in BPA treated group. There were significantly higher levels of serum glucose and insulin, and lower levels of serum ADP and plasma ZAG protein, and lower ADP and ZAG mRNA and protein expression in BPA-exposed female offspring compared with controls. The results suggested that BPA-exposed during early development had long-term deleterious effects on body weight and glucose metabolism, which was probably associated with the down-regulated expression of ZAG and ADP gene in early developmental female rats.

Does Cardiorespiratory Fitness Modify the Association between Birth Weight and Insulin Resistance in Adult Life?

ObjectiveLower birth weight is associated with higher insulin resistance in later life. The aim of this study was to determine whether cardiorespiratory fitness modifies the association of birth weight with insulin resistance in adults.MethodsThe subjects were 379 Japanese individuals (137 males, 242 females) aged 20–64 years born after 1943. Insulin resistance was assessed using a homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated from fasting blood glucose and insulin levels. Cardiorespiratory fitness (maximal oxygen uptake, VO2max) was assessed by a maximal graded exercise test on a cycle ergometer. Birth weight was reported according to the Maternal and Child Health Handbook records or the subject’s or his/her mother’s memory.ResultsThe multiple linear regression analysis revealed that birth weight was inversely associated with HOMA-IR (β = −0.141, p = 0.003), even after adjustment for gender, age, current body mass index, mean blood pressure, triglycerides, HDL cholesterol, and smoking status. Further adjustments for VO2max made little difference in the relationship between birth weight and HOMA-IR (β = −0.148, p = 0.001), although VO2max (β = −0.376, p<0.001) was a stronger predictor of HOMA-IR than birth weight.ConclusionsThe results showed that the association of lower birth weight with higher insulin resistance was little modified by cardiorespiratory fitness in adult life. However, cardiorespiratory fitness was found to be a stronger predictor of insulin resistance than was birth weight, suggesting that increasing cardiorespiratory fitness may have a much more important role in preventing insulin resistance than an individual’s low birth weight.

β-Cell Failure in Type 2 Diabetes: A Case of Asking Too Much of Too Few?

The islet in type 2 diabetes (T2DM) is characterized by a deficit in β-cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low β-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased β-cell workload results in T2DM in some but not all individuals. We propose that the extent of the β-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate β-cell mass in the face of subsequent insulin resistance may expose β-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising β-cell function and inducing β-cell apoptosis.

After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood

There is evidence that survivors of childhood cancers, such as acute lymphoblastic leukemia (ALL), have increased rates of long-term skeletal muscle dysfunction. This places them at higher risk of physical restriction and functional impairment as well as potentially contributing to observed increases in cardiovascular disease and insulin resistance in later life. The mechanisms underlying these changes in skeletal muscle are unknown but chemotherapy drugs used in treatment for ALL are strongly implicated. Normal skeletal muscle growth, development, and function are dependent on correctly functioning muscle satellite cells, muscle motor neurons, and muscle mitochondria. Each of these key components is potentially susceptible to damage by chemotherapy in childhood, particularly prolonged courses including repeated administration of combination chemotherapy. If this chemotherapy-induced damage is not fully reversible, impairment of satellite cells, muscle motor innervation, and mitochondria could, either singly or together, lead to the emergence of delayed or persistent skeletal muscle dysfunction many years later. The known effects of individual drugs used in the treatment of ALL are outlined and the need for specific targeted studies to investigate the mechanisms underlying persistent muscle dysfunction in survivors of ALL and other childhood cancers is highlighted.

The effect of preterm birth on adiposity and metabolic pathways and the implications for later life

The last few years have seen an increasing number of extremely preterm babies surviving to adulthood. The relationship between low birth weight, insulin resistance and Type 2 diabetes in adulthood is well established, but less is known regarding the effects of preterm birth on body composition and metabolic pathways. In this review, we consider the literature regarding the effects of prematurity on body composition in the neonatal period, infancy, childhood and adulthood. We also discuss prematurity and metabolic related changes including blood pressure and insulin resistance in later life. Although several studies suggest that ‘catch-up’ growth is the main factor influencing the risk of an adverse body composition and metabolic profile, there is growing evidence to indicate an independent effect of gestational age on liver fat content and blood pressure in adulthood. However, more research is needed regarding specific metabolic changes in adults born preterm.

The early origins of chronic heart failure: impaired placental growth and initiation of insulin resistance in childhood.

Low birth weight and low placental weight predict later coronary heart disease and hypertension. This has led to the hypothesis that these diseases are initiated by foetal programming, the process by which foetal malnutrition leads to permanent changes in the body in ways that lead to chronic disease in later life. Here we examine the association between body and placental size at birth and later chronic heart failure. We identified 187 patients taking medications for chronic heart failure in a birth cohort of 13,345 people born in Helsinki, Finland during 1934-44. Chronic heart failure was associated with a small placental surface area. In people born with a placental area less than 225 cm(2), the odds ratio for chronic heart failure was 1.7 (1.1-2.5), compared with people born with a placental area greater than 295 cm(2). The risk of heart failure was further increased by rapid gain in body mass index after the age of 2 years, a path of growth known to be linked to insulin resistance in later life. In a simultaneous regression, low body mass index at 2 years and high body mass index at 11 years were each associated with chronic heart failure (P = 0.008 and 0.001, respectively). Chronic heart failure in adult life may be initiated by impaired placental growth which adversely affects cardiac development. People born with a vulnerable heart are more likely to develop chronic heart failure if they become insulin resistant.

Moderate Caloric Restriction in Lactating Rats Protects Offspring against Obesity and Insulin Resistance in Later Life

We aimed to assess the lasting effects of caloric restriction in lactating rats on body weight and insulin sensitivity of their offspring. Dams were fed with either ad libitum standard diet or a 30% caloric restricted diet throughout lactation. After weaning, the offspring were fed with a normal-fat diet until the age of 15 wk, and then with a normal- or a high-fat (HF) diet until the age of 26 wk. Blood parameters were measured during ad libitum feeding conditions and after 14-h fasting. Food preferences were also measured. In dams, milk leptin concentration and leptin mRNA and protein levels in mammary gland were also determined. Caloric restricted dams showed higher mRNA and protein levels of leptin in mammary gland than controls, without significant changes in milk leptin concentration. The offspring of caloric restricted dams (CR) ate fewer calories and showed lower body weight gain and fat accumulation under the HF diet than their controls. CR also maintained unchanged circulating leptin levels under HF diet, whereas levels increased in controls. In addition, male CR were resistant to the increase of circulating triglycerides and of the homeostatic model assessment for insulin resistance produced in male controls under HF diet feeding; CR were also protected against the increased preference for fat-food occurring in females upon HF diet. These results suggest moderate caloric restriction during lactation protects from obesity development in offspring in adult life and from the related metabolic alterations, particularly dyslipidemia, insulin resistance, and hyperleptinemia, associated with HF diet feeding.

Relationships between early postnatal growth and metabolic function of 16-month-old female offspring born to ewes exposed to different environments during pregnancy.

It was hypothesized that exposure of the fetus to adverse conditions in utero due to either maternal constraint or nutrition may result in developmental adaptations altering metabolism and postnatal growth of the offspring. Heavy (H) and light (L) Romney dams (G0) were allocated to ad libitum (A) or maintenance (M) nutritional regimens, from day 21-day 140 of pregnancy. Female twin-born offspring (G1) born to the dams in the four treatment groups will be referred to as HA-ewes, LA-ewes, HM-ewes and LM-ewes. At 16 months of age, offspring were catheterized and given intravenous insulin tolerance test (ITT), glucose tolerance test (GTT) and epinephrine tolerance test challenges to assess their glucose and fat metabolism in relation to their birth weight and postnatal growth. In HA-ewes, the regression coefficients of growth rates prior to puberty on insulin and glucose curves in response to GTT (InsAUCGTT) and ITT (GluAUCITT), respectively, were different from 0 (P < 0.05) and were different from the regression coefficients of HM-ewes. This may indicate that HA-ewes may have showed puberty-related insulin resistance at 16 months of age with increasing growth rates prior to puberty compared to HM- or LM-ewes. In HM-ewes, the regression coefficients of growth rates after puberty on InsAUCGTT and GluAUCITT were different from 0 (P < 0.05) and were different from those of HA-ewes. These results may indicate that offspring born to heavy dams fed maintenance during pregnancy and with greater postnatal growth rates after puberty could develop glucose intolerance and insulin resistance in later life.

Human Fetal Adiponectin and Retinol-binding Protein (RBP)-4 Levels in Relation to Birth Weight and Maternal Obesity

Recent studies suggest that the perinatal period is a sensitive part in human development with respect to the pathogenesis of metabolic diseases in adulthood. Neonates, who are either small or large for gestational age (SGA or LGA) have a greater risk of developing obesity and insulin resistance in later life. The term "perinatal priming" is used to describe this phenomenon. Therefore, in the present study we first aimed to investigate if birth weight influences fetal adiponectin and RBP-4 metabolism. Umbilical cord blood was obtained form 40 neonates born on term+/-4 weeks and the adipokine concentrations in the serum were measured. In this analysis adiponectin but not RBP-4 levels showed a positive significant correlation to birth weight. Since maternal preconceptional obesity is associated with an increased birth weight and the risk for LGA neonates, we further aimed to investigate, if the maternal nutritional state influences fetal adiponectin and RBP-4. Therefore umbilical cord blood levels of the adipokines were correlated to maternal preconceptional BMI. In this analysis, neither adiponectin nor RBP-4 levels showed a significant correlation. Taken together, in the present study for the first time we directly compare fetal adiponectin and RBP-4 levels in respect to birth weight and maternal preconceptional BMI. Our data suggest that (1) adiponectin is more likely to have a role in perinatal priming of obesity and insulin resistance than RBP-4 and (2) that birth weight has a greater impact on fetal adipokine serum levels than maternal preconceptional obesity.

Dietary Fructose During the Suckling Period Increases Body Weight and Fatty Acid Uptake Into Skeletal Muscle in Adult Rats

The suckling period is one potentially "critical" period during which nutritional intake may permanently "program" metabolism to promote increased adult body weight and insulin resistance in later life. This study determined whether fructose introduced during the suckling period altered body weight and induced changes in fatty acid transport leading to insulin resistance in adulthood in rats. Pups were randomly assigned to one of four diets: suckle controls (SCs), rat milk substitute formula (Rat Milk Substitute), fructose-containing formula (Fructose), or galactose-containing formula (Galactose). Starting at weaning, all pups received the same diet; at 8 weeks of age, half of the SC rats began ingesting a diet containing 65% kcal fructose (SC-Fructose). This continued until animals were 12 weeks old and the study ended. At weeks 8, 10, and 11, the Fructose group weighed more than SC and SC-Fructose groups (P < 0.05). At weeks 8 and 10 of age, the Fructose group had significantly higher insulin concentrations vs. rats in the SC-Fructose group. (3)H-Palmitate transport into vesicles from hind limb skeletal muscle was higher in Fructose vs. SC rats (P < 0.05). CD36 expression was increased in the sarcolemma but not in whole tissue homogenates from skeletal muscle from Fructose rats (P < 0.05) suggesting a redistribution of this protein associated with fatty acid uptake across the plasma membrane. This change in subcellular localization of CD36 is associated with insulin resistance in muscle. Consuming fructose during suckling may result in lifelong changes in body weight, insulin secretion, and fatty acid transport involving CD36 in muscle and ultimately promote insulin resistance.