Rosiglitazone improves pancreatic mitochondrial function in an animal model of dysglycemia: role of the insulin-like growth factor axis

Thiazolidinediones (TZDs) improve insulin sensitivity and maintain beta cell mass. This study examined whether this effect is attributable to improved mitochondrial function in the pancreas and the potential involvement of the pancreatic insulin-like growth factor (IGF) axis in mediating this effect. Female Wistar rats were given either saline (vehicle) or nicotine (1 mg kg?1 day?1) during pregnancy and lactation. Following weaning, nicotine-exposed offspring were randomized to receive either vehicle or rosiglitazone (3 mg kg?1 day?1) until 26 weeks of age when serum and pancreas tissue were collected. The effect of rosiglitazone on nicotine-induced mitochondrial dysfunction was also examined in vitro. Fetal and neonatal nicotine exposure resulted in structural and functional mitochondrial deficits relative to saline controls. The nicotine-induced mitochondrial defects were attenuated by postnatal rosiglitazone administration. A similar effect was observed in vitro; nicotine (25 ng/ml) inhibited beta cell mitochondrial function and co-treatment with rosiglitazone (1 μM) restored enzyme activity to control levels. Fetal and neonatal nicotine exposure also altered key components of the adult pancreatic IGF axis, an effect that was not prevented by rosiglitazone treatment. Rosiglitazone treatment maintains mitochondrial structure and function in the pancreas of rats that are prone to diabetes, as well as mitochondrial function in beta cell culture. We propose that this may be an important part of the mechanism by which rosiglitazone improves beta cell mass and prevents diabetes in individuals with impaired glucose tolerance and/or impaired fasting glucose. The underlying mechanism through which rosiglitazone targets the mitochondria remains to be determined, but does not appear to involve the IGF axis.     

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

Aims/hypothesis Epidemiological studies report an increased risk of obesity and type 2 diabetes in children born to women who smoked during pregnancy. This study examines the effect of fetal and neonatal exposure to nicotine, the major addictive component of cigarettes, on postnatal growth, adiposity and glucose homeostasis. Methods Female Wistar rats were given either saline (vehicle) or nicotine (1 mg kg⁻¹ day⁻¹) during pregnancy and lactation. Serum and pancreas tissue were collected from the infant rats at birth. Postnatal growth was assessed weekly until the rats reached 26 weeks of age and glucose homeostasis was examined by OGTTs performed at 7 and 26 weeks of age. Results Exposure to nicotine resulted in increased postnatal growth and adiposity. Nicotine exposure also resulted in dysglycaemia at 7 and 26 weeks of age. Serum insulin concentrations were decreased in the pups exposed to nicotine at birth. This was associated with increased beta cell apoptosis (pups of saline-treated mothers 8.8±1.21% apoptotic beta cells; pups of nicotine-treated mothers 27.8±3.1% apoptotic beta cells). Conclusions/interpretation Fetal and neonatal exposure to nicotine results in metabolic changes in the offspring that are consistent with obesity and type 2 diabetes. We propose that these metabolic changes may be a consequence of the initial insult to the beta cell during fetal life and that this animal model has many characteristics of diabetes in humans.     

Fetal and neonatal exposure to nicotine disrupts ovarian function and fertility in adult female rats

Women born to mothers who smoked during pregnancy have been shown to have imparied fertility, although the mechanisms underlying this association are unknown. Nicotine administration in adult animals has adverse effects on the ovary and uterus; however, the effects of fetal exposure to nicotine on postnatal ovarian function have not been determined. The goal of this study was to assess the effect of fetal and neonatal exposure to nicotine on ovarian function and fertility of the offspring. Nulliparous female Wistar rats were given 1 mg·kg⁻¹·d⁻¹ nicotine bitartrate, subcutaneously for 14 d prior to mating, during pregnancy and throughout lactation until weaning. Measures of fertility, breeding success, and serum levels of ovarian steroid hormones in offspring were assessed at 4 and 6 mo of age. Fetal and neonatal exposure to nicotine significantly increased the time to pregnancy as the animals aged. Similarly, evidence of altered ovarian steroidogenesis in cluding increased serum progesterone concentrations and a decreased estrogen: progesterone ratio was observed in 6-mo-old animals. We conclude that fetal and neonatal exposure to nicotine results in delayed ovarian dysfunction in adult female offspring.     

Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition

Epidemiological and clinical data show that rapid weight gain early in life is strongly associated with several components of the metabolic syndrome. Strikingly, abnormal growth rates in early life can additionally influence diabetes risk in subsequent generations. Here we aim to study whether neonatal overgrowth induces diabetes in offspring and grand-offspring of affected individuals using a mouse model of neonatal overfeeding. We induced neonatal overgrowth (ON-F0) by culling offspring to four pups per dam during lactation. By age 4 months, ON-F0 mice developed many features of the metabolic syndrome, including obesity, insulin resistance, and glucose intolerance. We then studied whether male offspring (ON-F1) and grand-offspring (ON-F2) of ON-F0 male mice, which were not overfed during lactation, developed features of the metabolic syndrome with aging. ON-F1 mice developed fed and fasting hyperinsulimemia, hypertryglyceridemia, insulin resistance, and glucose intolerance, but not obesity, by age 4 months. In contrast, ON-F2 male mice showed a more moderate phenotype and only developed fasting hyperglycemia and glucose intolerance by age 4 months. Impaired glucose tolerance in ON-F1 and ON-F2 mice appeared to be accounted for primarily by peripheral insulin resistance, because beta-cell function remained normal or even increased in these cohorts. Nutritional challenges occurring during sensitive periods of development may have adverse metabolic consequences well beyond the lifespan of affected individuals and manifest in subsequent generations. Transgenerational progression of metabolic phenotypes through the male lineage supports a potential role for epigenetic mechanisms in mediating these effects.     

Antenatal antipsychotic exposure induces multigenerational and gender-specific programming of adiposity and glucose tolerance in adult mouse offspring

Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.     

Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3

Fetal glucocorticoid excess programs detrimental effects in the adult phenotype including hyperleptinemia and aberrant glycemic control. In this study, we determined the interactive effects of maternal dexamethasone (Dex) treatment and postnatal dietary omega-3 (n-3) fatty acids on adult proinflammatory cytokine production and skeletal muscle expression of genes central to glucose handling and fatty acid metabolism. Dex acetate was administered to pregnant rats (0.75 microg/ml drinking water) from day 13 to term. Offspring of treated and control mothers were cross-fostered to mothers on either a standard (Std) or high n-3 (Hn3) diet, and remained on these diets postweaning. Adult offspring exposed to Dex in utero exhibited fasting hyperinsulinemia when raised on the Std diet but not when raised on the Hn3 diet. Dex also programmed increased plasma tumour necrosis factor alpha and interleukin 1 beta (IL-1 beta), but the increase in IL-1 beta was also prevented by the Hn3 diet. In skeletal muscle, expression of insulin regulated Slc2a4 (formerly known as GLUT4) was elevated (up to 15-fold) after Dex in utero, and this resulted in elevated intracellular, but not membrane-associated, SLC2A4 protein. Fetal glucocorticoid excess also reduced adult skeletal muscle Ucp3 expression in all offspring, whereas skeletal muscle expression of both Ppard and Ppargc1a were increased in females but not males. In conclusion, our data show that fetal glucocorticoid excess programs adult hyperinsulinemia and increased proinflammatory cytokine production. Related changes in the skeletal muscle Slc2a4, Ucp3, and Ppard indicate that fetal glucocorticoid excess disturbs adult glucose/fatty acid transport and metabolism.     

Interaction between maternal obesity and post-natal over-nutrition on skeletal muscle metabolism

Background and aimsMaternal obesity and post-natal over-nutrition play an important role in programming glucose and lipid metabolism later in life. The aim of this study was to decipher the contributions of maternal obesity and post-natal over-nutrition on glucose and lipid metabolism in skeletal muscle.Method and resultsMale offspring of Sprague Dawley rat mothers fed either chow or high fat diet (HFD) for 5 weeks prior to mating were subsequently fed either chow or HFD until 18 weeks of age. Collection of plasma and skeletal muscle was performed at weaning (20 days) and 18 weeks. At weaning, offspring from obese mothers showed increased body weight, plasma insulin and lactate concentrations associated with reduced skeletal muscle glucose transporter 4 (GLUT4) and increased monocarboxylate transporter 1 (MCT1) protein. In 18-week old offspring, post-weaning HFD further exacerbated the elevated body weight caused by maternal obesity. Surprisingly this additive effect on body weight was not reflected in plasma glucose, insulin, lactate and MCT1; these markers were only increased by post-weaning HFD consumption. However, an additive effect of maternal obesity and post-weaning HFD led to decreased muscle GLUT4 levels, as well as mRNA levels of carnitine palmitoyl transferase-1, myogenic differentiation protein and myogenin.ConclusionPost-weaning HFD exerted an additive effect to that of maternal obesity on body weight and skeletal muscle markers of glucose and lipid metabolism but not on plasma glucose and insulin levels, suggesting that maternal obesity and post-natal over-nutrition impair skeletal muscle function via different mechanisms.     

Transient in utero nicotine exposure stimulates mechanosensory-dependent lung development

Nicotine receptors are present in the developing lung yet their function is unknown. The transient role of nicotine receptors in lung development has not been addressed. In this study, nicotine's direct effect on smooth muscle contraction, necessary for mechanosensory-dependent fetal lung development, is examined after transient nicotine stimulation to determine the relationship between nicotine exposure, smooth muscle contraction, and fetal lung development. Rat fetuses at 16 days’ gestation were exposed in utero to 5 different concentrations of nicotine or control injected directly into the amniotic fluid. Specific concentrations of in utero nicotine increased the phosphorylated Western blot analysis and immunohistochemistry of muscle contraction proteins. Respiratory function tests on nicotine-exposed rat pups showed a statistically significant decrease in airway resistance earlier in life compared to control and an upward shift of the pressure-volume curve pointing towards a structural maturation of the in utero nicotine-exposed lung. These results are consistent with transient nicotine exposure during intrauterine life stimulating stretch-induced lung organogenesis by altering phosphorylation of muscle contraction proteins. The increase in smooth muscle phosphorylation may stimulate stretch-induced lung organogenesis, which affects lung development and accelerates lung maturation in rats.     

Glucose intolerance and resistin expression in rat offspring exposed to ethanol in utero: modulation by postnatal high-fat diet

High-fat diet and intrauterine growth retardation may predispose to obesity, insulin resistance, and type 2 diabetes. Because prenatal ethanol (ETOH) exposure causes intrauterine growth retardation, we investigated its interactions with postnatal high-fat diet on glucose tolerance and adipocyte-derived hormones in the rat offspring. High-fat-fed offspring had increased adiposity, serum leptin, and muscle uncoupling protein-3, but decreased adiponectin mRNA, compared with corresponding chow-fed groups. ETOH-exposed offspring had normal adiponectin, but increased resistin mRNA and protein, compared with controls, regardless of postnatal diet. Skeletal muscle glucose transporter-4 content was decreased after both ETOH exposure and high-fat feeding. Glycemic and insulin responses to an ip glucose challenge were equally increased in non-ETOH-exposed high-fat-fed offspring and in ETOH-exposed chow-fed offspring, with additive effects of ETOH and high-fat diet. Pancreatic insulin content was elevated only in non-ETOH-exposed high-fat-fed offspring. The data suggest that high-fat diet worsens glucose intolerance in offspring of rats exposed to ETOH. Prenatal ETOH exposure and postnatal high-fat diet might cause insulin resistance through separate mechanisms, involving resistin and adiponectin, respectively.     

Neonatal leptin treatment reverses developmental programming

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition.     

Consequences of fetal exposure to maternal diabetes in offspring

CONTEXT: Type 2 diabetes is the result of both genetic and environmental factors. Fetal exposure to maternal diabetes is associated with a higher risk of abnormal glucose homeostasis in offspring beyond that attributable to genetic factors, and therefore, may participate in the excess of maternal transmission of type 2 diabetes. Evidence acquisition: A MEDLINE search covered the period from 1960-2005. EVIDENCE SYNTHESIS: Human studies performed in children and adolescents suggest that offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and markers of insulin resistance. Recent studies that directly measured insulin sensitivity and insulin secretion have shown an insulin secretory defect even in the absence of impaired glucose tolerance in adult offspring. In animal models, exposure to a hyperglycemic intrauterine environment also led to the impairment of glucose tolerance in the adult offspring. These metabolic abnormalities were transmitted to the next generations, suggesting that in utero exposure to maternal diabetes has an epigenetic impact. At the cellular level, some findings suggest an impaired pancreatic beta-cell mass and function. Several mechanisms such as defects in pancreatic angiogenesis and innervation, or modification of parental imprinting, may be implicated, acting either independently or in combination. CONCLUSION: Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.     

Interaction between maternal and postnatal high fat diet leads to a greater risk of myocardial dysfunction in offspring via enhanced lipotoxicity,IRS-1 serine phosphorylation and mitochondrial defects

Maternal overnutrition is associated with heart diseases in adult offspring. However, combined effect of maternal and postnatal fat intake on cardiac function is unknown. This study was designed to examine the impact of maternal and postnatal fat intake on metabolic, myocardial, insulin and mitochondrial responses in adult offspring. Pregnant FVB mice were fed a low fat (LF) or high fat (HF) diet during gestation and lactation. Weaning male offspring were placed on either LF or HF (calorie-restricted HF-fed mice used as weight control) for 4 months prior to assessment of metabolic indices, myocardial histology, cardiac function, insulin signaling, mitochondrial integrity and reactive oxygen species (ROS) generation. Compared with LF- and HF-fed weight-control mice, postnatal HF intake resulted in obesity, adiposity, dyslipidemia, insulin resistance, cardiac hypertrophy, interrupted cardiac contractile, intracellular Ca^2 + and mitochondrial properties, all of which were significantly accentuated by prenatal fat exposure. Despite the preserved cardiac contractile function, LF offspring from HF-fed dams displayed higher body weights, increased adiposity and glucose intolerance. HF-fed mice with prenatal HF exposure displayed upregulated serine phosphorylation of IRS-1, PTP1B, the rate-limiting fatty acid synthesis enzyme stearoyl-CoA desaturase (SCD1) and hypertrophic markers (calcineurin A, GATA4, ANP, β-MHC and skeletal α-actin), while suppressing AMP-dependent protein kinase, glucose uptake and PGC-1α levels. Importantly, myocardial and mitochondrial ultrastructural abnormalities were more pronounced in HF-fed offspring with prenatal fat exposure, shown as loss of mitochondrial density and membrane potential, increased ROS generation and apoptosis. Our data suggest that prenatal dietary fat exposure predisposes offspring to postnatal dietary fat-induced cardiac hypertrophy and contractile defect possibly via lipotoxicity, glucose intolerance and mitochondrial dysfunction. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".     

Transgenerational effects of obesogenic diets in rodents: A meta-analysis

Obesity is a major health condition that affects millions worldwide. There is an increased interest in understanding the adverse outcomes associated with obesogenic diets. A multitude of studies have investigated the transgenerational impacts of maternal and parental obesogenic diets on subsequent generations of offspring, but results have largely been mixed. We conducted a systematic review and meta-analysis on rodent studies to elucidate how obesogenic diets impact the mean and variance of grand-offspring traits. Our study focused on transgenerational effects (i.e., F2 and F3 generations) in one-off and multigenerational exposure studies. From 33 included articles, we obtained 407 effect sizes representing pairwise comparisons of control and treatment grand-offspring groups pertaining to measures of body weight, adiposity, glucose, insulin, leptin, and triglycerides. We found evidence that male and female grand-offspring descended from grandparents exposed to an obesogenic diet displayed phenotypes consistent with metabolic syndrome, especially in cases where the obesogenic diet was continued across generations. Further, we found stronger evidence for the effects of grand-maternal than grand-paternal exposure on grand-offspring traits. A high-fat diet in one-off exposure studies did not seem to impact phenotypic variation, whereas in multigenerational exposure studies it reduced variation in several traits.     

Relationships of maternal and paternal birthweights to features of the metabolic syndrome in adult offspring: an inter-generational study in South India

Aims/hypothesis The association between lower birthweight and metabolic syndrome may result from fetal undernutrition (fetal programming hypothesis) and/or genes causing both low birthweight and insulin resistance (fetal insulin hypothesis). We studied associations between the birthweight of parents and metabolic syndrome in the offspring. Methods We identified men and women (aged 35–68 years), who had been born in Holdsworth Memorial Hospital, Mysore, India. We also identified the offspring (20–46 years) of these men and women. In total, 283 offspring of 193 mothers and 223 offspring of 144 fathers were studied. Investigations included anthropometry, oral glucose tolerance, plasma insulin and lipid concentrations and blood pressure. The metabolic syndrome was defined using WHO criteria. Results Among the offspring, lower birthweight was associated with an increased risk of glucose intolerance (impaired glucose tolerance, impaired fasting glucose or type 2 diabetes) and higher cholesterol and triacylglycerol concentrations (p < 0.05 for all adjusted for sex and age). Most outcomes in the offspring, including most individual components of the metabolic syndrome, were unrelated to parental birthweight. However, both maternal and paternal birthweight were inversely related to offspring metabolic syndrome (odds ratio [OR] 0.36 [95% CI: 0.13–1.01] per kg, p = 0.053 for mother–offspring pairs; OR 0.26 [0.07–0.93], p = 0.04 for father–offspring pairs, adjusted for offspring age, sex, BMI and socioeconomic status). Maternal birthweight was inversely related to offspring systolic blood pressure (β = −2.5 mmHg [−5.00 to 0.03] per kg maternal birthweight; p = 0.052). Conclusions/interpretation Factors in both parents may influence the risk of metabolic syndrome in their offspring. There are several possible explanations, but the findings are consistent with the fetal insulin (genetic) hypothesis. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Influence of maternal metabolic control and insulin antibodies on neonatal complications and B cell function in infants of diabetic mothers

Circulating insulin antibodies at birth and the degree of maternal metabolic control were measured in 68 infants of insulin-treated diabetic mothers. Their correlation with neonatal B cell function and with the clinical features of the infants was evaluated in order to better understand their influence on fetal outcome. Maternal metabolic control was assessed on the basis of blood glucose levels, glycosuria and the occurrence of hypoglycemia and/or ketonuria. All infants were clinically evaluated for gestational age, macrosomia, hypoglycemia, hyperbilirubinemia, hypocalcemia, and respiratory distress syndrome. Cord blood plasma glucose, C peptide, and IgG insulin antibodies were also measured. It was shown that poor maternal metabolic control was associated with a higher prevalence of fetal morbidity as well as with signs of B cell hyperfunction. Also the presence of circulating insulin antibodies correlated well with higher C peptide levels and with several neonatal complications. B cell hyperfunction, indicated by high C peptide levels in the infants of diabetic mothers, may possibly play a causal role in the pathogenesis of fetal morbidity. In conclusion, a good fetal outcome in insulin-treated diabetic pregnancies was associated with and may have depended upon: (1) good maternal metabolic control, and (2) absence or low levels of circulating insulin antibodies.     

Maternal antioxidants prevent β-cell apoptosis and promote formation of dual hormone-expressing endocrine cells in male offspring following fetal and neonatal nicotine exposure

Background: Fetal and neonatal nicotine exposure causes β‐cell oxidative stress and apoptosis in neonates, leading to adult‐onset dysglycemia. The aim of the present study was to determine whether an antioxidant intervention could prevent nicotine‐induced β‐cell loss. Methods: Nulliparous female Wistar rats received daily subcutaneous injections of either saline or nicotine bitartrate (1.0 mg/kg per day) for 2 weeks prior to mating until weaning. Nicotine‐exposed dams received either normal chow or diet containing antioxidants (1000 IU/kg vitamin E, 0.25% w/w coenzyme Q10, and 0.1% w/w α‐lipoic acid) during mating, pregnancy, and lactation; saline‐exposed dams received normal chow. Pancreatic tissue was collected from male offspring at 3 weeks of age to measure β‐cell fraction, apoptosis, proliferation, and the presence of cells coexpressing insulin and glucagon. Results: The birth weight of offspring born to nicotine‐exposed dams was significantly reduced in those receiving dietary antioxidants compared with those fed normal chow. Most interestingly, the antioxidant intervention to nicotine‐exposed dams prevented the β‐cell loss and apoptosis observed in nicotine‐exposed male offspring whose mothers did not receive antioxidants. Male pups born to nicotine‐treated mothers receiving antioxidants also had a tendency for increased β‐cell proliferation and a significant increase in islets containing insulin/glucagon bihormonal cells compared with the other two treatment groups. Conclusion: The present study demonstrates that exposure to maternal antioxidants protects developing β‐cells from the damaging effects of nicotine, thus preserving β‐cell mass.     

Chronic maternal nicotine exposure alters neuronal systems in the arcuate nucleus that regulate feeding behavior in the newborn rhesus macaque.

It is well known that maternal smoking during pregnancy can lead to low birth weight and low body fat in human newborns. The purpose of this study was to determine whether chronic maternal nicotine treatment alters levels of known regulators of energy balance in the newborn offspring. Pregnant rhesus monkeys were treated with nicotine tartrate (1.5 mg/kg x d) starting on d 26 of pregnancy and maintained through d 160 of gestation. Nicotine exposure had no significant effect on absolute birth weights of the neonatal monkeys, although there was a 10% reduction in birth weights with nicotine exposure when they were normalized to maternal weight. Postnatal d 1 plasma leptin levels were significantly reduced by about 50% in the nicotine treatment group compared with saline controls, suggesting that the infant monkeys exposed to nicotine may also have lower body fat levels. In situ hybridization studies demonstrated that chronic nicotine exposure resulted in a significant decrease in arcuate NPY mRNA expression in the neonatal monkeys. In addition, there was a 2-fold increase in POMC mRNA in the arcuate nucleus in the nicotine-exposed group. These data suggest that nicotine exposure during pregnancy may increase energy expenditure in the developing fetus through actions on hypothalamic systems, resulting in lower birth weights and body fat levels.     

Dissection of the metabolic actions of insulin in adipocytes from early growth-retarded male rats.

Numerous studies have shown a relationship between early growth restriction and Type 2 diabetes. Studies have shown that offspring of rats fed a low protein (LP) diet during pregnancy and lactation have a worse glucose tolerance in late adult life compared with controls. In contrast, in young adult life LP offspring have a better glucose tolerance which is associated with increased insulin-stimulated glucose uptake into skeletal muscle. The aim of the present study was to compare the regulation of glucose uptake and lipolysis in adipocytes by insulin in control and LP offspring. LP adipocytes had increased basal and insulin-stimulated glucose uptake compared with controls. There was no difference in basal rates of lipolysis. Isoproterenol stimulated lipolysis in both groups, but it was more effective on LP adipocytes. Insulin reduced lipolytic rates in controls to basal levels but had a reduced effect in LP adipocytes. Protein kinase B activity matched glucose uptake, with LP adipocytes having elevated activities. These results suggest that early growth retardation has long-term effects on adipocyte metabolism. In addition, they show selective resistance to different metabolic actions of insulin and provide insight into the mechanisms by which insulin regulates glucose uptake and lipolysis.     

Prolonged interleukin-6 administration enhances glucose tolerance and increases skeletal muscle PPARalpha and UCP2 expression in rats

Chronic elevations in interleukin (IL)-6 have been associated with insulin resistance, but acute IL-6 administration can enhance insulin sensitivity. Our aim was to exogenously administer IL-6 to rats to elicit either chronic or repeated acute elevations in systemic IL-6. We hypothesized that a continuous elevation of IL-6 would inhibit glucose tolerance and insulin sensitivity while acute intermittent elevations would improve it. Male Wistar rats were treated for 14d with recombinant human IL-6 (2.4 microy) or saline administered either by miniosmotic pump (continuous IL-6) or via twice-daily injection (intermittent IL-6). Glucose and insulin tolerance tests were performed following 14-d treatment and 24 h later rats were administered a bolus of insulin (150 mU/g) or saline intraperitoneally. Approximately, 10 min after insulin injection soleus, gastrocnemius and liver were excised and rapidly frozen in liquid nitrogen for subsequent metabolic measures. Irrespective of the mode of delivery, IL-6 treatment increased basal insulin sensitivity, as measured by the homeostatic model assessment of insulin resistance, and enhanced glucose clearance during an i.p. glucose tolerance test. IL-6 increased circulating fatty acids, but did not increase triglyceride accumulation in either skeletal muscle or liver, while it increased the protein expression of both PPARalpha and UCP2 in skeletal muscle, suggesting that IL-6 can enhance fat oxidation via mitochondrial uncoupling. These data demonstrate that, irrespective of the mode of delivery, IL-6 administration over 2 weeks enhances glucose tolerance. Our results do not support the notion that prolonged chronically elevated IL-6 impairs insulin action in vivo.