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Folkhälsan Research Center, University of Helsinki, Helsinki, Finland
Department of Obstetrics and Gynecology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore
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developmental trajectories and their associations with T2D in later life ( Table 1 ). Potential underlying mechanisms explaining the associations will not be discussed in greater details. Table 1 Developmental pathways and programming of type 2 diabetes
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programs ( Gomez-Lopez et al . 2010 , Pérez Leirós & Ramhorst 2013 ). In this context, the modulation of chemokines and their receptors selectively controls the recruitment of different leukocyte populations ( Bromley et al . 2008 , Fraccaroli et al
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Many epidemiological studies in diverse populations have demonstrated a link between low birth weight and subsequent disease. This evidence has given rise to the fetal origins hypothesis, which suggests that exposure of the fetus to an adverse environment in utero leads to permanent programming of tIssue function and a risk of cardiovascular disease. An alternative hypothesis is that low birth weight and adult cardiovascular disease are independent features of a genetic predisposition to cardiovascular disease. This review describes evidence that the programming phenomenon may not be limited to the first generation offspring. Results of human and animal studies identify intergenerational programmed effects on both birth weight and cardiovascular disease. This may represent a mechanism for the non-genetic inheritance of a predisposition to low birth weight and adverse cardiovascular risk across a number of generations.
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Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.
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In a previous study, we showed that exposure of rats to dexamethasone (Dex) selectively in late pregnancy produces permanent induction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression and hyperglycaemia in the adult offspring. The mechanisms by which glucocorticoids cause this programming are unclear but may involve direct actions on the fetus/neonate, or glucocorticoids may act indirectly by affecting maternal postnatal nursing behaviour. Using a cross-fostering paradigm, the present data demonstrate that switching the offspring at birth from Dex-treated dams to control dams does not prevent induction of PEPCK or hyperglycaemia. Similarly, offspring born to control dams but reared by Dex-treated dams from birth maintain normal glycaemic control. During the neonatal period, injection of saline per se was sufficient to cause exaggeration in adult offspring responses to an oral glucose load, with no additional effect from Dex. However, postnatal treatment with either saline or Dex did not alter hepatic PEPCK activity. Prenatal Dex permanently raised basal plasma corticosterone levels, but under stress conditions there were no differences in circulating corticosterone levels. Likewise, Dex-exposed rats had similar plasma catecholamine concentrations to control animals. These findings show that glucocorticoids programme hyperglycaemia through mechanisms that operate on the fetus or directly on the neonate, rather than via effects that alter maternal postnatal behaviour during the suckling period. The hyperglycaemic response does not appear to result from abnormal sympathoadrenal activity or hypothalamic-pituitary-adrenal response during stress.
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cardiometabolic health ( Dashe et al. 2009 , HAPO Study Cooperative Research Group 2010 ). The observation that an adverse in utero environment programmes the long-term health of the offspring, called developmental programming, is now well-evidenced with a
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Laboratory of Livestock Physiology, ILVO Animal Sciences Unit, Division of MeBioS, Animal Science Unit, Department of Biosystems, KU Leuven, Kasteelpark Arenberg 30 Box 2456, 3001 Leuven, Belgium
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Laboratory of Livestock Physiology, ILVO Animal Sciences Unit, Division of MeBioS, Animal Science Unit, Department of Biosystems, KU Leuven, Kasteelpark Arenberg 30 Box 2456, 3001 Leuven, Belgium
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displayed changes in several hepatic enzymes important in glucose homeostasis ( Desai et al . 1997 ), which could lead to the programing of adult offspring glucose tolerance. In young life, the offspring exhibited improved glucose tolerance compared with
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
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Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
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Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada
Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada
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depressive-like behavior ( Chapman et al. 2004 , Vargas et al. 2016 ) and anxiety ( Lajud et al. 2012 ), and alters decision-making, learning, and memory ( Bilbo et al. 2005 ). In addition, ELS programs the hypothalamic–pituitary–adrenal (HPA) axis
Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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DM , Oltavi ZN, Yin XM, Milliman CL & Korsmeyer SJ 1993 Bcl-2 functions in an antioxidant pathway to prevent programmed cell death. Cell 75 241 –251. Huh K , Kwon TH, Kim JS & Park JM 1998 Role of the hepatic
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control of maternal stress responses and fetal programming by stress in pregnancy . Progress in Neuro-Psychopharmacology and Biological Psychiatry 35 1178 – 1191 . ( https://doi.org/10.1016/j.pnpbp.2010.12.023 ) 10.1016/j.pnpbp.2010.12.023 Camps SG
