Table 2.
Manipulation | Species | Treated from | Birth and postnatal body weight | Postnatal age at study | Cohort examined | Postnatal phenotype | References |
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TOTAL CALORIE RESTRICTION | |||||||
30%UNˆ | Rat | D1-21 | ↓birth and postnatal weight Vickers et al., 2000 or catch-up growth Riviere et al., 2005 | 4 months | Male offspring | ↑blood pressure, food intake, plasma insulin, leptin, Ang II, aldosterone and adiposity ↓relative kidney and liver weights ↓nephron number |
Vickers et al., 2000; Riviere et al., 2005 |
↓birth and postnatal weight# | 4 months | Male offspring | Glucose intolerant Altered hypothalamic-regulatory system (POMC neurons sensitivity) ↑food intake, adiposity, plasma and adipose leptin, plasma corticosterone |
Breton et al., 2009; Lukaszewski et al., 2011, 2013 | |||
35%UN | Rat | D15-20 | ↓birth weight followed by catch-up growth | 4 months | Male offspring | ↑plasma FFA ↓hepatic Akt-1, Akt-2 and PKCζ expression and skeletal muscle GLUT4 expression |
Camm et al., 2011 |
50%UN | Rat | D1-D22 | ↓birth weight followed by catch-up growth at 3 weeks but normalized by 5 months | Birth to ~5 months | Male and female offspring | 2 days: ↓plasma leptin and insulin Early onset of puberty ↓plasma progesterone levels (females only) |
Sloboda et al., 2009; Smith et al., 2014 |
5 months: ↑plasma leptin and insulin, plasma lipase and cholesterol (males only), adiposity, absolute and relative liver weight ↓plasma IGF-1, IGFBP3, hepatic IGFBP1 and IGFBP3 expression |
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50%UN | Rat | D1-weaning | ↓birth and postnatal weight at 3 weeks and 5 months |
Birth to ~5 months | Male and female offspring | Early onset of puberty 5 months: ↑plasma leptin and insulin, adiposity, insulin resistant |
Sloboda et al., 2009 |
50%UNˆ | Rat | D10-21 | ↓birth weight followed by catch-up growth and ↑weight at 9–10 months | 1 day to 10 months | Female and/or male offspring | 1 day: ↓plasma glucose, insulin and triglyceride ↑lean mass ↓adipose FAS and HSL and ↑PPARγ2 expression ↓hepatic PPARα and PPARγ and ↑LPL, FAS and CRP expression ↓renal developmental and proliferation/apoptotic proteins (GFRAα1 and pERK1/2) Altered vascular ECM composition ↓branching angiogenesis, VEGF expression but ↑eNOS in microvessels ↓plasma leptin and E2, ↑LH ↑ovarian Ob-Rb, ↓ERα receptor and steroidogenic enzymes (HSD3B1, HSD3B2) ↓hypothalamic GnRH and ↑Ob-Rb and ERα receptor expression (females only) |
Desai et al., 2005b, 2007a,b, 2008; Khorram et al., 2007a,b, 2010, 2015; Magee et al., 2008; Henry et al., 2010; Tafti et al., 2011; Fukami et al., 2012; Alves et al., 2015 |
3 weeks: ↑adipocyte cell size and renal MEK1/2 expression ↓nephron number |
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50%UNˆ | Rat | D10-21 | ↓birth weight followed by catch-up growth and ↑weight at 9–10 months |
1 day to 10 months | Female and/or male offspring | 4–8 weeks: ↑food intake related to impaired leptin signaling and appetite-regulatory pathways in the hypothalamus (Ob-Rb and STAT3, assessed in males) | Desai et al., 2005b, 2007a,b, 2008; Khorram et al., 2007a,b, 2010, 2015; Magee et al., 2008; Henry et al., 2010; Tafti et al., 2011; Fukami et al., 2012; Alves et al., 2015 |
2 months: ↑blood pressure, altered vascular ECM composition | |||||||
3–4 months: ↑blood pressure and VEGF expression in vasculature Alterations in food preferences and behavioral-neurochemical responses to sweet food (↑TH content in OFC and/or NAcc) | |||||||
9 months: glucose intolerant, ↑plasma glucose, insulin, triglyceride and CRP ↑adiposity (↑adipocyte cell size) ↓lean mass and relative heart, kidney, adrenal, liver, lung and brain weights ↑adipose SREBP1C, PPARγ2, FAS, HSL, LPL expression ↓hepatic PPARα and PPARγ and ↑SREBP1, LPL and FAS expression ↑adrenal leptin expression and altered steroidogenic enzyme expression (males: ↑CYP11A1, CYP11B2, HSD1, Ob-Ra/Ob-Rb and GCR, ↓CYP17A1 expression; females: ↑CYP11A1, ACTH-R and Ob-Ra, ↓GR and CYP17A1 expression) |
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10 months: ↓plasma insulin, altered appetite-regulatory pathways in the hypothalamus (females only: ↑NPY, AgRP and pAMPK/AMPK and ↓POMC) Estrous cyclicity disrupted with ↓number of corpora lutea and small follicles ↑plasma LH, FSH and T and ↓E2 ↑E2 ovarian receptor, ↓Ob-Rb, LH receptor and steroidogeneic enzymes (CYP11A1, HSD-3β1, CYP19A1) ↑hypothalamic GnRH and ↓Ob-Rb and ERα receptors (females only) |
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50%UN | Rat | D10-weaning | ↓birth weight followed by catch-up growth and ↑weight at 9 months |
1 day, 3 weeks and 9 months | Male and female offspring | 1 day: ↑plasma ghrelin and ↓plasma leptin, glucose and triglyceride | Desai et al., 2005a,b, 2007b |
3 weeks: ↓adiposity, pancreas and liver weights, plasma glucose and insulin ↑lean mass, relative lung and brain weight and plasma cholesterol |
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4–8 weeks: ↑food intake | |||||||
9 months: Glucose intolerant, ↑plasma ghrelin, glucose, cholesterol ↓relative heart and kidney weights and plasma insulin |
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50%UN | Rat | D14-weaning | ↓birth weight in male offspring and ↓weight in both male and female offspring at 3 weeks | Birth to 1 month | Male and female offspring | 3 weeks: Delayed puberty onset ↓plasma leptin, adiposity, testicular and ovarian weights ↓plasma FSH (males only) Altered plasma FSH (males↓; females↑) ↑UCP1 expression and altered development of gonadal WAT (favored acquisition of a brown-like phenotype, males only) |
Leonhardt et al., 2003; Delahaye et al., 2010 |
50%UN | Rat | D14-weaning | ↓postnatal weight | Birth to 8 months | Male offspring | 1 day-2 weeks: ↓plasma CBG and leptin | Leonhardt et al., 2002; Lesage et al., 2002b; Sebaai et al., 2002a,b, 2004; Vieau et al., 2007; Delahaye et al., 2008; Coupe et al., 2009; Laborie et al., 2011; Wattez et al., 2014 |
2 weeks-1 month: ↓hypothalamic POMC expression and delayed BDNF expression and cell proliferation in the hippocampus and hypothalamus | |||||||
3–4 months: ↓plasma CBG, ↑plasma aldosterone and VP ↓absolute and ↑relative adrenal weight, ↓absolute kidney, thymus and liver weights Altered adrenal and kidney ANP receptor expression ↑adrenal POMC expression |
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3 weeks, 4 and 8 months: altered MR, GR expression in hippocampus, ↑plasma corticosterone | |||||||
6 months: ↑blood pressure, plasma leptin, impaired glucose tolerance, increased food intake ↓locomotor activity |
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8 months: ↓plasma catecholamines ↑adrenal POMC, hypothalamic VP and adrenal GR and PC2 expression Alterations in adrenal medulla noradrenergic chromaffin cell aggregation and cholinergic innervation ↓expression of genes involved in cytoskeleton remodeling and vesicle trafficking in adrenal medulla |
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10–30%UN | Guinea pig | -D28-birth | ↓birth and postnatal weight (males only) ↔female offspring |
Birth to 4 months | Male and female offspring | 3–4 months: ↑plasma cholesterol and insulin, blood pressure, adiposity, adrenal weight and food intake ↓glucose tolerance and lean mass (males only) |
Kind et al., 1999, 2002, 2003 |
LOW-PROTEIN DIET | |||||||
8% vs. 20% protein | Rat | D1-21 | ↔birth weight ↓postnatal weight at 2 months |
Up to 6 months | Male offspring | ↑blood pressure ↓mesenteric artery vasodilatory response |
Brawley et al., 2003 |
8% vs. 20% protein | Rat | D1-21 | ↔birth weight ↓postnatal growth rate |
1, 3 and/or 6 months | Male and female offspring | 1 and/or 3 months (males only at 3 months): ↑blood pressure ↑hepatic PPARα, GR, Acyl-CoA expression (related to changes in DNA methylation and/or histone modifications) ↑cardiac PPARα and CPT-1 mRNA expression (related to changes in PPARα DNA methylation) |
Lillycrop et al., 2005, 2007, 2008; Torrens et al., 2006; Burdge et al., 2007; Elmes et al., 2007, 2008; Rodford et al., 2008; Hoile et al., 2011; Slater-Jefferies et al., 2011 |
8% vs. 20% protein | Rat | D1-21 | ↔birth weight ↓postnatal growth rate |
1, 3 and/or 6 months | Male and female offspring | Impaired mesenteric artery vasodilatory response, ↑aorta eNOS expression (males only) ↓mesenteric artery smooth muscle content ↓hepatic HO-1 expression (males only) |
Lillycrop et al., 2005, 2007, 2008; Torrens et al., 2006; Burdge et al., 2007; Elmes et al., 2007, 2008; Rodford et al., 2008; Hoile et al., 2011; Slater-Jefferies et al., 2011 |
6 months: Impaired left ventricular developed pressure recovery during reperfusion following myocardial ischaemia (males only) | |||||||
Male offspring | 3 months: Altered hepatic transcriptome (e.g. ion transport, developmental processes, response to oxidative species and steroid hormones) ↓hepatic GR110 and PPARα DNA methylation, ↑hepatic PEPCK expression ↑blood pressure Impaired mesenteric artery vasodilatory response ↓aorta eNOS expression |
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Female offspring | 2.5 months: ↑plasma glucose, altered hepatic transcriptome | ||||||
8% vs. 20% protein | Rat | D1-21 | ↔birth weight ↓postnatal growth rate |
~1 to 6.5 months | Male and female offspring, F2 generation | ↑blood pressure in male and female F2 offspring at 3.5 months Impaired mesenteric artery vasodilatory response at 3.5 and 6.5 months in male F2 offspring (female offspring not assessed) | Torrens et al., 2008; Hoile et al., 2011 |
Male offspring, F2 generation | ↓hepatic GR110 and PPARα DNA methylation and ↑hepatic PEPCK expression | ||||||
Female offspring, F2 generation | ↑plasma glucose and altered hepatic transcriptome | ||||||
8% vs. 20% protein | Rat | D1-21 | ↔birth weight ↓postnatal growth rate |
2.5 months | Female offspring, F3 generation | Altered hepatic transcriptome | Hoile et al., 2011 |
6% vs. 20% protein | Rat | D1-21 | ↓birth and postnatal weight | 4 months | Female offspring | ↑blood pressure and plasma testosterone ↓plasma oestradiol and aorta ERα expression |
Sathishkumar et al., 2012 |
Not reported | 6 months | Female offspring | ↑blood pressure, plasma testosterone and vascular Agtr1/Agtr2 ratio Enhanced mesenteric artery contractile response to Ang II |
Sathishkumar et al., 2015 | |||
↓birth and postnatal weight | 12 months | Female offspring | ↓estrous cyclicity ↑blood pressure Greater hypotensive and hypertensive response ↑mesenteric artery contractility and ↓vasodilatory responses ↓NO-mediated vascular responsivity |
Sathishkumar et al., 2009 | |||
D4-21 | ↓birth weight followed by catch-up growth | 4 months | Male offspring | Glucose intolerant though ↑plasma insulin during glucose challenge ↑skeletal muscle IR and AS160 expression Defective phosphorylation of IRS-1 and GLUT4 translocation |
Blesson et al., 2014 | ||
5% vs. 19% protein | Rat | D1-22 | ↓birth weight followed by catch-up growth | 1 month | Male and female offspring | ↑hepatic and muscle glycogen ↓hepatic oxygen uptake, mitochondrial swelling and lipid peroxidation ↑hepatic ADP/O ratio |
Moraes et al., 2014 |
HIGH-CALORIE DIETS | |||||||
5.4x fat | Mouse | -D56-weaning | ↑postnatal weight at 3 weeks | 3 weeks and ~4.5 months | Male and female offspring | 3 weeks: ↑plasma triglycerides (males only) ↑liver weight and lipid accumulation, ↓fatty acid oxidation genes |
Mazzucco et al., 2016 |
4.5 months: ↑liver FFA (females only), liver weight and lipid accumulation, ↓CPT1 (males only) and ACO expression |
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12x fat | Mouse | -D28-weaning | ↑postnatal weight at 6 months | 6 and 12 months | Female offspring | 6 months: ↑plasma glucose, ↓bone mineral density | Liang et al., 2009b |
12 months: ↑plasma insulin and glucose, blood pressure, trabecular spacing, ↓trabecular connectivity density | |||||||
4.8x fat | Rat | D1-weaning | ↓birth weight followed by catch-up growth and ↑weight at 3 weeks and 5 months |
Birth to ~5 months | Male and/or female offspring | 2 days: ↓plasma leptin and insulin | Howie et al., 2009, 2013; Sloboda et al., 2009; Connor et al., 2010, 2012; Smith et al., 2014 |
3 weeks: ↑plasma insulin Early onset of puberty |
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4–5 months: ↑plasma leptin and insulin, adiposity, bone mineral content, absolute liver weight, insulin resistant ↓plasma IGF-1, IGFBP3, corticosterone (males only) ↓hepatic IGFBP1 and IGFBP3 expression, ↑plasma lipase and cholesterol (males only) ↑pancreatic INS1, INS2, IRS1, IRS2, IL-1R1 and CD68 (males only) ↑plasma progesterone levels and prolonged and persistent oestrus ↓testes: body weight ratio and ↑adrenal ACTH-R |
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4.8x fat | Rat | -D78-weaning | ↓birth and postnatal weight at 3 weeks | Birth to ~5 months | Male and/or female offspring | 3 weeks: ↑plasma insulin and food intake (to 2 months) Early onset of puberty ↑plasma progesterone |
Howie et al., 2009, 2013; Sloboda et al., 2009; Connor et al., 2010 |
5 months: ↑bone mineral content ↑pancreatic STAT3, TNF-α, CD68 and ↓PI3K expression |
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2.5x fat | Rat | D1-weaning | ↓birth weight followed by catch-up growth and ↑weight in adulthood |
Birth to ~5 months | Male and female offspring | 2 days: ↓plasma leptin and insulin Impaired hepatic proliferation (related to ↑expression and ↓DNA methylation of Cdkn1α, males only) |
Dudley et al., 2011 |
1 month: ↓liver and liver: brain weight ratio (males only) | |||||||
Excess of 20% fructose in drinking water | Rat | D1-P10 | ↑birth weight ↔postnatal weight at 10 days |
Birth to 10 days | Male and female offspring | 10 days: ↓absolute and relative liver and kidney weight ↑stomach content of leptin and ↓plasma insulin ↑hepatic triglycerides and SREBP1c expression |
Vickers et al., 2011; Clayton et al., 2015 |
Excess of 20% fructose in drinking water | Rat | D1-P10 | ↑birth weight ↔postnatal weight at 10 days |
Birth to 10 days | Male and female offspring | ↓hepatic SIRT1 expression (females only) Alterations in the expression of genes regulating beta oxidation and the inflammasome, particularly in males |
Vickers et al., 2011; Clayton et al., 2015 |
Excess of 10% fructose in drinking water | Rat | D1-D21 | ↔postnatal weight | 3 months | Male and female offspring | ↑retroperiotoneal adiponectin, FTO, MCP1 and TLR4 mRNA | Lineker et al., 2015 |
HYPOXIA | |||||||
12% hypoxia | Mouse | D14-19 | ↓birth weight of male and female offspring followed by catch-up growth | ~2.5 months | Male and female offspring | Impaired mesenteric artery vasodilatory response and ↓elastin content in aorta ↑mesenteric artery stiffness and collagen content in aorta (males only) |
Walton et al., 2015 |
13% hypoxia | Rat | D6-D20 | ↔birth weight | 4 months | Male offspring | ↓vasodilatory response of femoral arteries ↑myocardial contractility, LF/HF heart variability ratio, baroreflex gain and maximal and minimal heart rates |
Giussani et al., 2012; Kane et al., 2013 |
IRON RESTRICTION | |||||||
Iron restriction | Rat | -D21/28-birth | ↓birth and postnatal weight but greater growth rate between postnatal days 20 and 40 | 3 weeks and ~1.5 months | Not specified | 3 weeks: ↓blood pressure, ↑relative heart and kidney weights | Crowe et al., 1995 |
1.5 months: ↑blood pressure and relative heart and kidney weights | |||||||
Iron restriction | Rat | -D7-birth | ↓birth and postnatal weight | 3, 16, and 18 months | Male and female offspring | 3 months: ↑blood pressure and serum ACE, ↓serum triglyceride | Lewis et al., 2001c, 2002 |
16 months: ↑blood pressure and relative heart and kidney weights, glucose tolerance, ↓serum triglycerides | |||||||
UTERINE SUBSTRATE SUPPLY | |||||||
Uterine ligationˆ | Rat | D18 | ↓birth weight followed by catch-up growth (catch-up growth females only) | Birth to 18 months | Male and female offspring | ↔blood pressure or nephron number ↔vascular stiffness or reactivity (males only) ↔age of onset of puberty |
Wlodek et al., 2007, 2008; Siebel et al., 2008, 2010; Wadley et al., 2008, 2013; Moritz et al., 2009; Mazzuca et al., 2010, 2012; Black et al., 2012; Lauritz et al., 2012; Tare et al., 2012; Gallo et al., 2012a,b; Master et al., 2014; Romano et al., 2014, 2015; Tran et al., 2015 |
Uterine ligation† | Rat | D18 | ↓birth weight and postnatal weight | Birth to 18 months | Male and female offspring | ↑blood pressure and left ventricular mass, ↓nephron number ↓femur length, trabecular and cortical bone mineral contents, trabecular density and bone geometry measures Delayed onset of puberty, ↓plasma leptin levels at puberty onset and altered concentrations of sex steroids |
Wlodek et al., 2007, 2008; Siebel et al., 2008, 2010; Wadley et al., 2008, 2013; Moritz et al., 2009; Mazzuca et al., 2010, 2012; Black et al., 2012; Gallo et al., 2012a,b; Lauritz et al., 2012; Tare et al., 2012; Master et al., 2014; Romano et al., 2014, 2015; Tran et al., 2015 |
Female only phenotypes: Glomerular hypertrophy, ↑plasma creatine and renal TGF-β1, MMP-9 and collagen IV expression ↑HOMA and intramuscular triglycerides (6 months), ↓HOMA and improved insulin sensitivity (12 months) ↓relative islet and β-cell mass ↑plasma triglycerides, uterine artery stiffness and proportion of thick collagen fibers and ↓uterine artery relaxation ↑spatial memory Delayed developmental ↓cardiac PGC-1α and GLUT1 expression |
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Male only phenotypes: Impaired glucose tolerance and ↓insulin ecretion ↓skeletal muscle glycogen and mitochondrial regulators (PGC-1α, COX IV, mtTFA COX III) ↑mesenteric artery wall stiffness and impaired relaxation, ↓femoral artery relaxation ↑left ventricular Agtr1A receptor and collagen 3 expression ↓cardiomyocyte number and ↑cardiac Agtr1a, Agtr1b, Blc2 and C-myc expression Altered sensorimotor gating function and enhanced motor function Exacerbated ↓cardiac PGC-1α and mtTFA expression |
ACE, angiotensin converting enzyme; Acyl-CoA, acetyl coenzyme A; ACO, acyl-CoA oxidase; AgRP, Agouti-related peptide; Agtr, angiotensin II receptor; ACTHr, adrenocorticotropic hormone receptor; ADP/O, adenosine diphosphate/oxygen ratio; AMPK, activated protein kinase; Ang, angiotensin; Akt, protein kinase B; ANP, atrial natriuretic peptide; AS160, TBC1 domain family member 4; BDNF, brain derived neurotropic factor; Blc2, B-cell lymphoma 2; CBG, corticosterone-binding globulin; CD68, cluster of differentiation 68; Cdkn1α, cyclin-dependent kinase inhibitor 1α; COX, cytochrome oxidase; CPT-1, carnitine palmitoyltransferase I; CRP, c-reactive peptide; CYP, Cytochrome P450; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated protein kinase; ERα, estrogen receptor α; FAS, fatty acid synthase; FFA, free fatty acids; FSH, follicle stimulating hormone; FTO, fat mass and obesity-associated protein; GFRA, growth factor receptor alpha; GLUT, glucose transporter; GnRH, gonadotropin-releasing hormone; GR110, glucocorticoid receptor 1(10) promoter; GR, glucocorticoid receptor; HO, heme oxygenase; HOMA, homeostasis model assessment; HSD, hydroxysteroid dehyrodenase; HSL, hormone sensitive lipase; HSP, heat shock protein; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; INS, insulin; IR, insulin receptor; IRS, insulin receptor substrate; LF/HF, low/high frequency; LH, luteinizing hormone; LPL, lipoprotein lipase; MCP1, monocyte chemoattractant protein-1; MEK, mitogen-activated protein kinase; MMP, matrix metallopeptidase; MR, mineralocorticoid receptor; MtTFA, mitochondrial transcription factor A; NAcc, nucleus accumbens; NO, nitric oxide; NPY, neuropeptide Y; NT, nitro tyrosine; Ob-Ra, leptin receptor (short); Ob-Rb, leptin receptor (long); OFC, orbitofrontal cortex; P, postnatal; PC2, prohormone-convertase 2; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K, phosphoinositol-3 kinase; PKC, protein kinase C; POMC, proopiomelanocortin; PPAR, peroxisome proliferator-activated receptor; SIRT1, sirtuin 1; STAT3, signal transducer and activator of transcription 3; SREBP, sterol regulatory element binding protein; T, testosterone; TGF, transforming growth factor; TH, tyrosine hydroxylase; TLR, toll-like receptor; TNF, tumor-necrosis factor; UCP1, uncoupling protein 1; VEGF, vascular endothelial growth factor; VP, vasopressin; WAT, white adipose tissue.
Cross-fostered to ad libitum control dam,
dams allowed to eat ad libitum post-partum,
offspring cross-fostered to placentally-restricted dam.
Gestational age: mouse ~20 days, rats ~23 days, guinea pigs ~70 days.