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The impact of maternal obesity on inflammatory processes and consequences for later offspring health outcomes

Part of: DOHaD ANZ Conference 2016

Published online by Cambridge University Press:  27 March 2017

S. A. Segovia Open the ORCID record for S. A. Segovia [Opens in a new window] ,
M. H. Vickers  and
C. M. Reynolds
S. A. Segovia*
Affiliation:
Liggins Institute, University of Auckland, Auckland, New Zealand
M. H. Vickers
Affiliation:
Liggins Institute, University of Auckland, Auckland, New Zealand
C. M. Reynolds
Affiliation:
Liggins Institute, University of Auckland, Auckland, New Zealand
*
*Address for correspondence: C.M. Reynolds, Liggins Institute, The University of Auckland, Auckland 1023, New Zealand. (Email c.reynolds@auckland.ac.nz)
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Abstract

Obesity is a global epidemic, affecting both developed and developing countries. The related metabolic consequences that arise from being overweight or obese are a paramount global health concern, and represent a significant burden on healthcare systems. Furthermore, being overweight or obese during pregnancy increases the risk of offspring developing obesity and other related metabolic complications in later life, which can therefore perpetuate a transgenerational cycle of obesity. Obesity is associated with a chronic state of low-grade metabolic inflammation. However, the role of maternal obesity-mediated alterations in inflammatory processes as a mechanism underpinning developmental programming in offspring is less understood. Further, the use of anti-inflammatory agents as an intervention strategy to ameliorate or reverse the impact of adverse developmental programming in the setting of maternal obesity has not been well studied. This review will discuss the impact of maternal obesity on key inflammatory pathways, impact on pregnancy and offspring outcomes, potential mechanisms and avenues for intervention.

Keywords

developmental programminginflammationinterventionsmaternal obesity

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Type
Review
Information
Journal of Developmental Origins of Health and Disease , Volume 8 , Issue 5: Themed Issue: Australian Perspectives: Outcomes from the 2016 ANZ , October 2017 , pp. 529 - 540
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2017 

Introduction

Obesity continues to be a global health concern. Although the increasing obesity rates in developed countries has slowed in the past 10 years, obesity rates in developing countries continue to increase, as much as tripling in some developing countries over the past 30 years.Reference Ng, Fleming and Robinson 1 , Reference Hossain, Kawar and El Nahas 2 This is largely attributed to a growing shift to a western lifestyle, including reduced physical activity and widespread availability of cheap and calorically dense food (typically high in sugar, salt and saturated fat).Reference Hossain, Kawar and El Nahas 2 , Reference Cordain, Eaton and Sebastian 3 Obesity is a major risk factor for a number of adverse health conditions [including type 2 diabetes (T2DM), hypertension, hypercholesterolemia, asthma, arthritis, some cancers and general poor health] and therefore represents a significant burden on the healthcare system.Reference Mokdad, Ford and Bowman 4

Rates of overweight and obesity in women of reproductive age can be as high as 64% depending on the population studied.Reference Wilson and Messaoudi 5 Being overweight or obese during pregnancy not only increases the risk of a number of obstetric and fetal complications,Reference Sebire, Jolly and Harris 6 , Reference Catalano and Ehrenberg 7 but predisposes these children to obesity and metabolic syndrome.Reference Whitaker 8 – Reference Vickers 11 Maternal obesity not only has immediate consequences, but has the potential to perpetuate a transgenerational cycle of obesity.Reference Vickers 11

There are a number of physiological differences between normal-weight and obese pregnancies. In normal-weight pregnancies, given fetal nutrient requirements, it is typical for a woman to undergo a reduction in insulin sensitivity, increased protein synthesis, and increased lipogenesis and fat accretion.Reference O’Reilly and Reynolds 12 Women who are obese while pregnant are more likely to become more insulin resistant earlier in pregnancy (and more likely to develop gestational diabetes)Reference O’Reilly and Reynolds 12 and have exaggerated increases in inflammatory cytokines, glucose, lipids and amino acids.Reference King 13 , Reference Ramsay, Ferrell and Crawford 14 Therefore, the developing fetus may be exposed to a combination of inflammatory cytokines and excess nutrition in utero, with lasting consequences in postnatal life.

Obesity in the non-pregnant state is associated with a state of chronic low-grade inflammation.Reference Lumeng and Saltiel 15 However, the role of maternal obesity-mediated changes in inflammatory processes as a mechanism underpinning developmental programming in offspring is not well defined. The use of anti-inflammatory agents as an intervention strategy to ameliorate or reverse the impact of adverse developmental programming in the setting of maternal obesity has not been well studied. This review will discuss the impact of maternal obesity on key inflammatory pathways, impact on pregnancy and offspring outcomes, potential mechanisms and avenues for intervention.

Obesity results in metabolic inflammation

Once traditionally considered an inert depot for energy storage, the white adipose tissue is now recognized as a highly metabolically active endocrine organ.Reference Kershaw and Flier 16 In the lean state, the adipose tissue maintains a state of homeostasis. Excess energy is stored as lipids in adipocytes, there is adequate vascularization to the tissue and a predominance of M2 alternatively activated macrophages which preferentially secrete the anti-inflammatory cytokine interleukin (IL)-10.Reference Lumeng, Bodzin and Saltiel 17 In general, as an individual becomes obese, the adipose tissue undergoes a number of key structural and functional alterations which can negatively impact whole-body metabolism. Adipocytes become enlarged and undergo hypertrophy (and/or hyperplasia) to cope with increased energy storage demands.Reference Drolet, Bélanger and Fortier 18 If the adipose tissue’s capacity to store lipid is exceeded, lipids may be ectopically stored in other tissues including the skeletal muscle and liver, which can promote local insulin resistance (IR) in these tissues.Reference Kim, Gavrilova and Chen 19 As the adipose tissue expands, vascularization of the tissue may become inadequate and hypoxia can occur.Reference Ye, Gao and Yin 20 There is an increased secretion of pro-inflammatory cytokines including tumor necrosis factor-α (TNFα), IL-6, IL-1β and monocyte chemoattractant protein-1 (MCP1), which cause an infiltration of M1 classically activated macrophages and further exacerbate inflammation.Reference Weisberg, McCann and Desai 21 , Reference Fain 22 The secretion of a number of adipose tissue-derived cytokines are also dysregulated. Circulating leptin (suppresses food intake and promotes energy expenditure) concentrations are increased,Reference Silha, Krsek and Skrha 23 while adiponectin (an insulin sensitizing hormone) concentrations are reduced.Reference Cnop, Havel and Utzschneider 24 In obesity, the complex interplay of these molecular alterations promote metabolic inflammation and IR in the adipose tissue, which also contributes to whole-body metabolic derangements.

However, these impairments may not necessarily occur in all obese individuals, as a significant proportion of obese individuals may be considered metabolically healthy.Reference Wildman, Muntner and Reynolds 25 This concept is under current debate, as metabolically healthy obese individuals are still at an increased risk of metabolic syndromeReference Mongraw-Chaffin, Foster and Kalyani 26 and mortalityReference Hinnouho, Czernichow and Dugravot 27 compared to non-obese healthy individuals, suggesting that metabolically healthy obesity is a transient state, before the progression to metabolic dysfunction.

Key cytokines involved in metabolic inflammation

The following section discusses some of the key cytokines involved in obesity-induced metabolic inflammation and their impact on insulin sensitivity in the non-pregnant state. Further research is required to understand how these cytokines become dysregulated in both the mother and her offspring as a result of maternal obesity.

TNFα

Hotamisligil et al.Reference Hotamisligil, Shargill and Spiegelman 28 was first to demonstrate that TNFα expression and secretion from adipose tissue was higher in obese compared with lean mice. Further, in vivo neutralization of TNFα increased insulin-stimulated glucose utilization in obese-diabetic rats. They also confirmed elevated TNFα expression in the adipose tissue of obese humans, which strongly correlated with the degree of hyperinsulinemia.Reference Hotamisligil, Arner and Caro 29 TNFα has since been shown as a major regulator of lipid metabolism, acting through multiple mechanisms, including increasing free fatty acid production, inducing lipolysis, inhibiting enzyme activity and regulating cholesterol metabolism.Reference Chen, Xun and Chen 30 In both high fat diet (HFD)-induced and genetic (ob/ob) models of obesity, TNFα knockout improves insulin sensitivity.Reference Uysal, Wiesbrock and Marino 31 However, ob/ob mice with knockout of TNFα receptors were still technically insulin resistant, implying that TNFα is not the only factor responsible for obesity-induced IR.

IL-1β

Chronic treatment of human and murine adipocytes with IL-1β inhibits insulin-induced phosphorylation of insulin receptor subunits and Akt, thus reducing insulin-stimulated glucose uptake and lipogenesis.Reference Lagathu, Yvan-Charvet and Bastard 32 IL-1β treatment also reduces lipid content in adipocytes, which may be due to a reduction in peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα), two key regulators of adipogenesis.Reference Lagathu, Yvan-Charvet and Bastard 32 HFD-induced obesity in mice lacking the IL-1 receptor I (IL-1RI) show improved glucose tolerance compared with their wildtype counterparts and are partially protected from developing IR.Reference McGillicuddy, Harford and Reynolds 33 Despite having no difference in M1 or M2 macrophage number, macrophages from IL-1RI knockout mice were less immunogenic, with reduced secretion of IL-6 and TNFα. Adipose tissue from obese IL-1RI knockout mice also had a less inflammatory phenotype compared with obese wildtype mice. Furthermore, in wildtype but not IL-1RI mice, there was synergism between TNFα and IL-1β to induce macrophage and adipose tissue inflammation.

IL-6

IL-6 has a pleiotropic hormone-like role, with functions dependent on the tissue, physiological state, and whether it is elevated acutely or chronically.Reference Kim, Bachmann and Chen 34 An estimated 15–35% of circulating IL-6 originates from adipose tissue.Reference Mohamed-Ali, Goodrick and Rawesh 35 Adipose tissue secretion of IL-6 can be 15-fold higher in insulin resistant individuals.Reference Rotter, Nagaev and Smith 36 Treating adipocytesReference Rotter, Nagaev and Smith 36 or hepatocytesReference Senn, Klover and Nowak 37 with IL-6 impairs insulin signaling. In contrast, upon exercise, the muscle secretes a large amount of IL-6, which can act on the liver (to maintain glucose homeostasis) and the adipose tissue (to promote lipolysis).Reference Pedersen, Steensberg and Schjerling 38 However, in large population studies (American Nurses’ Health Study), elevated IL-6 is a predictive indicator for later diabetes risk.Reference Hu, Meigs and Li 39 In a smaller study of morbidly obese patients who underwent gastric surgery, reduced circulating IL-6 was significantly correlated with a reduction in IR.Reference Kopp, Kopp and Festa 40 However, IL-6 knockout mice develop hypertrophic obesity, IR, hepatic inflammation and lipid accumulation.Reference Matthews, Allen and Risis 41

IL-10

In contrast to the pro-inflammatory cytokines, IL-10 has an anti-inflammatory or counter-regulatory role. IL-10 has been postulated to be protective against the development of T2DM and the metabolic syndrome in humans.Reference van Exel, Gussekloo and de Craen 42 In lipopolysaccharide-stimulated macrophages, IL-10 prevented the production of the cytokines TNFα and IL-6.Reference Fiorentino, Zlotnik and Mosmann 43 Lumeng et al.Reference Lumeng, Bodzin and Saltiel 17 have shown a number of beneficial effects of IL-10. IL-10 is highly expressed on M2 macrophages, with adipose tissue macrophages from obese mice having reduced IL-10 expression. Moreover, treatment of adipocytes with IL-10 resulted in rapid phosphorylation of Akt (which promotes glucose uptake) and also reduced adipocyte secretion of MCP1. In addition, pre-treatment of adipocytes with IL-10 prevented TNFα-induced downregulation of glucose transporter type 4 (GLUT4) and the insulin receptor and downregulation of insulin-stimulated glucose uptake.

Maternal obesity and metabolic inflammation

Pregnancy itself is associated with heightened systemic and adipose tissue inflammation.Reference Belo, Santos-Silva and Rocha 44 , Reference Zhang, Sugiyama and Murabayashi 45 However, in pregnancies complicated by obesity, the state of low-grade inflammation is greater in magnitude than observed in normal-weight pregnancies.Reference Ramsay, Ferrell and Crawford 14 , Reference Madan, Davis and Craig 46 – Reference Basu, Haghiac and Surace 48 Maternal obesity is associated with increased risk of pre-eclampsia and gestational diabetes mellitus, conditions in which inflammation is also inherently involved.Reference Kalagiri, Carder and Choudhury 49 Breastfeeding is generally considered to be protective against offspring obesity.Reference Arenz, Rückerl and Koletzko 50 However, breast milk composition is highly variable, and emerging research has revealed relationships between maternal obesity and increased pro-inflammatory factors in breast milk.Reference Panagos, Vishwanathan and Penfield-Cyr 51 Therefore, in multiple aspects, inflammation may represent a key mechanism mediating the adverse outcomes arising from maternal obesity.

Maternal obesity is also associated with dysregulation of a number of other circulating factors and hormones, which can contribute to developmental programming in offspring. In obesity, lipolysis and circulating free fatty acids are increased, potentially contributing to impaired insulin signaling through several mechanisms as recently reviewed by Morignya et al.Reference Morigny, Houssier and Mouisel 52 These include accelerating ectopic lipid deposition, altering adipose tissue adipokine secretion and/or further promoting adipose tissue inflammation.Reference Morigny, Houssier and Mouisel 52 Glucocorticoids may also act as a programming factor, as plasma glucocorticoids are increased in obese dams and offspring at postnatal days 2 and 110.Reference Zambrano and Nathanielsz 53 Concentrations of ghrelin, an appetite stimulating hormone, are reduced in human obesity.Reference Tschop, Weyer and Tataranni 54 Neonatal overnutrition in mice (by reducing litter size to increase milk consumption) programs obesity in offspring, concomitant with reductions in circulating ghrelin and potential ghrelin resistance.Reference Collden, Balland and Parkash 55 In addition, in human cohorts early life feeding choices, such early introduction of solids and breastfeeding, can impact obesity risk in offspring.Reference Arenz, Rückerl and Koletzko 50 , Reference Huh, Rifas-Shiman and Taveras 56

There is a long period of time required for the manifestation of metabolic disease in humans. Few human studies have been able to investigate the impact of maternal obesity-induced metabolic inflammation on long-term offspring adiposity and metabolic outcomes, with many studies only able to report associations between maternal inflammation and neonatal and early life outcomes. In a study of 18 mother–offspring pairs, Radaelli et al. Reference Radaelli, Uvena-Celebrezze and Minium 57 reported a significant correlation between maternal IL-6 concentrations at term and neonatal fat mass; however there was no correlation between cord blood IL-6 and neonatal fat mass. This suggested maternal inflammation may drive the increased risk of adiposity in offspring. McCloskey et al.Reference McCloskey, Ponsonby and Collier 58 reported a significant correlation between maternal pre-pregnancy body mass index (BMI) and maternal C-reactive protein (CRP) during the 28th week of gestation. Maternal pre-pregnancy BMI was significantly correlated with cord blood CRP and adiposity in newborns, suggesting that maternal pre-pregnancy obesity influences offspring adiposity, with inflammation likely a mediating factor. A longitudinal study in 1116 mothers–offspring pairs examined CRP as a biomarker of low-grade inflammation in maternal plasma during mid-pregnancy.Reference Gaillard, Rifas‐Shiman and Perng 59 Pre-pregnancy BMI was significantly associated with maternal CRP concentrations during mid-pregnancy. CRP concentrations were also associated with increased total and truncal fat mass in offspring aged 7–10 years, independent of maternal pre-pregnancy BMI and other confounding factors. Taken together, these studies demonstrate that maternal inflammation during pregnancy is linked to increased adiposity in offspring.

Several studies have also reported no association between maternal inflammation and offspring outcomes. A study in 71 pregnant women found that maternal IL-6 and IL-8 concentrations were significantly correlated with maternal adiposity at 28 weeks of gestation.Reference Farah, Hogan and O’Connor 60 However, maternal TNFα, IL-1β, IL-6 and IL-8 concentrations were not associated with fetal body composition at 28 and 37 weeks of gestation (assessed by ultrasound) or with birth weight. A recent study reported a significant correlation between maternal BMI and cord blood TNFα concentrations, however there was no correlation with offspring body weight at 9 months of age.Reference Toledo Baldi, Dias Bóbbo and Melo Lima 61 A study of 439 mother-offspring pairs reported no significant relationship of maternal CRP, TNFα, IL-1β or IL-6 measured during the third trimester of pregnancy and features of the metabolic syndrome in offspring at 20 years of age.Reference Danielsen, Granström and Rytter 62 However, this study was conducted in healthy, mostly normal-weight women and they adjusted for maternal pre-pregnancy BMI. In the absence of the physiological changes related to obesity, these findings may not necessarily be applicable to maternal obesity.

Animal models have been invaluable in elucidating the mechanisms underlying metabolic inflammation and developmental programming. Rodent models demonstrate that maternal immune activation during pregnancy results in enhanced immunogenic potential in offspring.Reference Onore, Schwartzer and Careaga 63 , Reference Kirsten, Lippi and Bevilacqua 64 Treatment of non-obese pregnant rats with endotoxin (mimicking infection or classic inflammation) results in obesity and IR in adult male offspring.Reference Nilsson, Larsson and Jennische 65 Therefore, it is plausible that low-grade inflammation resulting from maternal obesity could have a similar impact on offspring. In a model of HFD-induced obesity, pregnant dams had increased circulating TNFα concentrations, increased adipose tissue gene expression of TNFα and MCP1 and increased adipose tissue macrophage infiltration on day 17 of pregnancy.Reference Murabayashi, Sugiyama and Zhang 66 Fetuses had significantly higher insulin and glucose concentrations, accompanied by increased subcutaneous adipose tissue expression of TNFα and CD68 (macrophage marker) and reduced expression of the glucose transporter GLUT4. These findings suggest that offspring exposed to maternal obesity may have impaired insulin sensitivity via inflammatory mechanisms in the adipose tissue. Interestingly, Alfaradhi et al.Reference Alfaradhi, Kusinski and Fernandez-Twinn 67 have recently shown that maternal obesity programs adipose tissue inflammation in young mice without obesity, with altered expression of miRNAs as a potential mechanism.

Potential inflammatory mechanisms of developmental programming

The state of low-grade systemic and adipose tissue inflammation induced by maternal obesity is linked to a number of consequences that may contribute to developmental programming. Maternal adipose tissue inflammation can not only influence maternal insulin sensitivity, but it is also associated with aberrant secretion of adipose tissue-derived hormones. Animal and human evidence demonstrates that maternal obesity is associated with increased placental inflammation,Reference Challier, Basu and Bintein 68 , Reference Zhu, Du and Nathanielsz 69 which may contribute to abnormal placental function and/or nutrient transport. Therefore, the fetus may develop in an inflammatory environment which has the potential to impact development and lifelong health of the offspring. Adverse placental function may impact fetal nutrient supply and therefore development. Understanding the mechanisms underpinning developmental programming is key to identifying effective intervention strategies. However, the mechanisms are likely multifactorial in nature, with a range of mechanisms likely involved.

Dysregulation of adipose tissue-derived hormones

Obesity causes dysregulated secretion of hormones from the adipose tissue, which impact inflammatory processes and metabolic health. The two most well-defined adipose tissue-derived hormones are leptin and adiponectin.

Leptin is a hormone primarily secreted by adipocytes, which is released into the circulation, and acts on the brain to regulate long-term energy balance by suppressing food intake and increasing energy expenditure.Reference Halaas, Gajiwala and Maffei 70 Leptin also acts as a pro-inflammatory factor. Treating macrophages with leptin causes a significant upregulation of inflammatory cytokines including TNFα, IL-12 and IL-6.Reference Loffreda, Yang and Lin 71 Treating human placental explants with leptin results in significantly increased secretion of TNFα, IL-1β and IL-6.Reference Lappas, Permezel and Rice 72 Elevated plasma and cerebral spinal fluid leptin concentrations are associated with a higher body fat percentage and BMI,Reference Schwartz, Peskind and Raskind 73 indicating a central resistance to leptin in obesity.

In rodent models of maternal obesity, mothers and adult offspring commonly display hyperleptinemia.Reference Shankar, Harrell and Liu 74 Oben et al. Reference Oben, Mouralidarane and Samuelsson 75 demonstrated that obese dams had increased circulating leptin concentrations compared with lean dams, and therefore leptin may mediate programmed alterations to appetite regulation. The use of drugs or specific bioactive food components with anti-inflammatory properties, especially in the hypothalamus, may help to overcome leptin resistance.Reference Sáinz, González-Navarro and Martínez 76

Adiponectin is an adipose tissue-derived insulin sensitizing and anti-inflammatory protein. In contrast to leptin, adiponectin mRNA expressionReference Lihn, Bruun and He 77 and circulating concentrationsReference Park, Park and Kim 78 are inversely correlated to body fat, whereas reduced adiponectin is correlated with obesity, hyperlipidemia and IR.Reference Cnop, Havel and Utzschneider 24 Adiponectin’s insulin sensitizing activity is linked to its ability to increase fatty acid oxidation and inhibit hepatic gluconeogenesis.Reference Yamauchi, Kamon and Minokoshi 79 Adiponectin polarizes adipose tissue macrophages toward an M2 activated state, promoting the production of anti-inflammatory cytokines such as IL-10.Reference Ohashi, Parker and Ouchi 80

In models of maternal obesity, circulating concentrations of adiponectin are also reduced.Reference Jones, Woollett and Barbour 81 Aye et al. Reference Aye, Rosario and Powell 82 assessed the effects of adiponectin infusion during embryonic days 14.5–18.5 in mice fed a HFD before and during pregnancy. Adiponectin treatment did not affect maternal fat mass, but normalized maternal fasting leptin and insulin and fetal hyperglycemia with maternal obesity. Further, adiponectin normalized nutrient transport and insulin signaling in the placentas from mothers fed a HFD.

Placental inflammation and dysfunction

The placenta has a vital role during pregnancy, supplying the developing fetus with nutrients and oxygen from the mother to accommodate fetal development. Maternal obesity is associated with a lipotoxic placental environment, including increased lipid accumulation, reduced expression of angiogenic markers and increased expression of markers related to inflammation and oxidative stress.Reference Saben, Lindsey and Zhong 83

Challier et al.Reference Challier, Basu and Bintein 68 compared the placentas of obese and lean women at term. Obese women had increased circulating IL-6, CRP and leptin concentrations and increased IR. This was accompanied by increased accumulation of macrophages in the placenta and increased expression of IL-6, TNFα, IL-1β and MCP1 compared with lean women. The authors speculated that fetal exposure to an inflammatory environment might contribute to the programmed alterations observed in offspring following a maternal obesogenic environment. Interestingly, increases in maternal peripheral blood mononuclear (PBMC) inflammatory gene expression in obese women were not mirrored in the expression in umbilical PBMCs. In contrast, Dosch et al. Reference Dosch, Guslits and Weber 84 reported increased CRP and TNFα in umbilical cord plasma from class II obese women (BMI 35–39.99), as well as increased mononuclear secretion of TNFα, IL-1β and IL-6 when stimulated. Thus maternal obesity and the resulting placental inflammation may act as programming factors with or without directly inducing fetal inflammation.

Using a sheep model, Zhu et al. Reference Zhu, Du and Nathanielsz 69 examined whether maternal obesity-induced inflammatory changes in the placenta were evident in mid-gestation. Obese dams had increased expression of toll-like receptor (TLR)2, TLR4, CD11b, CD68, TNFα, IL-6, IL-8 and IL-16 in the cotyledonary tissue of their placentas, which was accompanied by increased NF-κB and JNK signaling. Fetuses from obese ewes had elevated free fatty acids, cholesterol and triglycerides in their circulation. These findings suggest that increased fatty acid uptake by the placenta may cause a TLR4-mediated activation of inflammatory pathways in the placenta.

Abnormal placentation and trophoblast differentiation and invasion can result in a number of complications, including those associated with maternal obesity such as pre-eclampsia and intrauterine growth restriction (IUGR).Reference Kroener, Wang and Pisarska 85 In maternal obesity, trophoblast invasion is altered and there is reduced remodeling of the spiral arteries.Reference Hayes, Tessier and Percival 86 These proposed changes occur as a result of the increased cytokines in maternal obesity. Elevated IL-6 concentrations also increase fatty acid accumulation in trophoblasts, which could contribute to increased fetal nutrient transfer.Reference Lager, Jansson and Olsson 87 Placentas from obese women are also more likely to have placental insufficiency, increased pathology including vascular lesions, villous lesions and fetal membrane meconium compared with placentas of women of normal weight.Reference Huang, Liu and Feng 88 In the rat, a maternal HFD results in fetal and placental junctional zone growth restriction, maternal and fetal hyperleptinemia but gene expression of markers of placental vascular development were not altered.Reference Mark, Sisala and Connor 89 It has also been shown experimentally that the inflammatory state of the placental labyrinth zone increases near term coincident with the known increase in local glucocorticoid concentrations. These data suggest that the classic anti-inflammatory actions of glucocorticoids do not occur in the placental labyrinth zone.Reference Mark, Lewis and Jones 90

Altered placental nutrient transport

Farley et al.Reference Farley, Choi and Dudley 91 found that obese pregnant women with hyperleptinemia and placental leptin resistance had decreased placental sodium-dependant neutral amino acid transporter activity. These changes did not affect birth weights, however it is unclear if these results were confounded by small sample size (only an n=7 women per group) or offspring sex. A larger cohort of over 400 women compared placental histopathology between normal and obese women. Independent of diabetes (T2DM and gestational), obese women had larger placentas, decreased placental efficiency, increased hypoxic stress, increased placental inflammation (measured by chronic villitis, increased vasculopathy of the decidua and a higher proportion of fetal overgrowth).Reference Leon-Garcia, Roeder and Nelson 92 The large sample size allowed the data to be stratified by offspring sex, revealing that in obese women placentas had greater inflammation when offspring were female rather than male. Ditchfield et al.Reference Ditchfield, Desforges and Mills 93 also demonstrated that obese women had decreased placental taurine transporter protein, which they speculated may reduce taurine concentration in the syncytiotrophoblast, thus hampering the development and function of the placenta, while also reducing taurine transport to the fetus. Obese women had increased lipoprotein lipase activity and placental expression of fatty acid translocase and reduced expression of fatty acid-binding protein (FABP) 1 and FABP3.Reference Dube, Gravel and Martin 94 Therefore in human obese pregnancy, a range of nutrient transporters have been shown to be altered. It is possible that these alterations affect nutrient supply to the fetus, contributing, at least in part, to the programmed effects in offspring.

Potential intervention strategies to prevent developmental programming

Developmental programming was once believed to result in permanent physiological effects that contributed to obesity and metabolic disease risk.Reference Langley-Evans 95 Accumulating evidence demonstrates the capability to ameliorate or reverse programming by targeted interventions during specific periods of developmental plasticity. In particular, intervention before pregnancy, during pregnancy or in the early life of offspring before disease has manifested appear to be the most effective times for intervention.Reference Hanson and Gluckman 96 The following section will discuss lifestyle, pharmaceutical and nutritional intervention strategies which have impacted maternal and/or offspring inflammatory status.

Maternal exercise

In addition to the benefits of weight loss, it has been proposed that the anti-inflammatory effects of exercise may partially contribute to the beneficial health effects of exercise.Reference Petersen and Pedersen 97 , Reference Ford 98 While there are a number of studies examining maternal exercise as an intervention in obese pregnancy, these studies have not thoroughly assessed inflammatory regulation in the mother and/or offspring in response to maternal exercise, highlighting a need for further research in this area.

In a Wistar rat model of maternal obesity, exercise improved maternal metabolism (circulating glucose, insulin, triglycerides and oxidative stress markers), and partially reduced triglycerides, fat mass and circulating leptin in P36 male (but not female) offspring.Reference Vega, Reyes-Castro and Bautista 99 Although this study demonstrated a clear benefit of maternal exercise independent of weight loss, it did not examine if inflammatory markers were altered. A recent study examined the impact of voluntary maternal exercise during pregnancy in HFD-induced obese mice.Reference Bae-Gartz, Janoschek and Kloppe 100 At postnatal day 21, male offspring from obese and obese exercised dams had similar weights and fat mass. However, male offspring from obese dams had impaired glucose tolerance and significantly increased circulating, hypothalamic and adipose tissue IL-6 expression, while these changes were blunted in offspring from obese exercised dams. Tinius et al. Reference Tinius, Cahill and Strand 101 compared obese women who were either active or inactive during late pregnancy. Maternal circulating CRP and circulating lipids were significantly higher in inactive obese women compared with active obese women. While there were no significant differences in offspring birth weight, fat mass, skin fold thickness or cord blood CRP, longer term follow-up is still required.

Pharmaceutical interventions

Exendin-4

Exendin-4 (EX4, an analog of glucagon-like peptide-1) is a hypoglycemic drug. Chen et al. Reference Chen, Simar and Pegg 102 treated male offspring from mothers who were fed either a control or HFD before and throughout pregnancy and lactation with EX4 (intraperitoneal injection of 15 μg/kg/day) at weaning for a period of 6 weeks. They found that EX4 administration to males was effective at reducing the programmed effects of a maternal HFD (increased adiposity, glucose intolerance and hyperlipidemia), and was beneficial when these offspring were fed a HFD postnatally. These improvements were accompanied by reduced adipose tissue expression of TNFα and hepatic expression of IL-6 and MCP1.

Pioglitazone

Pioglitazone is a thiazolidinedione which activates PPARγ, and has antidiabetic and anti-inflammatory effects.Reference Heliövaara, Herz and Teppo 103 In mice fed either a control or HFD for 3 months before and throughout gestation and lactation, pioglitazone administration to offspring daily between weeks 10 and 12 was effective at reducing body weight, visceral adipose tissue, triglycerides, insulin and increasing insulin sensitivity in male offspring.Reference Kalanderian, Abate and Patrikeev 104 The authors speculated that drugs which activate PPARγ may be beneficial in preventing developmental programming induced metabolic syndrome in offspring.

Metformin

Desai et al. investigated the effect of the antidiabetic drug metformin in a rat model of maternal obesity on maternal, placental and fetal outcomes. Metformin treatment did not significantly affect increased maternal weight, and altered lipid, insulin, leptin or cytokine concentrations associated with maternal obesity.Reference Desai, Roman and Rochelson 105 Fetal weight, litter size and placenta weight were not significantly affected by metformin treatment. Maternal metformin decreased inflammatory markers in both the placenta and the fetus. Direct treatment of metformin to the placental JAR cell line indicated that metformin inhibits inflammatory signaling by reducing TNFα dependent IL-6 production via the NF-κB pathway. Furthermore, in a similarly designed study by the same research group, maternal metformin treatment prevented a programmed increase in fetal hepatic inflammation.Reference Harris, Desai and Gupta 106 In a separate study prenatal exposure to metformin in HFD-fed mice was protective against weight gain when adult offspring were challenged with a period of HFD feeding.Reference Salomäki, Heinäniemi and Vähätalo 107

The EMPOWaR trial is a unique multicentre, double-blind randomized clinical trial investigating a preventative treatment for the adverse offspring outcomes associated with maternal obesity (in the absence of diabetes).Reference Chiswick, Reynolds and Denison 108 The primary study outcome, birth weight as a surrogate marker for later life health of offspring, was not significantly altered by maternal metformin.Reference Chiswick, Reynolds and Denison 109 However, researchers will follow-up the children for potential long-term effects of maternal metformin.

Nutritional interventions

Omega-3 polyunsaturated fatty acids (PUFAs)

Omega-3 PUFAs exhibit beneficial anti-inflammatory effects by regulating NF-κB-mediated inflammatory gene expressionReference Novak, Babcock and Jho 110 and lipid metabolism and adipogenesis through PPARs.Reference Neschen, Morino and Rossbacher 111 A number of studies have investigated their therapeutic potential in pregnancies complicated by maternal obesity.

Omega-3 PUFA supplementation reduces maternal adipose tissue and placental inflammation in obese pregnant women.Reference Haghiac, Yang and Presley 112 Treatment of human placental explants with physiologically relevant mixtures of omega-6 and omega-3 PUFAs, found no benefit of omega-3 PUFAs in reducing placental inflammation.Reference Melody, Vincent and Mori 113 Several human studies report no significant effects of maternal omega-3 PUFA intake on offspring body composition or cardiometabolic outcomes.Reference Moon, Harvey and Robinson 114 – Reference Brei, Stecher and Much 116 Indeed a meta-analysis has concluded that there is insufficient evidence that omega-3 PUFA supplementation during pregnancy or lactation reduces childhood adiposity.Reference Stratakis, Gielen and Chatzi 117 These findings may be due to the critical role of the omega-3 to omega-6 PUFA ratio in cardiometabolic disease.Reference Simopoulos 118 This ratio can vary among participants depending on the PUFA content of their diet (also population dependent) and with genetic variants in PUFA metabolism.Reference Simopoulos 119 However, there is still a need for more clinical trials with larger sample sizes and longer term follow-up.

In contrast, in animal models maternal omega-3 PUFAs have been shown to modulate adiposity and adipose tissue metabolism in offspring.Reference Heerwagen, Stewart and de la Houssaye 120 – Reference Bagley, Wang and Campbell 122 For example, male offspring from Fat-1 transgenic mice (capable of converting endogenous omega-6 PUFAs to omega-3 PUFAs) were protected from development of metabolic inflammation, and their offspring were protected from programmed adiposity, adipose tissue macrophage accumulation, IR and systemic inflammation.Reference Heerwagen, Stewart and de la Houssaye 120 In contrast, maternal omega-3 supplementation to a control diet has been shown to increase adiposity in male and female rat offspring.Reference Muhlhausler, Miljkovic and Fong 123 In a rat model of glucocorticoid-induced programming, postnatal administration of omega-3 PUFAs mitigated programmed hypertension and hyperlipidemia in male offspringReference Zulkafli, Waddell and Mark 124 and adipose tissue inflammation in male and female offspring.Reference Mark, Wyrwoll and Zulkafli 125 Post-weaning incorporation of fish oil into the diet prevented programmed dyslipidemia and liver steatosis in males in a high sucrose diet programming model.Reference Chicco, Creus and Illesca 126 In a model of uteroplacental insufficiency-induced IUGR, maternal administration of docosahexaenoic acid during pregnancy and lactation prevented programmed adiposity and alterations in PPARγ expression and increased circulating adiponectin concentrations in males but not females.Reference Balogun and Cheema 127

Omega-3 PUFA administration has been shown to be beneficial in a range of programming models, and effective during various exposure periods. Nevertheless, interpreting the current data is complicated given the differences in study design including range of doses used, timing of exposures and potential for sexually dimorphic outcomes in offspring. Consequently, there is still disagreement about the effectiveness of omega-3 PUFAs during pregnancy/lactation on reducing adiposity in offspring. Further research is warranted.Reference Muhlhausler, Gibson and Makrides 128 , Reference Mennitti, Oliveira and Morais 129

Conjugated linoleic acid (CLA)

CLA refers to a mixture of positional and geometrical isomers derived from the omega-6 PUFA linoleic acid (C18:2 cis-9, cis-12).Reference Kennedy, Martinez and Schmidt 130 CLA is naturally produced in ruminants through biohydrogenationReference Bauman, Baumgard and Corl 131 or endogenous synthesis in tissue.Reference Viladomiu, Hontecillas and Bassaganya-Riera 132 Meat and dairy products from cattle are one of the richest dietary sources of CLA.Reference Dhiman, Nam and Ure 133 A total of 28 isomers of CLA have been found, but the cis-9,trans-11 (c9,t11) and trans-10,cis-12 (t10,c12) isomers are the most common naturally occurring and bioactive isomers attributed to beneficial health effects.Reference Banni 134

There is strong evidence in animal models that administration of a mixture of the c9,t11 and t10,c12 isomers has anti-obesityReference West, Delany and Camet 135 , antidiabeticReference Houseknecht, Heuvel and Moya-Camarena 136 and anti-atheroscleroticReference Kritchevsky, Tepper and Wright 137 effects. While many studies administer a mixture, the two isomers actually have distinct functions.Reference de Roos, Rucklidge and Reid 138 The c9,t11 isomer is associated with anti-inflammatory effects in conditions including inflammatory bowel disease and T2DM.Reference Jaudszus, Krokowski and Mockel 139 – Reference Bassaganya-Riera, Reynolds and Martino-Catt 141 c9,t11-CLA has the capability to regulate gene expression as a potent ligand of the PPAR group of nuclear receptors which regulate the expression of genes involved in adipogenesis, inflammation and lipid metabolism.Reference Bassaganya-Riera, Reynolds and Martino-Catt 141 , Reference Belury, Moya-Camarena and Lu 142 c9,t11-CLA also modulates NF-κB activation,Reference Cheng, Lii and Chen 143 contributing to decreased pro-inflammatory cytokine production.Reference Reynolds, Loscher and Moloney 144 , Reference Reynolds, Draper and Keogh 145 The anti-obesity effects of CLA are linked to the t10,c12 isomer.Reference Park, Storkson and Albright 146

We have previously demonstrated that maternal CLA supplementation to a HFD during pregnancy and lactation significantly reduced maternal metabolic inflammation (circulating TNFα and IL-1β concentrations) during pregnancy, independent of changes in body weight.Reference Segovia, Vickers and Zhang 147 Furthermore, male and female offspring from HFD-fed dams displayed significantly reduced fetal size at gestation day 20, accelerated postnatal catch-up growth and impaired insulin sensitivity at postnatal day 24. These parameters were completely normalized in offspring from CLA-supplemented mothers on a HFD.

Discussion

The evidence that maternal obesity programs obesity and related metabolic complications in offspring is overwhelming. Obesity is an incredibly complex syndrome, with a number of key negative features. In the case of obese pregnancy, a complex interplay of these factors contribute to adverse developmental programming (Fig. 1). One of the key features of obesity is low-grade metabolic inflammation, which is maintained in pregnancy and induces inflammation in the placenta. While these relationships have been established there is a considerable gap in our knowledge of the precise role of inflammation and whether it directly contributes to developmental programming or simply arises a consequence of metabolic dysregulation.

Fig. 1

Summary of the impact of maternal obesity on inflammation. Maternal obesity (or maternal consumption of an obesogenic diet) can result in altered adipokine secretion, insulin resistance and/or increased circulating lipids in the mother. These alterations are associated with metabolic inflammation. Reducing maternal metabolic inflammation with anti-inflammatory agents may represent a key target for preventing developmental programming. Maternal metabolic inflammation is also linked to placental inflammation, altered placental nutrient transport and altered placental structure. These changes may mediate developmental programming of obesity and related metabolic conditions in offspring.

Given the consequences for offspring, there is growing interest in interventions which can mitigate developmental programming. These interventions typically aim to improve maternal metabolism and reduce body weight, however some have directly administered interventions to offspring in early life. There are limited numbers of studies which focus on the use of anti-inflammatory agents as an intervention strategy in the developmental programming paradigm. While some animal models show promise, many of the interventions that have been translated to human studies do not show the same clear benefits. Furthermore, many of these studies have reported sex-specific differences in offspring, underscoring a complexity in translating intervention strategies from animal models to humans. Further research is required to better understand the precise role of inflammation in developmental programming thereby allowing development of targeted interventions.

Acknowledgments

None.

Financial Support

SAS is funded by a Doctoral Scholarship from Gravida: National Centre for Growth and Development and CMR is funded by the Health Research Council of New Zealand (Sir Charles Hercus Research Fellowship 16/083 and Emerging Researcher 15/510). The authors also acknowledge funding support from the Marsden Fund of the Royal Society of New Zealand (12-UOA-015) and the Health Research Council of New Zealand.

Conflicts of Interest

The authors declare that that there is no conflict of interests regarding the publication of this paper.

References

1. Ng, M, Fleming, T, Robinson, M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014; 384, 766–781.Google Scholar
2. Hossain, P, Kawar, B, El Nahas, M. Obesity and diabetes in the developing world – a growing challenge. N Engl J Med. 2007; 356, 213–215.CrossRefGoogle ScholarPubMed
3. Cordain, L, Eaton, SB, Sebastian, A, et al. Origins and evolution of the western diet: health implications for the 21st century. Am J Clin Nutr. 2005; 81, 341–354.CrossRefGoogle Scholar
4. Mokdad, AH, Ford, ES, Bowman, BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003; 289, 76–79.CrossRefGoogle ScholarPubMed
5. Wilson, RM, Messaoudi, I. The impact of maternal obesity during pregnancy on offspring immunity. Mol Cell Endocrinol. 2015; 418, 134–142.CrossRefGoogle ScholarPubMed
6. Sebire, NJ, Jolly, M, Harris, J, et al. Maternal obesity and pregnancy outcome: a study of 287 213 pregnancies in London. Int J Obes (Lond). 2001; 25, 1175–1182.CrossRefGoogle Scholar
7. Catalano, PM, Ehrenberg, HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG. 2006; 113, 1126–1133.Google Scholar
8. Whitaker, RC. Predicting preschooler obesity at birth: the role of maternal obesity in early pregnancy. Pediatrics. 2004; 114, e29–e36.CrossRefGoogle ScholarPubMed
9. Boney, CM, Verma, A, Tucker, R, et al. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005; 115, e290–e296.Google Scholar
10. Yu, Z, Han, S, Zhu, J, et al. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: a systematic review and meta-analysis. PLoS One. 2013; 8, e61627.CrossRefGoogle ScholarPubMed
11. Vickers, M. Developmental programming and transgenerational transmission of obesity. Ann Nutr Metab. 2014; 64, 26–34.Google Scholar
12. O’Reilly, JR, Reynolds, RM. The risk of maternal obesity to the long‐term health of the offspring. Clin Endocrinol (Oxf). 2013; 78, 9–16.CrossRefGoogle Scholar
13. King, JC. Maternal obesity, metabolism, and pregnancy outcomes. Annu Rev Nutr. 2006; 26, 271–291.Google Scholar
14. Ramsay, JE, Ferrell, WR, Crawford, L, et al. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocr Metab. 2002; 87, 4231–4237.CrossRefGoogle ScholarPubMed
15. Lumeng, CN, Saltiel, AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011; 121, 2111–2117.Google Scholar
16. Kershaw, EE, Flier, JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004; 89, 2548–2556.Google Scholar
17. Lumeng, CN, Bodzin, JL, Saltiel, AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007; 117, 175–184.Google Scholar
18. Drolet, R, Bélanger, C, Fortier, M, et al. Fat depot‐specific impact of visceral obesity on adipocyte adiponectin release in women. Obesity. 2009; 17, 424–430.Google Scholar
19. Kim, JK, Gavrilova, O, Chen, Y, et al. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem. 2000; 275, 8456–8460.Google Scholar
20. Ye, J, Gao, Z, Yin, J, et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007; 293, E1118–E1128.CrossRefGoogle Scholar
21. Weisberg, SP, McCann, D, Desai, M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112, 1796–1808.CrossRefGoogle ScholarPubMed
22. Fain, JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006; 74, 443–477.Google Scholar
23. Silha, JV, Krsek, M, Skrha, JV, et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol. 2003; 149, 331–335.Google Scholar
24. Cnop, M, Havel, P, Utzschneider, K, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003; 46, 459–469.Google Scholar
25. Wildman, RP, Muntner, P, Reynolds, K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med. 2008; 168, 1617–1624.CrossRefGoogle ScholarPubMed
26. Mongraw-Chaffin, M, Foster, MC, Kalyani, RR, et al. Obesity severity and duration are associated with incident metabolic syndrome: evidence against metabolically healthy obesity from the multi-ethnic study of atherosclerosis. J Clin Endocrinol Metab. 2016; 101, 4117–4124.Google Scholar
27. Hinnouho, GM, Czernichow, S, Dugravot, A, et al. Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter? Diabetes Care. 2013; 36, 2294–2300.Google Scholar
28. Hotamisligil, GS, Shargill, NS, Spiegelman, BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259, 87–91.CrossRefGoogle ScholarPubMed
29. Hotamisligil, GS, Arner, P, Caro, JF, et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95, 2409–2415.CrossRefGoogle ScholarPubMed
30. Chen, X, Xun, K, Chen, L, et al. TNF‐α, a potent lipid metabolism regulator. Cell Biochem Funct. 2009; 27, 407–416.Google Scholar
31. Uysal, KT, Wiesbrock, SM, Marino, MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature. 1997; 389, 610–614.CrossRefGoogle ScholarPubMed
32. Lagathu, C, Yvan-Charvet, L, Bastard, J, et al. Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes. Diabetologia. 2006; 49, 2162–2173.Google Scholar
33. McGillicuddy, FC, Harford, KA, Reynolds, CM, et al. Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis. Diabetes. 2011; 60, 1688–1698.Google Scholar
34. Kim, J, Bachmann, RA, Chen, J. Interleukin‐6 and insulin resistance. Vitam Horm. 2009; 80, 613–633.CrossRefGoogle ScholarPubMed
35. Mohamed-Ali, V, Goodrick, S, Rawesh, A, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo 1. J Clin Endocrinol Metab. 1997; 82, 4196–4200.Google ScholarPubMed
36. Rotter, V, Nagaev, I, Smith, U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003; 278, 45777–45784.Google Scholar
37. Senn, JJ, Klover, PJ, Nowak, IA, et al. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002; 51, 3391–3399.Google Scholar
38. Pedersen, BK, Steensberg, A, Schjerling, P. Muscle‐derived interleukin‐6: possible biological effects. J Physiol (Lond). 2001; 536, 329–337.CrossRefGoogle ScholarPubMed
39. Hu, FB, Meigs, JB, Li, TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004; 53, 693–700.CrossRefGoogle ScholarPubMed
40. Kopp, HP, Kopp, CW, Festa, A, et al. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol. 2003; 23, 1042–1047.Google Scholar
41. Matthews, V, Allen, T, Risis, S, et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia. 2010; 53, 2431–2441.Google Scholar
42. van Exel, E, Gussekloo, J, de Craen, AJ, et al. Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. Diabetes. 2002; 51, 1088–1092.Google Scholar
43. Fiorentino, DF, Zlotnik, A, Mosmann, TR, et al. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991; 147, 3815–3822.Google Scholar
44. Belo, L, Santos-Silva, A, Rocha, S, et al. Fluctuations in C-reactive protein concentration and neutrophil activation during normal human pregnancy. Eur J Obstet Gynecol Reprod Biol. 2005; 123, 46–51.CrossRefGoogle ScholarPubMed
45. Zhang, L, Sugiyama, T, Murabayashi, N, et al. The inflammatory changes of adipose tissue in late pregnant mice. J Mol Endocrinol. 2011; 47, 157–165.Google Scholar
46. Madan, JC, Davis, JM, Craig, WY, et al. Maternal obesity and markers of inflammation in pregnancy. Cytokine. 2009; 47, 61–64.Google Scholar
47. Retnakaran, R, Hanley, AJ, Raif, N, et al. C-reactive protein and gestational diabetes: the central role of maternal obesity. J Clin Endocrinol Metab. 2003; 88, 3507–3512.CrossRefGoogle ScholarPubMed
48. Basu, S, Haghiac, M, Surace, P, et al. Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation. Obesity. 2011; 19, 476–482.Google Scholar
49. Kalagiri, RR, Carder, T, Choudhury, S, et al. Inflammation in complicated pregnancy and its outcome. Am J Perinatol. 2016; 14, 1337–1356.Google Scholar
50. Arenz, S, Rückerl, R, Koletzko, B, et al. Breast-feeding and childhood obesity – a systematic review. Int J Obes. 2004; 28, 1247–1256.CrossRefGoogle ScholarPubMed
51. Panagos, P, Vishwanathan, R, Penfield-Cyr, A, et al. Breastmilk from obese mothers has pro-inflammatory properties and decreased neuroprotective factors. J Perinatol. 2016; 36, 284–290.CrossRefGoogle ScholarPubMed
52. Morigny, P, Houssier, M, Mouisel, E, et al. Adipocyte lipolysis and insulin resistance. Biochimie. 2016; 125, 259–266.CrossRefGoogle ScholarPubMed
53. Zambrano, E, Nathanielsz, PW. Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies. Nutr Rev. 2013; 71(Suppl. 1), S42–S54.Google Scholar
54. Tschop, M, Weyer, C, Tataranni, PA, et al. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001; 50, 707–709.CrossRefGoogle ScholarPubMed
55. Collden, G, Balland, E, Parkash, J, et al. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Mol Metab. 2015; 4, 15–24.Google Scholar
56. Huh, SY, Rifas-Shiman, SL, Taveras, EM, et al. Timing of solid food introduction and risk of obesity in preschool-aged children. Pediatrics. 2011; 127, e544–e551.CrossRefGoogle ScholarPubMed
57. Radaelli, T, Uvena-Celebrezze, J, Minium, J, et al. Maternal interleukin-6: marker of fetal growth and adiposity. J Soc Gynecol Investig. 2006; 13, 53–57.CrossRefGoogle ScholarPubMed
58. McCloskey, K, Ponsonby, A, Collier, F, et al.The association between higher maternal pre‐pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn. Pediatr Obes. 2016. https://doi.org/10.1111/ijpo.12187.CrossRefGoogle Scholar
59. Gaillard, R, Rifas‐Shiman, SL, Perng, W, et al. Maternal inflammation during pregnancy and childhood adiposity. Obesity. 2016; 24, 1320–1327.CrossRefGoogle ScholarPubMed
60. Farah, N, Hogan, AE, O’Connor, N, et al. Correlation between maternal inflammatory markers and fetomaternal adiposity. Cytokine. 2012; 60, 96–99.CrossRefGoogle ScholarPubMed
61. Toledo Baldi, E, Dias Bóbbo, V, Melo Lima, M, et al. Tumor necrosis factor‐alpha levels in blood cord is directly correlated with the body weight of mothers. Obes Sci Pract. 2016; 2, 210–214.Google Scholar
62. Danielsen, I, Granström, C, Rytter, D, et al. Subclinical inflammation during third trimester of pregnancy was not associated with markers of the metabolic syndrome in young adult offspring. Obesity. 2014; 22, 1351–1358.CrossRefGoogle Scholar
63. Onore, CE, Schwartzer, JJ, Careaga, M, et al. Maternal immune activation leads to activated inflammatory macrophages in offspring. Brain Behav Immun. 2014; 38, 220–226.Google Scholar
64. Kirsten, TB, Lippi, LL, Bevilacqua, E, et al. LPS exposure increases maternal corticosterone levels, causes placental injury and increases IL-1Beta levels in adult rat offspring: relevance to autism. PLoS One. 2013; 8, e82244.Google Scholar
65. Nilsson, C, Larsson, B, Jennische, E, et al. Maternal endotoxemia results in obesity and insulin resistance in adult male offspring 1. Endocrinology. 2001; 142, 2622–2630.Google Scholar
66. Murabayashi, N, Sugiyama, T, Zhang, L, et al. Maternal high-fat diets cause insulin resistance through inflammatory changes in fetal adipose tissue. Eur J Obstet Gyn R B. 2013; 169, 39–44.Google Scholar
67. Alfaradhi, MZ, Kusinski, LC, Fernandez-Twinn, DS, et al. Maternal obesity in pregnancy developmentally programs adipose tissue inflammation in young, lean male mice offspring. Endocrinology. 2016; 157, 4246–4256.Google Scholar
68. Challier, JC, Basu, S, Bintein, T, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta. 2008; 29, 274–281.Google Scholar
69. Zhu, MJ, Du, M, Nathanielsz, PW, et al. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta. 2010; 31, 387–391.Google Scholar
70. Halaas, JL, Gajiwala, KS, Maffei, M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995; 269, 543–546.Google Scholar
71. Loffreda, S, Yang, SQ, Lin, HZ, et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998; 12, 57–65.Google Scholar
72. Lappas, M, Permezel, M, Rice, GE. Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-κB, peroxisomal proliferator-activated receptor-γ and extracellularly regulated kinase 1/2. Endocrinology. 2005; 146, 3334–3342.Google Scholar
73. Schwartz, MW, Peskind, E, Raskind, M, et al. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996; 2, 589–593.Google Scholar
74. Shankar, K, Harrell, A, Liu, XL, et al. Maternal obesity at conception programs obesity in the offspring. Am J Physiol-Reg I. 2008; 294, R528–R538.Google Scholar
75. Oben, JA, Mouralidarane, A, Samuelsson, AM, et al. Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatol. 2010; 52, 913–920.Google Scholar
76. Sáinz, N, González-Navarro, CJ, Martínez, JA, et al. Leptin signaling as a therapeutic target of obesity. Expert Opin Ther Targets. 2015; 19, 893–909.CrossRefGoogle ScholarPubMed
77. Lihn, AS, Bruun, JM, He, G, et al. Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol. 2004; 219, 9–15.CrossRefGoogle ScholarPubMed
78. Park, K, Park, KS, Kim, M, et al. Relationship between serum adiponectin and leptin concentrations and body fat distribution. Diabetes Res Clin Pract. 2004; 63, 135–142.CrossRefGoogle ScholarPubMed
79. Yamauchi, T, Kamon, J, Minokoshi, Ya, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002; 8, 1288–1295.Google Scholar
80. Ohashi, K, Parker, JL, Ouchi, N, et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem. 2010; 285, 6153–6160.CrossRefGoogle ScholarPubMed
81. Jones, HN, Woollett, LA, Barbour, N, et al. High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J. 2009; 23, 271–278.Google Scholar
82. Aye, IL, Rosario, FJ, Powell, TL, et al. Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc Natl Acad Sci U S A. 2015; 112, 12858–12863.Google Scholar
83. Saben, J, Lindsey, F, Zhong, Y, et al. Maternal obesity is associated with a lipotoxic placental environment. Placenta. 2014; 35, 171–177.Google Scholar
84. Dosch, NC, Guslits, EF, Weber, MB, et al. Maternal obesity affects inflammatory and iron indices in umbilical cord blood. J Pediatr. 2016; 172, 20–28.Google Scholar
85. Kroener, L, Wang, ET, Pisarska, MD. Predisposing factors to abnormal first trimester placentation and the impact on fetal outcomes. Semin Reprod Med. 2016; 34, 27–35.Google Scholar
86. Hayes, EK, Tessier, DR, Percival, ME, et al. Trophoblast invasion and blood vessel remodeling are altered in a rat model of lifelong maternal obesity. Reprod Sci. 2014; 21, 648–657.Google Scholar
87. Lager, S, Jansson, N, Olsson, A, et al. Effect of IL-6 and TNF-α on fatty acid uptake in cultured human primary trophoblast cells. Placenta. 2011; 32, 121–127.Google Scholar
88. Huang, L, Liu, J, Feng, L, et al. Maternal prepregnancy obesity is associated with higher risk of placental pathological lesions. Placenta. 2014; 35, 563–569.Google Scholar
89. Mark, P, Sisala, C, Connor, K, et al. A maternal high-fat diet in rat pregnancy reduces growth of the fetus and the placental junctional zone, but not placental labyrinth zone growth. J DOHaD. 2011; 2, 63–70.Google Scholar
90. Mark, P, Lewis, J, Jones, M, et al. The inflammatory state of the rat placenta increases in late gestation and is further enhanced by glucocorticoids in the labyrinth zone. Placenta. 2013; 34, 559–566.Google Scholar
91. Farley, D, Choi, J, Dudley, D, et al. Placental amino acid transport and placental leptin resistance in pregnancies complicated by maternal obesity. Placenta. 2010; 31, 718–724.Google Scholar
92. Leon-Garcia, SM, Roeder, HA, Nelson, KK, et al. Maternal obesity and sex-specific differences in placental pathology. Placenta. 2016; 38, 33–40.Google Scholar
93. Ditchfield, A, Desforges, M, Mills, T, et al. Maternal obesity is associated with a reduction in placental taurine transporter activity. Int J Obes. 2014; 4, 557–564.Google Scholar
94. Dube, E, Gravel, A, Martin, C, et al. Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta. Biol Reprod. 2012; 87, 1–11.Google Scholar
95. Langley-Evans, SC. Developmental programming of health and disease. Proc Nutr Soc. 2006; 65, 97–105.CrossRefGoogle ScholarPubMed
96. Hanson, MA, Gluckman, PD. Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev. 2014; 94, 1027–1076.Google Scholar
97. Petersen, AM, Pedersen, BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005; 98, 1154–1162.Google Scholar
98. Ford, ES. Does exercise reduce inflammation? Physical activity and C-reactive protein among US adults. Epidemiology. 2002; 13, 561–568.CrossRefGoogle Scholar
99. Vega, CC, Reyes-Castro, LA, Bautista, CJ, et al. Exercise in obese female rats has beneficial effects on maternal and male and female offspring metabolism. Int J Obes. 2013; 4, 712–719.Google Scholar
100. Bae-Gartz, I, Janoschek, R, Kloppe, CS, et al. Running exercise in obese pregnancies prevents IL-6 trans-signaling in male offspring. Med Sci Sports Exerc. 2016; 48, 829–838.Google Scholar
101. Tinius, RA, Cahill, AG, Strand, EA, et al. Maternal inflammation during late pregnancy is lower in physically active compared with inactive obese women. Appl Physiol Nutr Metab. 2015; 41, 191–198.Google Scholar
102. Chen, H, Simar, D, Pegg, K, et al. Exendin-4 is effective against metabolic disorders induced by intrauterine and postnatal overnutrition in rodents. Diabetologia. 2014; 57, 614–622.Google Scholar
103. Heliövaara, M, Herz, M, Teppo, A, et al. Pioglitazone has anti-inflammatory effects in patients with type 2 diabetes. J Endocrinol Invest. 2007; 30, 292–297.Google Scholar
104. Kalanderian, A, Abate, N, Patrikeev, I, et al. Pioglitazone therapy in mouse offspring exposed to maternal obesity. Am J Obstet Gynecol. 2013; 208, 308 e1–7.Google Scholar
105. Desai, N, Roman, A, Rochelson, B, et al. Maternal metformin treatment decreases fetal inflammation in a rat model of obesity and metabolic syndrome. Am J Obstet Gynecol. 2013; 209, 136.e1–9.Google Scholar
106. Harris, K, Desai, N, Gupta, M, et al. The effects of prenatal metformin on obesogenic diet-induced alterations in maternal and fetal fatty acid metabolism. Nutr Metab (Lond). 2016; 13, 55.Google Scholar
107. Salomäki, H, Heinäniemi, M, Vähätalo, LH, et al. Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring. PLoS One. 2014; 9, e115778.Google Scholar
108. Chiswick, CA, Reynolds, RM, Denison, FC, et al. Efficacy of metformin in pregnant obese women: a randomised controlled trial. BMJ Open. 2015; 5, e006854.Google Scholar
109. Chiswick, C, Reynolds, RM, Denison, F, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015; 3, 778–786.Google Scholar
110. Novak, TE, Babcock, TA, Jho, DH, et al. NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Lung Cell Mol Physiol. 2003; 284, L84–L89.Google Scholar
111. Neschen, S, Morino, K, Rossbacher, JC, et al. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006; 55, 924–928.Google Scholar
112. Haghiac, M, Yang, X, Presley, L, et al. Dietary omega-3 fatty acid supplementation reduces inflammation in obese pregnant women: a randomized double-blind controlled clinical trial. PLoS One. 2015; 10, e0137309.Google Scholar
113. Melody, S, Vincent, R, Mori, T, et al. Effects of omega-3 and omega-6 fatty acids on human placental cytokine production. Placenta. 2015; 36, 34–40.CrossRefGoogle ScholarPubMed
114. Moon, R, Harvey, N, Robinson, S, et al. Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood. J Clin Endocrinol Metab. 2012; 98, 299–307.Google Scholar
115. Rytter, D, Bech, BH, Halldorsson, T, et al. No association between the intake of marine n-3 PUFA during the second trimester of pregnancy and factors associated with cardiometabolic risk in the 20-year-old offspring. Br J Nutr. 2013; 110, 2037–2046.Google Scholar
116. Brei, C, Stecher, L, Much, D, et al. Reduction of the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on offspring body composition: follow-up results from a randomized controlled trial up to 5 y of age. Am J Clin Nutr. 2016; 103, 1472–1481.CrossRefGoogle ScholarPubMed
117. Stratakis, N, Gielen, M, Chatzi, L, et al. Effect of maternal n-3 long-chain polyunsaturated fatty acid supplementation during pregnancy and/or lactation on adiposity in childhood: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2014; 68, 1277–1287.Google Scholar
118. Simopoulos, AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002; 56, 365–379.Google Scholar
119. Simopoulos, AP. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity. Nutrients. 2016; 8, 128.Google Scholar
120. Heerwagen, MJ, Stewart, MS, de la Houssaye, BA, et al. Transgenic increase in n-3/n-6 fatty acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental programming in mice. PLoS One. 2013; 8, e67791.Google Scholar
121. Hussain, A, Nookaew, I, Khoomrung, S, et al. A maternal diet of fatty fish reduces body fat of offspring compared with a maternal diet of beef and a post‐weaning diet of fish improves insulin sensitivity and lipid profile in adult C57BL/6 male mice. Acta Physiol (Oxf). 2013; 209, 220–234.CrossRefGoogle Scholar
122. Bagley, HN, Wang, Y, Campbell, MS, et al. Maternal docosahexaenoic acid increases adiponectin and normalizes IUGR-induced changes in rat adipose deposition. J Obes. 2013; 2013, 312153.Google Scholar
123. Muhlhausler, BS, Miljkovic, D, Fong, L, et al. Maternal omega-3 supplementation increases fat mass in male and female rat offspring. Front Genet. 2011; 2, 48.Google Scholar
124. Zulkafli, IS, Waddell, BJ, Mark, PJ. Postnatal dietary omega-3 fatty acid supplementation rescues glucocorticoid-programmed adiposity, hypertension, and hyperlipidemia in male rat offspring raised on a high-fat diet. Endocrinology. 2013; 154, 3110–3117.Google Scholar
125. Mark, PJ, Wyrwoll, CS, Zulkafli, IS, et al. Rescue of glucocorticoid-programmed adipocyte inflammation by omega-3 fatty acid supplementation in the rat. Reprod Biol Endocrinol. 2014; 12, 1.Google Scholar
126. Chicco, A, Creus, A, Illesca, P, et al. Effects of post-suckling n-3 polyunsaturated fatty acids: prevention of dyslipidemia and liver steatosis induced in rats by a sucrose-rich diet during pre-and post-natal life. Food Funct. 2016; 7, 445–454.Google Scholar
127. Balogun, KA, Cheema, SK. Dietary omega-3 fatty acids prevented adipocyte hypertrophy by downregulating DGAT-2 and FABP-4 in a sex-dependent fashion. Lipids. 2016; 51, 25–38.CrossRefGoogle Scholar
128. Muhlhausler, B, Gibson, R, Makrides, M. The effect of maternal omega-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation during pregnancy and/or lactation on body fat mass in the offspring: a systematic review of animal studies. Prostaglandins Leukot Essent Fatty Acids. 2011; 85, 83–88.Google Scholar
129. Mennitti, LV, Oliveira, JL, Morais, CA, et al. Type of fatty acids in maternal diets during pregnancy and/or lactation and metabolic consequences of the offspring. J Nutr Biochem. 2015; 26, 99–111.Google Scholar
130. Kennedy, A, Martinez, K, Schmidt, S, et al. Antiobesity mechanisms of action of conjugated linoleic acid. J Nutr Biochem. 2010; 21, 171–179.Google Scholar
131. Bauman, D, Baumgard, L, Corl, B, et al. Biosynthesis of conjugated linoleic acid in ruminants. J Anim Sci. 2000; 77, 1–15.Google Scholar
132. Viladomiu, M, Hontecillas, R, Bassaganya-Riera, J. Modulation of inflammation and immunity by dietary conjugated linoleic acid. Eur J Pharmacol. 2015; 785, 87–95.Google Scholar
133. Dhiman, TR, Nam, S, Ure, AL. Factors affecting conjugated linoleic acid content in milk and meat. Crit Rev Food Sci Nutr. 2005; 45, 463–482.CrossRefGoogle ScholarPubMed
134. Banni, S. Conjugated linoleic acid metabolism. Curr Opin Lipidol. 2002; 13, 261–266.Google Scholar
135. West, DB, Delany, JP, Camet, PM, et al. Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse. Am J Physiol. 1998; 275, R667–R672.Google Scholar
136. Houseknecht, KL, Heuvel, JPV, Moya-Camarena, SY, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun. 1998; 244, 678–682.Google Scholar
137. Kritchevsky, D, Tepper, SA, Wright, S, et al. Influence of graded levels of conjugated linoleic acid (CLA) on experimental atherosclerosis in rabbits. Nutr Res. 2002; 22, 1275–1279.Google Scholar
138. de Roos, B, Rucklidge, G, Reid, M, et al. Divergent mechanisms of cis9, trans11-and trans10, cis12-conjugated linoleic acid affecting insulin resistance and inflammation in apolipoprotein E knockout mice: a proteomics approach. FASEB J. 2005; 19, 1746–1748.Google Scholar
139. Jaudszus, A, Krokowski, M, Mockel, P, et al. Cis-9, trans-11-conjugated linoleic acid inhibits allergic sensitization and airway inflammation via a PPARgamma-related mechanism in mice. J Nutr. 2008; 138, 1336–1342.Google Scholar
140. Moloney, F, Toomey, S, Noone, E, et al. Antidiabetic effects of cis-9, trans-11-conjugated linoleic acid may be mediated via anti-inflammatory effects in white adipose tissue. Diabetes. 2007; 56, 574–582.Google Scholar
141. Bassaganya-Riera, J, Reynolds, K, Martino-Catt, S, et al. Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease. Gastroenterology. 2004; 127, 777–791.Google Scholar
142. Belury, MA, Moya-Camarena, SY, Lu, M, et al. Conjugated linoleic acid is an activator and ligand for peroxisome proliferator-activated receptor-gamma (PPAR gamma). Nutr Res. 2002; 22, 817–824.Google Scholar
143. Cheng, W, Lii, C, Chen, H, et al. Contribution of conjugated linoleic acid to the suppression of inflammatory responses through the regulation of the NF-κB pathway. J Agric Food Chem. 2004; 52, 71–78.Google Scholar
144. Reynolds, CM, Loscher, CE, Moloney, AP, et al. Cis-9, trans-11-conjugated linoleic acid but not its precursor trans-vaccenic acid attenuate inflammatory markers in the human colonic epithelial cell line Caco-2. Br J Nutr. 2008; 100, 13–17.Google Scholar
145. Reynolds, CM, Draper, E, Keogh, B, et al. A conjugated linoleic acid-enriched beef diet attenuates lipopolysaccharide-induced inflammation in mice in part through PPARgamma-mediated suppression of toll-like receptor 4. J Nutr. 2009; 139, 2351–2357.Google Scholar
146. Park, Y, Storkson, JM, Albright, KJ, et al. Evidence that the trans-10, cis-12 isomer of conjugated linoleic acid induces body composition changes in mice. Lipids. 1999; 34, 235–241.Google Scholar
147. Segovia, SA, Vickers, MH, Zhang, XD, et al. Maternal supplementation with conjugated linoleic acid in the setting of diet-induced obesity normalises the inflammatory phenotype in mothers and reverses metabolic dysfunction and impaired insulin sensitivity in offspring. J Nutr Biochem. 2015; 26, 1448–1457.Google Scholar
Figure 0

Fig. 1 Summary of the impact of maternal obesity on inflammation. Maternal obesity (or maternal consumption of an obesogenic diet) can result in altered adipokine secretion, insulin resistance and/or increased circulating lipids in the mother. These alterations are associated with metabolic inflammation. Reducing maternal metabolic inflammation with anti-inflammatory agents may represent a key target for preventing developmental programming. Maternal metabolic inflammation is also linked to placental inflammation, altered placental nutrient transport and altered placental structure. These changes may mediate developmental programming of obesity and related metabolic conditions in offspring.