Evidence from human studies

Fetal macrosomia is regarded as one of the greatest immediate risks of obese pregnancies, and obese pregnancies have been shown to be associated with a 2–3-fold increase in prevalence of fetal macrosomia at term^{(Reference Ehrenberg, Mercer and Catalano21)}. This is associated with increased absolute fetal size and infant fat mass^{(Reference Sewell, Huston-Presley and Super22,Reference Whitelaw23)} . This change in body composition of the offspring continues throughout childhood, adolescence and adulthood, with various studies showing that maternal obesity leads to increased incident of offspring obesity^{(Reference Schack-Nielsen, Michaelsen and Gamborg24–Reference Whitaker, Wright and Pepe30)}, including alterations in offspring body composition with higher childhood fat mass^{(Reference Andres, Hull and Shankar26–Reference Kaar, Crume and Brinton29,Reference Castillo-Laura, Santos and Quadros31)} . Some studies have also suggested that the programming of offspring obesity by maternal obesity may be, in part, sex specific, with male offspring having increased susceptibility to increased adiposity compared to female offspring of obese mothers^{(Reference Andres, Hull and Shankar26)}.

Evidence of offspring adiposity from animal models

Animal models are useful tools to help define the mechanisms underlying the programming of increased offspring adiposity by maternal obesity. A variety of model species, including rodents^{(Reference Liang, Yang and Fu32–Reference Chang, Hafner and Varghese40)}, sheep^{(Reference Liang, Oest and Prater39,Reference Fensterseifer, Austin and Ford41,Reference Long, Rule and Zhu42)} and non-human primates^{(Reference Lewis, Bertrand and McMahan43)}, have all recapitulated the observations made in human cohorts that offspring of obese mothers have increased risk of developing obesity compared to offspring of control mothers, with increased offspring body weight and fat mass observed^{(Reference Menting, Mintjens and van de Beek44)}.

Sheep models have shown that fetuses of obese ewes have increased fat depots at both mid- and late-gestation compared to fetuses of lean mothers^{(Reference Fensterseifer, Austin and Ford41,Reference Long, Rule and Zhu42)} . This may be in part driven by adipocyte hypertrophy as increased adipocyte cell size has been observed in late-gestation sheep^{(Reference Long, Rule and Zhu42)} fetuses of obese mothers compared to lean controls, with similar findings reported in the mouse^{(Reference Murabayashi, Sugiyama and Zhang45)}. Adult offspring of obese rodent dams show a similar phenotype, with increased fat mass driven by a combination of adipocyte hypertrophy and hyperplasia. Rat models have shown male offspring of obese dams have adipocyte hypertrophy compared to controls^{(Reference Liang, Yang and Fu32–Reference Litzenburger, Huber and Dinger35)}. However reports of adipocyte hyperplasia are more conflicted with some showing evidence of increased adipocyte hyperplasia^{(Reference Lecoutre, Deracinois and Laborie34)}, while others have shown it to be impaired^{(Reference Liang, Yang and Fu32)}. Furthermore, while increased white adipose tissue mass has been seen in offspring of both sexes, the mechanisms for this expansion may be sexually dimorphic. Rat models of maternal obesity showing increased adipocyte cell size in males, did not see a similar increase in female offspring adipocytes^{(Reference Lecoutre, Deracinois and Laborie34,Reference Litzenburger, Huber and Dinger35)} . However, conversely, in a baboon model of pre-weaning over-nutrition, offspring adipocyte hypertrophy was seen in only female offspring at 5 years of age^{(Reference Lewis, Bertrand and McMahan43)}.

There is also evidence of altered adipocyte metabolism and increased fatty acid accumulation in fetuses of obese pregnancies, with increased expression of fatty acid and glucose transporters and of fatty acid biosynthesis enzymes in fetal sheep adipose tissue in response to maternal obesity^{(Reference Long, Rule and Zhu42)}. This is accompanied by altered expression of genes which regulate adipogenesis, lipogenesis and the synthesis of adipokines^{(Reference Muhlhausler, Duffield and McMillen46)}, leading to increased lamb fat mass observed in early postnatal life^{(Reference Muhlhausler, Duffield and McMillen46)}. Increased fetal insulin concentration and the development of fetal insulin resistance may also contribute to increased fetal fat accretion, with fetuses of mice fed with a high-fat diet before and throughout pregnancy showing evidence of adipose tissue insulin resistance^{(Reference Murabayashi, Sugiyama and Zhang45)}. Furthermore, increased inflammation of the subcutaneous adipose tissue has been reported in fetal mice of high-fat diet-fed dams^{(Reference Murabayashi, Sugiyama and Zhang45)}. Similarly postnatally, a rat model of maternal diet-induced obesity showed dysregulated expression of adipogenic and lipogenic genes at both 2 weeks and 2 months of age in offspring of obese dams compared to controls^{(Reference Sen and Simmons47)}. Adult mouse offspring also show evidence of increased adipose tissue inflammation^{(Reference Chang, Hafner and Varghese40,Reference Bae-Gartz, Janoschek and Kloppe48)} . This may be sex specific as mouse offspring of obese dams, when themselves are exposed to a high-fat diet challenge in adulthood, showed increased visceral adipose tissue inflammation in male, but not female, offspring^{(Reference Chang, Hafner and Varghese40)}. Altered miRNA expression is one potential mechanism for programming of adipose tissue inflammation, with one mouse model of maternal diet-induced obesity showing reduced expression of miR-706 (known to regulate inflammatory protein expression) in adipose tissue from male offspring^{(Reference Alfaradhi, Kusinski and Fernandez-Twinn49)}.

Evidence of offspring hyperphagia from animal models

Maternal obesity has also been shown to programme offspring obesity via offspring hyperphagia and thus increased energy intake. Offspring hyperphagia has been observed in several different rodent models of maternal obesity, in both male and female offspring^{(Reference Chang, Gaysinskaya and Karatayev50–Reference Glavas, Kirigiti and Xiao53)}. It is thought that this hyperphagic phenotype may be driven by altered development and function of the hypothalamic circuits which regulate appetite and energy expenditure. Both leptin and insulin, which are altered in the maternal circulation during obesity, are known to affect neural development and have therefore both been implicated as factors mediating the programming effects of hypothalamic development.

The timing of the rodent neonatal leptin surge is a critical window for hypothalamic neuronal circuitry development and maturation. Neonatal rats born from obese mothers have an enhanced and prolonged postnatal leptin surge^{(Reference Kirk, Samuelsson and Argenton52)}. In contrast in lambs, maternal obesity has been shown to result in a reduced neonatal leptin surge^{(Reference Long, Ford and Nathanielsz54)}. However, despite the reduced neonatal leptin surge in lambs exposed to maternal obesity in utero, postnatally they have increased subcutaneous adipose tissue fat mass and adipose tissue leptin gene expression compared to offspring of controls^{(Reference Muhlhausler, Duffield and McMillen55)}. As the hypothalamus requires the correct levels and timings of exposure in order to correctly develop, any perturbations leading to either under- or over-exposure to leptin during these critical developmental windows can have negative impacts. Furthermore, rat fetuses of high-fat diet-fed dams have hypothalamic leptin resistance, with reduced expression of downstream leptin signalling components despite elevated plasma leptin levels compared to fetuses from healthy pregnancies, which is accompanied by increased mRNA expression of the orexigenic neuropeptides neuropeptide Y and agouti-related protein^{(Reference Gupta, Srinivasan and Thamadilok56)}. This leptin resistance persists postnatally in adult rodent offspring exposed to either gestational or lactational over-nutrition^{(Reference Kirk, Samuelsson and Argenton52,Reference Glavas, Kirigiti and Xiao53)} , and leptin infusion into these offspring fails to reduced food intake in offspring of both sexes^{(Reference Kirk, Samuelsson and Argenton52)}.

In addition to leptin, neonatal insulin signalling also plays an important role in regulation of hypothalamic development. Maternal obesity in mice has been shown to result in impaired offspring proopiomelanocortin neurone projection development, which was corrected by inhibition of insulin signalling in proopiomelanocortin neurones^{(Reference Vogt, Paeger and Hess57)}. The fetal hypothalamus also develops insulin resistance in a maternal obesogenic environment, and both mid- and late-gestation rodent fetuses of obese dams have reduced downstream insulin signalling despite increased serum insulin levels^{(Reference Gupta, Srinivasan and Thamadilok56,Reference Dearden, Buller and Furigo58)} . The inability of these offspring to appropriately respond to satiety signals may therefore contribute to the programming of offspring hyperphagia, and thus the risk of developing increased adiposity and obesity.

Overall, maternal obesity can lead to increased offspring adiposity accompanied by altered adipose tissue metabolism, inflammation and insulin resistance, as well as dysregulation of appetite regulation in the hypothalamus, thus predisposing them to obesity in later life (Fig. 1).

Evidence from human studies

Maternal obesity is known to result in increased risk of offspring developing type 2 diabetes, characterised by insulin resistance and β-cell dysfunction^{(Reference Galicia-Garcia, Benito-Vicente and Jebari59)}. Studies in human subjects have shown that maternal obesity leads to increased fetal insulin resistance compared to lean controls^{(Reference Catalano, Presley and Minium60)}. This insulin resistance persists into childhood, where maternal obesity is associated with increased risk of insulin resistance^{(Reference Kaar, Crume and Brinton29,Reference Maftei, Whitrow and Davies61)} , developing type 2 diabetes^{(Reference Dabelea, Mayer-Davis and Lamichhane62)} and the metabolic syndrome^{(Reference Boney, Verma and Tucker63)}. This association continues in adulthood, with maternal obesity increasing the risk of insulin resistance^{(Reference Hochner, Friedlander and Calderon-Margalit64)} and type 2 diabetes^{(Reference Eriksson, Sandboge and Salonen14,Reference Fall, Stein and Kumaran65,Reference Lahti-Pulkkinen, Bhattacharya and Wild66)} .

Evidence of offspring insulin resistance from animal models

Consistent with human studies, animal models have also shown that maternal obesity results in the development of altered offspring insulin sensitivity. Although the exact offspring phenotype varies depending on the species and model of maternal over-nutrition/obesity, the programming of offspring metabolic dysfunction is consistently observed. Indeed, several rodent models have shown that maternal over-nutrition results in offspring hyperinsulinaemia^{(Reference Rajia, Chen and Morris67–Reference Samuelsson, Matthenws and Argenton73)}, glucose intolerance^{(Reference Desai, Jellyman and Han38,Reference Rajia, Chen and Morris67,Reference Fernandez-Twinn, Alfaradhi and Martin-Gronert74)} and insulin resistance^{(Reference Desai, Jellyman and Han38,Reference Rajia, Chen and Morris67–Reference Zambrano, Sosa-Larios and Calzada69,Reference Shankar, Harrell and Liu75–Reference Graus-Nunes, Dalla Corte Frantz and Lannes77)} . Studies in Agouti yellow mice, a model of normoglycemic obesity, have highlighted that maternal obesity alone, in the absence of maternal hyperinsulinaemia, is sufficient to impair offspring insulin signalling and glucose tolerance^{(Reference Han, Xu and Epstein78,Reference Li, Young and Maloney79)} . While many early studies focused mainly on the phenotype of male offspring^{(Reference Rajia, Chen and Morris67,Reference Buckley, Keserü and Briody70,Reference Samuelsson, Matthenws and Argenton73,Reference Shankar, Harrell and Liu75)} , studies investigating both offspring sexes have revealed some sex-specific differences in the programming of offspring metabolic dysfunction by maternal obesity. However, whether males^{(Reference Chang, Hafner and Varghese40,Reference Li, Young and Maloney79,Reference Yokomizo, Hasegawa and Ishitobi80)} or females^{(Reference Han, Xu and Epstein78,Reference Akhaphong, Gregg and Kumusoglu81,Reference Dearden and Balthasar82)} are more susceptible to the programming of insulin resistance and glucose intolerance by maternal obesity varies between studies.

Skeletal muscle is a key insulin responsive tissue, with insulin promoting glucose uptake into muscle cells. Thus, impairment of the skeletal muscle response to insulin can contribute to the pathogenesis of type 2 diabetes. In an ovine model of diet-induced obesity, late-gestation fetuses were shown to have impaired skeletal muscle insulin action with decreased Akt phosphorylation despite higher circulating levels of insulin compared to fetuses of control ewes^{(Reference Yan, Zhu and Xu83)}. However, conversely, in mice, high-fat diet feeding prior to conception resulted in increased fetal and neonatal activation of insulin signalling in skeletal muscle, compared to offspring of lean control mothers^{(Reference Qiao, Wattez and Lim84)}. However, in adult offspring, maternal obesity has been shown consistently to cause skeletal muscle insulin resistance^{(Reference Yan, Huang and Zhao85)}, with disrupted expression of key downstream insulin signalling molecules seen in both sheep^{(Reference Nicholas, Morrison and Rattanatray86)} and rodent^{(Reference de Fante, Simino and Reginato87,Reference Shelley, Martin-Gronert and Rowlerson88)} models of maternal obesity. Similarly, rat offspring of cafeteria diet-fed dams had altered skeletal muscle metabolism at weaning indicative of insulin resistance^{(Reference Bayol, Simbi and Stickland89)}.

The liver also plays an important role in regulation of glucose homoeostasis, with insulin signalling acting to promote hepatic storage of glucose as glycogen. Similarly to skeletal muscle, maternal obesity influences insulin signalling in the fetal liver, with dysregulated expression of miRNAs associated with insulin signalling, accompanied by increased liver lipid accumulation seen in the late-gestation primate fetal liver^{(Reference Puppala, Li and Glenn90)}, and increased activation of fetal hepatic insulin signalling in mice^{(Reference Qiao, Wattez and Lim84)}. A similar phenotype is also seen in the adult offspring liver in rats^{(Reference Buckley, Keserü and Briody70)}, mice^{(Reference de Fante, Simino and Reginato87,Reference Martin-Gronert, Fernandez-Twinn and Poston91)} and sheep^{(Reference Nicholas, Rattanatray and MacLaughlin92)}. For example, maternal obesity in sheep alters the expression of key insulin signalling molecules and factors which regulate gluconeogenesis in the male and female offspring liver^{(Reference Nicholas, Rattanatray and MacLaughlin92,Reference Rattanatray, Muhlhausler and Nicholas93)} . Similar to the primate fetus, this may be due to dysregulated expression of miRNAs related to insulin signalling^{(Reference Nicholas, Rattanatray and MacLaughlin92)}. In rodents some of these effects have been shown to be sex specific as transcriptomic analysis of livers of offspring born to obese dams has shown a male-specific dysregulation of pathways involved in insulin signalling and glycolysis/gluconeogenesis^{(Reference Lomas-Soria, Reyes-Castro and Rodríguez-González94)}.

Adipose tissue is also sensitive to insulin action, where insulin promotes adipocyte glucose uptake and inhibits lipolysis. Several studies in mouse models have shown that maternal obesity impairs offspring white adipose tissue insulin signalling^{(Reference Alfaradhi, Fernandez-Twinn and Martin-Gronert72,Reference Fernandez-Twinn, Alfaradhi and Martin-Gronert74,Reference de Fante, Simino and Reginato87)} , and similar to the liver, this may be associated with altered regulatory miRNA expression in offspring adipose tissue^{(Reference Fernandez-Twinn, Alfaradhi and Martin-Gronert74)}.

Evidence of offspring pancreatic β-cell dysfunction from animal models

In addition to systemic insulin resistance, insufficient insulin production, processing and release from pancreatic β-cells is also characteristic of type 2 diabetes. In the initial stages of type 2 diabetes, when peripheral tissues become insulin resistant, the pancreas can attempt to compensate, increasing β-cell number, size and insulin production. However, as disease progresses β-cell exhaustion can lead to reduced function and cell death. Animal models have shown significant evidence of offspring β-cell dysfunction in response to exposure to maternal obesity.

In the fetus, maternal obesity in sheep results in increased relative pancreatic weight and β-cell number and proliferation at mid-gestation^{(Reference Ford, Zhang and Zhu95)}, but reduced pancreatic weight and β-cell numbers in late-gestation^{(Reference Zhang, Long and Hein96)}, with increased β-cell apoptosis and a resultant decrease in blood insulin levels and increase in glucose levels at birth^{(Reference Zhang, Long and Hein96)}. Similarly, maternal obesity has been shown to significantly reduce β-cell mass in neonatal mice^{(Reference Bringhenti, Moraes-Teixeira and Cunha97)} and rats^{(Reference Cerf, Williams and Nkomo98)}, resulting in neonatal hyperglycaemia^{(Reference Cerf, Williams and Nkomo98)}. However, in contrast, another model of mice fed with a high-fat diet prior to pregnancy resulted in increased fetal pancreatic β-cell mass and thus elevated fetal blood insulin levels and reduced glucose concentrations, compared to control fetuses^{(Reference Qiao, Wattez and Lim84)}. Regardless of the exact phenotype, if these alterations to fetal pancreatic growth and function are not corrected in later life it can lead to a predisposition for offspring glucose intolerance and thus increased risk of developing type 2 diabetes.

In rodents, postnatal offspring of dams fed with a high-fat diet during gestation show progressive β-cell dysfunction with increased β-cell hypertrophy^{(Reference Graus-Nunes, Dalla Corte Frantz and Lannes77,Reference Cerf and Louw99)} and proliferation^{(Reference Bringhenti, Moraes-Teixeira and Cunha97,Reference Cerf and Louw99,Reference Zheng, Zhang and Wang100)} seen in the young adult offspring of obese dams compared to controls, accompanied by increased β-cell insulin content^{(Reference Zheng, Zhang and Wang100)}, and enhanced glucose-stimulated insulin release^{(Reference Bringhenti, Moraes-Teixeira and Cunha97)}, characteristic of the initial β-cell response to increased peripheral insulin resistance. However, as insulin resistance progresses, loss of β-cell function leads to decreased pancreatic insulin content^{(Reference Taylor, McConnell and Khan68,Reference Samuelsson, Matthenws and Argenton73)} , impaired insulin secretion from pancreatic islets^{(Reference Taylor, McConnell and Khan68)} and offspring hypoinsulinaemia^{(Reference Cerf, Muller and Toit101)}.

Some studies suggest that male mouse offspring may be more vulnerable to the programming of poor β-cell development^{(Reference Yokomizo, Inoguchi and Sonoda71)}, function^{(Reference Casasnovas, Damron and Jarrell102)}, survival and oxidative stress^{(Reference Yokomizo, Inoguchi and Sonoda71)}, with the female offspring pancreas being more protected^{(Reference Yokomizo, Inoguchi and Sonoda71)}. In fact the female offspring pancreas may be primed by exposure to maternal obesity to be better able to cope with exposure to over-nutrition in postnatal life^{(Reference Nicholas, Nagao and Kusinski103)}. However, conflicting studies have reported a more severe phenotype in females with increased pancreatic dysfunction^{(Reference Han, Xu and Epstein78)}, disrupted islet metabolism^{(Reference Han, Xu and Epstein78)} and significantly reduced glucose-stimulated insulin release^{(Reference Han, Xu and Epstein78)} specifically in female mouse offspring of obese mothers compared to offspring of controls.

This evidence suggests that exposure to a maternal obesogenic environment has long-term effects on β-cell function and peripheral organ insulin resistance, contributing to the increased risk of offspring developing insulin resistance and type 2 diabetes (Fig. 1).

Evidence from human studies

Maternal obesity in human subjects is known to be associated with increased risk of congenital heart disease^{(Reference Liu, Ding and Yang104)}, however relatively little research has been carried out to study the effect of maternal obesity on other aspects of the fetal heart. At mid-gestation the effects of maternal obesity appear relatively small with evidence of reduced left and right ventricular strain suggesting impaired contractile function, but no observed effects on fetal cardiac dimensions, heart rate, blood flow velocities or standard echocardiographic parameters of systolic and diastolic function^{(Reference Ingul, Lorås and Tegnander105,Reference Kulkarni, Li and Craft106)} . However, later in gestation there is persistence of reduced ventricular strain, accompanied by the development of impaired diastolic function, although no clear changes in cardiac systolic function are observed^{(Reference Ingul, Lorås and Tegnander105,Reference Ece, Uner and Balli107)} . Additionally, there are late-gestational changes in cardiac morphology in fetuses exposed to maternal obesity with increased ventricular wall widths and reduced chamber widths^{(Reference Ingul, Lorås and Tegnander105,Reference Mat Husin, Schleger and Bauer108)} . However, there are still no observed differences in heart rate or cardiac blood flow in human fetuses of obese mothers in the third trimester, suggesting that maternal obesity does not cause overt fetal cardiac dysfunction despite the observed diastolic impairment^{(Reference Ingul, Lorås and Tegnander105,Reference Ece, Uner and Balli107)} .

In adulthood, several studies have shown a significant association between maternal BMI and increased risk of CVD in her children^{(Reference Eriksson, Sandboge and Salonen14,Reference Reynolds, Allan and Raja15,Reference Forsén, Eriksson and Tuomilehto109–Reference Labayen, Ruiz and Ortega113)} . One early study in a population of 3302 Finnish men showed that a higher maternal BMI was associated with increased risk of death due to coronary heart disease in her adult offspring^{(Reference Forsén, Eriksson and Tuomilehto109)}. These results were later supported by similar results seen in a larger Scottish cohort of 37 709 men and women, where offspring of obese mothers were shown to have increased risk of hospital admissions for a cardiovascular event aged 31–64 years^{(Reference Reynolds, Allan and Raja15)}. Data from men and women in the Helsinki Birth Cohort have also shown an association between maternal BMI and increased risk of offspring coronary heart disease and stroke^{(Reference Eriksson, Sandboge and Salonen14)}, while offspring from the 1958 British birth cohort have shown that parental BMI is positively associated with increased CVD risk factors in offspring aged 44–45 years^{(Reference Cooper, Pinto Pereira and Power111)}. Furthermore, a more recent large Swedish cohort has also shown increased risk of childhood and young adult CVD with increasing maternal BMI^{(Reference Razaz, Villamor and Muraca110)}. Importantly, this association was maintained in a sibling-controlled analysis, supporting a more causal relationship between maternal BMI and offspring CVD, after controlling for shared sibling environmental and genetic factors^{(Reference Razaz, Villamor and Muraca110)}.

Human studies looking more specifically at offspring cardiac structure and function in childhood have shown that high maternal BMI was associated with increased left ventricular mass and hypertrophy in 6 year old offspring^{(Reference Toemen, Gishti and van Osch-Gevers114)}, but not relative wall thickness^{(Reference Toemen, Gishti and van Osch-Gevers114)}, fractional shortening^{(Reference Toemen, Gishti and van Osch-Gevers114)} or other indices of left ventricular systolic or diastolic function as assessed by echocardiography^{(Reference Litwin, Sundholm and Rönö112)}. Overall, these studies suggest that, while maternal obesity does not programme overt cardiac dysfunction in early childhood, it does increase the risk of offspring developing CVD in adulthood.

Evidence of offspring cardiac dysfunction from animal models

The effects of maternal obesity on the offspring heart at the cellular and molecular levels have been investigated further using animal models. While a range of species and maternal obesity models have been used, similar cardiac phenotypes are observed across species. Despite inconsistencies in the effect of maternal obesity to increase fetal heart weights, in mid-gestation fetal sheep^{(Reference Kandadi, Hua and Zhu115–Reference George, Uthlaut and Long118)} and neonatal rats^{(Reference Zhang, Cao and Tan119–Reference Xue, Chen and Zhang121)}, although not in late-gestation sheep^{(Reference Kandadi, Hua and Zhu115,Reference Fan, Turdi and Ford116)} or baboons^{(Reference Maloyan, Muralimanoharan and Huffman122)}, there is consistent evidence that maternal obesity leads to offspring cardiomyocyte hypertrophy. Indeed, increased cell size and expression of hypertrophy markers have been consistently reported in the hearts of fetal sheep^{(Reference Kandadi, Hua and Zhu115,Reference Wang, Zhu and Sun123)} and neonatal minipigs^{(Reference Guzzardi, Liistro and Gargani124)} and rodents^{(Reference Zhang, Cao and Tan119–Reference Xue, Chen and Zhang121)}. In adulthood, mouse offspring of obese mothers have also been shown to exhibit increased left ventricular mass and area^{(Reference Loche, Blackmore and Carpenter125–Reference Blackmore, Niu and Fernandez-Twinn127)}, with increased cardiomyocyte cell size in 3-^{(Reference Blackmore, Niu and Fernandez-Twinn127)} and 8-^{(Reference Loche, Blackmore and Carpenter125–Reference Beeson, Blackmore and Carr128)}week-old male offspring, although this was a transient phenotype which was lost by 12 weeks of age^{(Reference Blackmore, Niu and Fernandez-Twinn127)}. This increased cardiomyocyte cell size was accompanied by re-expression of fetal genes and miRNAs associated with pathological hypertrophy in young adult male mouse offspring of obese mothers^{(Reference Loche, Blackmore and Carpenter125–Reference Beeson, Blackmore and Carr128)}. One potential mechanism for the programming of this pathological remodelling is hyperinsulinaemia-induced overactivation of cardiac insulin signalling. Consistent with this hypothesis, in a mouse model of maternal diet-induced obesity, although insulin receptor levels were reduced in the hearts of offspring of obese dams, the downstream signalling components were upregulated^{(Reference Fernandez-Twinn, Blackmore and Siggens126)}.

Changes in fetal cardiomyocyte growth have been reported to be accompanied by changes in cardiomyocyte structure with irregular orientation of myofibrils in mid- and late-gestational fetal sheep^{(Reference Kandadi, Hua and Zhu115,Reference Fan, Turdi and Ford116,Reference Wang, Zhu and Sun123)} and rats^{(Reference Mdaki, Larsen and Wachal120,Reference Xue, Chen and Zhang121)} exposed to maternal obesity, in parallel with altered expression of contractile proteins which could affect cardiac ionotropic function^{(Reference Kandadi, Hua and Zhu115,Reference Fan, Turdi and Ford116,Reference Wang, Zhu and Sun123)} . Indeed, cardiomyocytes isolated from fetuses of obese ewes showed impaired contractility and calcium handling^{(Reference Wang, Zhu and Sun123)}. Furthermore, hearts isolated from late-gestational fetal sheep showed impaired cardiac function as they were unable to maintain increased contractile performance when subjected to a higher workload, although baseline cardiac function was unaffected by maternal obesity^{(Reference Ingul, Lorås and Tegnander105,Reference Ece, Uner and Balli107,Reference Wang, Ma and Tong129)} . Similarly, neonatal rats^{(Reference Mdaki, Larsen and Wachal120)} and pigs^{(Reference Guzzardi, Liistro and Gargani124)} when exposed to maternal obesity and diabetes in utero showed cardiac systolic and diastolic in vivo dysfunction.

Impaired cardiac contractility programmed by maternal obesity persists into adulthood, with a mouse model of diet-induced obesity showing impaired in vivo systolic and diastolic function, as assessed by echocardiography in male offspring of obese dams compared to controls at 8 weeks of age^{(Reference Loche, Blackmore and Carpenter125,Reference Beeson, Blackmore and Carr128)} , and in ex vivo Langendorff preparations at 12 weeks of age^{(Reference Blackmore, Niu and Fernandez-Twinn127)}. Furthermore, administration of parasympathetic and sympathetic agents to these heart preparations showed a blunted response to parasympathetic stimulation, but enhanced contractile response to sympathetic stimulation, indicative of sympathetic dominance, a marker of heart failure, in the hearts of offspring of obese dams^{(Reference Blackmore, Niu and Fernandez-Twinn127)}.

Further changes in the fetal heart in response to maternal obesity include increased lipid droplet accumulation in fetal sheep^{(Reference Kandadi, Hua and Zhu115)} and neonatal rat^{(Reference Mdaki, Larsen and Wachal120)}, and increased fibrosis in fetal sheep and neonatal mouse^{(Reference Zhang, Cao and Tan119)} which may increase cardiac stiffness, potentially leading to impaired cardiac function^{(Reference Fan, Turdi and Ford116,Reference Maloyan, Muralimanoharan and Huffman122,Reference Huang, Yan and Zhao130)} . Increased cardiac fibrosis was also seen in 8-week-old mouse offspring of obese dams, when challenged with a high-fat diet in postnatal life^{(Reference Loche, Blackmore and Carpenter125)}.

There is also increased cardiac inflammation seen in the hearts of fetal sheep exposed to maternal obesity^{(Reference Kandadi, Hua and Zhu115)}, as well as attenuated sensitivity to insulin^{(Reference Wang, Ma and Tong129)}, and reduced expression of the cardioprotective AMP-activated protein kinase signalling pathway, which may be involved in metabolic regulation and substrate metabolism^{(Reference Wang, Ma and Tong129)}. Altered energy metabolism was also seen in the hearts of neonatal pigs and fetal mice born to high-fat diet-fed mothers suggestive of changes in cardiomyocyte energy metabolism shifting from glycolytic towards oxidative cardiac metabolism^{(Reference Guzzardi, Liistro and Gargani124,Reference Pantaleão, Inzani and Furse131)} .

Maternal obesity in rodents has been shown to result in impaired offspring mitochondrial structure and function in both early and adult life^{(Reference Mdaki, Larsen and Wachal120,Reference Xue, Chen and Zhang121,Reference Larsen, Sabey and Knutson132,Reference Ferey, Boudoures and Reid133)} , which may lead to impaired mitochondrial function, cellular metabolism and increased reactive oxygen species production. Indeed, neonatal rat cardiomyocytes of obese dams had lower basal oxygen consumption^{(Reference Mdaki, Larsen and Wachal120)}, and increased cardiac oxidative stress^{(Reference Zhang, Cao and Tan119,Reference Mdaki, Larsen and Wachal120,Reference Lin, Han and Fang134)} and reactive oxygen species production^{(Reference Zhang, Cao and Tan119)}. Increased oxidative stress and reactive oxygen species production in the heart has also been seen in adult male offspring of obese mouse dams^{(Reference Fernandez-Twinn, Blackmore and Siggens126)}, although this result has not been recapitulated in every study^{(Reference Loche, Blackmore and Carpenter125)}.

Importantly, many of these differences in cardiac structure and function have been observed in the absence of a difference in body weight between the offspring of obese and lean dams, and thus show that in rodents maternal obesity is able to programme cardiac function independent of offspring obesity^{(Reference Fernandez-Twinn, Blackmore and Siggens126,Reference Blackmore, Niu and Fernandez-Twinn127)} . Potential mechanisms for the programming of altered cardiac function include epigenetic alterations. Rat offspring exposed to maternal high-fat diet have differential histone modifications linked to altered regulation of genes involved in metabolic stress and cardiac dysfunction^{(Reference Upadhyaya, Larsen and Barwari135)}, and altered histone marks and DNA methylation resulting in the de-repression of pro-fibrotic and pro-hypertrophic genes^{(Reference Blin, Liand and Mauduit136)}. Furthermore, dysregulation of miRNA expression may also play a role, and analysis of miRNA expression in the hearts of fetal baboons found altered expression of miRNAs associated with adult CVD, cardiac hypertrophy, enhanced fibrosis, growth, proliferation and cellular development^{(Reference Maloyan, Muralimanoharan and Huffman122)}.

Exposure to maternal obesity also increases susceptibility of the offspring heart to damage from subsequent challenges. This includes a more severe cardiac phenotype when offspring of obese mothers are exposed to high-fat diet feeding in adult life with enhanced cardiac contractile dysfunction, cardiac hypertrophy, fibrosis, lipid accumulation, inflammation, reactive oxygen species accumulation, mitochondrial dysfunction and apoptosis seen in both rodent and sheep models^{(Reference Turdi, Ge and Hu137,Reference Ghnenis, Odhiambo and McCormick138)} . Another postnatal stress via transverse aortic constriction in rats also resulted in exacerbated cardiac dysfunction if offspring were exposed to a maternal high fructose diet^{(Reference Leu, Wu and Lee139)}. Programming by maternal obesity also increases susceptibility to ischaemia-reperfusion injury in offspring of obese dams in both rats and mice^{(Reference Xue, Chen and Li140,Reference Calvert, Lefer and Gundewar141)} . While some phenotypes appear shared by both male and female offspring^{(Reference Zhang, Cao and Tan119,Reference Ferey, Boudoures and Reid133)} , there is inconsistent evidence in both rat and mouse models that some programming of cardiac dysfunction by maternal obesity shows sexual dimorphism, with male-specific cardiac hypertrophy^{(Reference Xue, Chen and Li140)} and susceptibility to ischaemia-reperfusion injury^{(Reference Xue, Chen and Li140,Reference Calvert, Lefer and Gundewar141)} in offspring of obese dams, but female-specific impairment of systolic and diastolic function in offspring of obese mice^{(Reference Ferey, Boudoures and Reid133)}.

Together this shows that maternal obesity effects offspring cardiac development and function, thus predisposing offspring to increased risk of developing CVD (Fig. 1).

Evidence of offspring hypertension from human studies

Blood pressure is primarily influenced by a combination of cardiac output and systemic vascular resistance. Cardiac output in turn is affected by blood volume, cardiac contractility, heart rate and afterload, while systemic vascular resistance can be affected by increased vasoconstriction and arterial stiffness. Cardiac function (discussed earlier), kidney function, vascular responsiveness to vasoactive signals and vascular compliance therefore all play a role in the regulation of blood pressure.

A variety of global cohorts have shown an association between maternal obesity during pregnancy and increased risk of hypertension with raised blood pressure in her children at various ages from early childhood to adulthood^{(Reference Gaillard, Steegers and Duijts28,Reference Hochner, Friedlander and Calderon-Margalit64,Reference Cox, Luyten and Dockx142–Reference Laor, Stevenson and Shemer148)} . Some studies and meta-analyses have reported that observations of increased childhood blood pressure are independent of childhood BMI^{(Reference Gaillard, Steegers and Duijts28,Reference Cox, Luyten and Dockx142,Reference Eitmann, Mátrai and Németh149)} . However, another systematic review has suggested hypertension may be at least partially programmed secondary to the programming of increased adiposity in offspring of obese mothers^{(Reference Ludwig-Walz, Schmidt and Günther150)}. Controlling for childhood BMI was also shown to significantly decrease the association between maternal pre-pregnancy BMI and offspring hypertension in childhood^{(Reference Gaillard, Steegers and Duijts28,Reference Gademan, van Eijsden and Roseboom143)} and adulthood^{(Reference Cooper, Pinto Pereira and Power111,Reference Brunton, Dufault and Dart151)} , although a significant effect of maternal obesity did remain, indicating both direct and indirect programming mechanisms may be involved. One potential mechanism by which maternal obesity programmes increased offspring hypertension is by alterations in vascular function. This is supported by observations that maternal obesity is associated with increased carotid intima-media thickness^{(Reference Sundholm, Litwin and Rönö152)}, and increased retinal vessel tortuosity^{(Reference Cox, Luyten and Dockx142)}, a non-invasive assessment of alterations in the microcirculation, in her children.

Evidence of offspring hypertension from animal models

Animal models of maternal obesity have shown similar phenotypes to those seen in clinical studies. In particular, many different rodent models have shown an increased risk of hypertension in adult offspring of obese mothers compared to lean controls^{(Reference Desai, Jellyman and Han38,Reference Samuelsson, Matthenws and Argenton73,Reference Loche, Blackmore and Carpenter125,Reference Guberman, Jellyman and Han153–Reference Torrens, Ethirajan and Bruce157)} . In a rat model of maternal diet-induced obesity, offspring hypertension was observed in juvenile offspring, prior to the development of offspring adiposity, providing evidence for the direct programming of offspring hypertension by maternal obesity, independent of offspring obesity^{(Reference Samuelsson, Morris and Igosheva156)}. Furthermore, mouse models have shown the effects of maternal obesity and offspring postnatal high-fat diet to increase young adult offspring blood pressure to be additive^{(Reference Loche, Blackmore and Carpenter125)}. Thus, maternal obesity and offspring obesity are able to independently promote hypertension.

The increase in offspring hypertension in response to maternal obesity may be, at least in part, due to the programming of altered vascular structure and function. Rat offspring of dams fed with a high-fat diet during pregnancy and lactation show alterations in aortic structure at 6 months of age with reduced aortic endothelial cell volume and smooth muscle cell number^{(Reference Armitage, Lakasing and Taylor158)}. Structural changes in the offspring abdominal aorta have also been seen in non-human primate offspring of high-fat diet-fed mothers with increased intima media thickness compared to offspring of control mothers^{(Reference Fan, Lindsley and Comstock159)}. Rat offspring of obese dams also have abnormal aortic fatty acid composition^{(Reference Ghosh, Bitsanis and Ghebremeskel160)}, and increased aortic stiffness^{(Reference Armitage, Lakasing and Taylor158)}. Furthermore, rodent offspring of high-fat diet-fed mothers have impaired endothelial-dependent vasodilation of the aorta^{(Reference Armitage, Lakasing and Taylor158)}, femoral^{(Reference Torrens, Ethirajan and Bruce157,Reference Ghosh, Bitsanis and Ghebremeskel160,Reference Koukkou, Ghosh and Lowy161)} and mesenteric^{(Reference Samuelsson, Matthenws and Argenton73,Reference Taylor, Khan and Hanson162–Reference Khan, Taylor and Dekou164)} arteries, as well as an enhanced femoral vasoconstrictor response to noradrenaline^{(Reference Koukkou, Ghosh and Lowy161)}, and reduced mesenteric vasoconstrictor response to phenylephrine^{(Reference Gray, Vickers and Segovia163)}. This may, at least in part, be due to impaired nitric oxide bioavailability^{(Reference Torrens, Ethirajan and Bruce157)} and thus impaired nitric oxide-dependent endothelial function^{(Reference Gray, Vickers and Segovia163)}.

Studies of maternal diet-induced obesity in rats have suggested that the hypertension observed in offspring of obese dams has a sympathetic origin, as analysis of heart rate viability indicated an increase in the sympathetic component of blood pressure regulation, while β-adrenergic blockage was shown to inhibit the hypertensive phenotype^{(Reference Samuelsson, Morris and Igosheva156)}. There was also altered responses to phenylephrine or sodium nitroprusside indicative of reduced baroreflex sensitivity^{(Reference Samuelsson, Morris and Igosheva156)}. Similarly, in mouse offspring of obese dams, observations of increased blood pressure without a difference in heart rate suggest a resetting of the arterial baroreflex to allow an elevated resting arterial blood pressure^{(Reference Loche, Blackmore and Carpenter125)}. It is possible that programming of adult offspring hypertension is, at least in part, due to fetal and neonatal hyperleptinaemia affecting the development of hypothalamic neural circuits involved in blood pressure regulation^{(Reference Taylor, Samuelsson and Poston165)}. Leptin is known to affect the development and function of neural circuits involved in the autonomic nervous system regulation of blood pressure in mice^{(Reference Bouret, Draper and Simerly166)}. Furthermore, treatment of control-fed rat pups with exogenous leptin, mimicking the neonatal hyperleptinaemia seen in offspring of obese dams, increased offspring systolic blood pressure at 1 month of age with evidence of heightened sympathetic tone compared to saline-treated control offspring^{(Reference Samuelsson, Clark and Rudyk167)}.

Evidence of offspring kidney dysfunction from human studies and animal models

With regards to kidney function, human studies have shown maternal obesity to be associated with congenital abnormalities of the kidney and urinary tract^{(Reference Macumber, Schwartz and Leca168,Reference Hsu, Yamamoto and Henry169)} and reduced late-gestational fetal kidney volume relative to fetal body weight^{(Reference Lee, Lumbers and Oldmeadow170)}. As kidney volume is suggested as an approximate measure of renal nephron number^{(Reference Luyckx and Brenner171)}, maternal adiposity may be associated with reduced fetal nephron count, which can potentially lead to nephron hyperfiltration in order to maintain renal function, and thus progressive kidney damage and the development of hypertension in later life^{(Reference Brenner and Chertow172)}. Consistent with these observations, maternal obesity has been associated with increased risk of offspring developing childhood chronic kidney disease in a US-based cohort^{(Reference Hsu, Yamamoto and Henry169)}.

In contrast, a study in rats has shown that exposure to maternal obesity in the late-gestation fetus did not affect fetal kidney nephron number^{(Reference Zhou, Guan and Guo173)}. However, there was evidence for increased cellular stress, inflammation and apoptosis in the kidney of fetuses of obese dams compared to healthy controls^{(Reference Zhou, Guan and Guo173)}. Furthermore, late-gestation proteomic analysis of male fetal mouse kidneys from dams fed with a high-fat diet showed differential expression of proteins linked to transcription/translation, mitochondrial processes and membrane remodelling compared to offspring of controls^{(Reference Nüsken, Turnwald and Fink174)}.

Postnatally, studies in rodents have found that young offspring of dams fed with an obesogenic diet have impaired renal structure, function and inflammation^{(Reference Shamseldeen, Ali Eshra and Ahmed Rashed175)}. This persists in adulthood with increased renal inflammation, oxidative stress and fibrosis^{(Reference Glastras, Chen and McGrath176–Reference Yamada-Obara, Yamagishi and Taguchi178)}, accompanied by markers of kidney dysfunction^{(Reference Armitage, Lakasing and Taylor158,Reference Yamada-Obara, Yamagishi and Taguchi178)} in both the presence^{(Reference Yamada-Obara, Yamagishi and Taguchi178)} and absence^{(Reference Armitage, Lakasing and Taylor158)} of altered renal histology. A potential mechanism for the programming of offspring renal dysfunction is maternal obesity-induced depression of sirtuin 1 expression^{(Reference Nguyen, Chen and Pollock179)}, a key regulator promoting lipid utilisation and suppressing lipogenesis. In an mouse model, both overexpression and administration of a sirtuin 1 activator were able to attenuate some, but not all, of the negative programming effects of maternal obesity in the offspring kidney^{(Reference Nguyen, Mak and Chen180)}. Exposure to maternal obesity in utero may also lead to increased offspring susceptibility to subsequent renal injury, with enhanced offspring renal damage following streptozotocin-induced diabetes^{(Reference Glastras, Tsang and Teh177)}, as well as enhanced renal inflammation, fibrosis, glomerulosclerosis and kidney dysfunction in mouse and rat offspring challenged with a postnatal obesogenic diet^{(Reference Glastras, Chen and McGrath176,Reference Jackson, Alexander and Roach181,Reference Flynn, Alexander and Lee182)} .

Studies which have investigated offspring outcomes in both male and female offspring suggest there may be differences in the programming of offspring renal damage by maternal obesity^{(Reference Nguyen, Chen and Pollock179,Reference Tain, Lin and Sheen183)} , although there are some inconsistencies as to which sex is more vulnerable to adverse effects. For example, a rat model of maternal diet-induced obesity has shown increased renal lipid accumulation and more prominent renal fibrosis in male offspring^{(Reference Nguyen, Chen and Pollock179)}, while in contrast another study has shown that maternal diet-induced obesity resulted in greater changes in the female rat offspring renal transcriptome, compared to males^{(Reference Tain, Lin and Sheen183)}.

Overall maternal obesity has been shown to affect offspring renal and vascular function, predisposing offspring to increased risk of developing hypertension in later life (Fig. 1).

Evidence from human studies

With the significant body of evidence associating maternal obesity with adverse offspring cardiometabolic outcomes (Fig. 1), there is a clear need for the development of effective interventions in obese pregnancy to protect offspring health. In human subjects, intervention studies exploring the effects of exercise during overweight or obese pregnancy either alone^{(Reference Seneviratne, Jiang and Derraik184–Reference Dekker Nitert, Barrett and Denny197)} or combined with other lifestyle and dietary changes^{(Reference Mottola, Giroux and Gratton198–Reference Petrella, Malavolti and Bertarini221)} have shown mixed and somewhat inconsistent success for the prevention of adverse maternal, pregnancy and neonatal outcomes.

In terms of maternal outcomes, gestational weight gain was shown to be reduced by exercise intervention in some studies^{(Reference Wang, Wei and Zhang188,Reference Bisson, Alméras and Dufresne189,Reference Daly, Farren and McKeating192,Reference Mottola, Giroux and Gratton198,Reference Poston, Bell and Croker200,Reference Simmons, Devlieger and van Assche205,Reference Vinter, Jensen and Ovesen210,Reference Renault, Nørgaard and Nilas211,Reference Claesson, Sydsjö and Brynhildsen216,Reference Shirazian, Monteith and Friedman217,Reference Bogaerts, Devlieger and Nuyts219–Reference Petrella, Malavolti and Bertarini221)} , although not in others^{(Reference Seneviratne, Jiang and Derraik184,Reference Garnæs, Mørkved and Salvesen185,Reference Nascimento, Surita and Parpinelli193,Reference Dekker Nitert, Barrett and Denny197,Reference Dodd, Turnbull and McPhee199,Reference Rönö, Grotenfelt and Klemetti207,Reference Phelan, Phipps and Abrams215,Reference Guelinckx, Devlieger and Mullie218)} . There is some evidence of reduced maternal adiposity^{(Reference Poston, Bell and Croker200)} and post-partum weight retention^{(Reference Kong, Campbell and Wagner191,Reference Mottola, Giroux and Gratton198,Reference Phelan, Phipps and Abrams215)} with exercise interventions during pregnancy, although this is not consistent across all studies^{(Reference Seneviratne, Jiang and Derraik184,Reference Garnæs, Mørkved and Salvesen185)} . A similar pattern is seen for incidence of gestational diabetes with evidence of reduced risk by intervention in some^{(Reference Garnæs, Mørkved and Salvesen185,Reference Wang, Wei and Zhang188,Reference Ong, Guelfi and Hunter194,Reference Dieberger, Desoye and Stolz208,Reference Brankston, Mitchell and Ryan214,Reference Petrella, Malavolti and Bertarini221)} , but not all cohorts^{(Reference Bisson, Alméras and Dufresne189,Reference Daly, Farren and McKeating192,Reference Callaway, Colditz and Byrne196,Reference Poston, Bell and Croker200,Reference Simmons, Devlieger and van Assche205,Reference Rönö, Grotenfelt and Klemetti207,Reference Vinter, Tanvig and Christensen209,Reference Vinter, Jensen and Ovesen210,Reference Kennelly, Ainscough and Lindsay213,Reference Phelan, Phipps and Abrams215,Reference Shirazian, Monteith and Friedman217)} . Physical activity interventions were also shown to promote improved maternal vascular function with decreased blood pressure reported in some^{(Reference Garnæs, Mørkved and Salvesen185,Reference Petrella, Malavolti and Bertarini221)} , but not all^{(Reference Nascimento, Surita and Parpinelli193,Reference Vinter, Jensen and Ovesen210)} studies. Some studies also suggest that maternal exercise intervention promotes improved maternal cardiorespiratory fitness^{(Reference Seneviratne, Jiang and Derraik184,Reference Bisson, Alméras and Dufresne189,Reference Santos, Stein and Fuchs190)} and metabolic profiles^{(Reference Mills, Patel and White203)}, although results were again inconsistent^{(Reference Dekker Nitert, Barrett and Denny197,Reference Renault, Carlsen and Hædersdal212)} .

Generally no effects of exercise interventions have been observed on birth weight or frequency of large for gestational age infants^{(Reference Seneviratne, Jiang and Derraik184,Reference Garnæs, Nyrnes and Salvesen186,Reference Bisson, Alméras and Dufresne189,Reference Daly, Farren and McKeating192,Reference Nascimento, Surita and Parpinelli193,Reference Oostdam, van Poppel and Wouters195,Reference Dekker Nitert, Barrett and Denny197–Reference Poston, Bell and Croker200,Reference Vinter, Jensen and Ovesen210,Reference Phelan, Phipps and Abrams215–Reference Bogaerts, Devlieger and Nuyts219)} , although some studies did report reduced birth weight^{(Reference Wang, Wei and Zhang188)}. There is also, albeit inconsistent^{(Reference Garnæs, Nyrnes and Salvesen186,Reference Kong, Campbell and Wagner191,Reference Dekker Nitert, Barrett and Denny197)} , evidence of reduced adiposity in neonates^{(Reference van Poppel, Simmons and Devlieger206)} and 6 month old infants^{(Reference Patel, Godfrey and Pasupathy201)}, although this phenotype was lost by 3 years^{(Reference Dalrymple, Tydeman and Taylor204)}. Analysis of cord blood metabolites has shown no difference in some studies^{(Reference Dekker Nitert, Barrett and Denny197,Reference Patel, Hellmuth and Uhl202)} , while others reported reduced cord leptin levels^{(Reference van Poppel, Simmons and Devlieger206)}. Few studies have considered the offspring cardiovascular system, however one study suggested that exercise intervention in maternal obesity does not affect newborn systolic or diastolic cardiac functional parameters^{(Reference Nyrnes, Garnæs and Salvesen187)}, although there is evidence of reduced resting pulse rate in 3 year old offspring^{(Reference Dalrymple, Tydeman and Taylor204)}, which may indicate reduced cardiovascular risk.

The large variation in human intervention studies may be due to a combination of the different intervention protocols utilised, poor adherence to intervention programmes^{(Reference Seneviratne, Jiang and Derraik184,Reference Nyrnes, Garnæs and Salvesen187,Reference Oostdam, van Poppel and Wouters195,Reference Phelan, Phipps and Abrams215)} and variations in factors such as population ethnicity. Furthermore, due to the time scales involved in follow-up studies, there is a severe lack of long-term offspring data for the effect of maternal exercise intervention in the context of obese pregnancy, with the oldest study to date following offspring up to 3 years of age^{(Reference Dalrymple, Tydeman and Taylor204)}. Thus, animal models are an important tool to investigate the long-term effects of exercise interventions on offspring health, as well as underlying mechanisms.

Evidence from animal models

Most studies of maternal exercise intervention in obese pregnancy have been carried out in rodent models. Although there is some variation in the nature of the intervention with different studies utilising voluntary or involuntary wheel running^{(Reference Bae-Gartz, Janoschek and Kloppe48,Reference Vega, Reyes-Castro and Bautista222–Reference Zheng, Alves-Wagner and Stanford230)} , treadmill running^{(Reference Beeson, Blackmore and Carr128,Reference Fernandez-Twinn, Gascoin and Musial231–Reference Son, Zhao and Chen235)} or swimming^{(Reference Zhu, Ma and Ye236)}, some consistent patterns have emerged in terms of maternal and offspring outcomes.

Rodent models have shown that exercise interventions can improve the maternal metabolic profile, including improvement of the impaired glucose tolerance, increased insulin concentrations and impaired insulin signalling usually seen in obese dams^{(Reference Vega, Reyes-Castro and Bautista222,Reference Fernandez-Twinn, Gascoin and Musial231–Reference Musial, Fernandez-Twinn and Duque-Guimaraes233)} , although not maternal weight or adiposity^{(Reference Bae-Gartz, Janoschek and Kloppe48,Reference Vega, Reyes-Castro and Bautista222,Reference Raipuria, Bahari and Morris223,Reference Fernandez-Twinn, Gascoin and Musial231,Reference Musial, Fernandez-Twinn and Duque-Guimaraes233)} . Exercise intervention during obese rodent pregnancy can also partially prevent some aspects of increased oxidative stress in maternal tissues^{(Reference Vega, Reyes-Castro and Bautista222)} and the placenta^{(Reference Fernandez-Twinn, Gascoin and Musial231)}. Furthermore, maternal exercise prevents obesity-induced increases in rodent placental lipid accumulation, inflammation and alterations in placental morphology to reduce vascularisation^{(Reference Fernandez-Twinn, Gascoin and Musial231,Reference Son, Liu and Tian232)} .

In the offspring, the elevated blood glucose and insulin levels seen in both male and female offspring of obese rodent dams can be improved in the pup^{(Reference Raipuria, Bahari and Morris223)} and adult offspring^{(Reference Bae-Gartz, Janoschek and Kloppe48,Reference Vega, Reyes-Castro and Bautista222,Reference Stanford, Lee and Getchell225–Reference Laker, Altıntaş and Lillard228,Reference Fernandez-Twinn, Gascoin and Musial231,Reference Ribeiro, Tófolo and Martins234,Reference Zhu, Ma and Ye236)} by exercise intervention during pregnancy. Maternal exercise intervention is also protective against other adverse effects of maternal obesity in rats and mice, including preventing increased adiposity^{(Reference Stanford, Lee and Getchell225,Reference Ribeiro, Tófolo and Martins234,Reference Zhu, Ma and Ye236)} , cognitive impairment^{(Reference Moser, McDaniel and Woolard229)}, dysregulation of hypothalamic gene expression^{(Reference Bae-Gartz, Janoschek and Kloppe48)}, hepatic dysfunction and insulin resistance^{(Reference Stanford, Takahashi and So226)}, epigenetic and transcriptional changes in skeletal muscle leading to impaired muscle oxidative capacity^{(Reference Raipuria, Bahari and Morris223,Reference Laker, Lillard and Okutsu227,Reference Laker, Altıntaş and Lillard228)} , increased inflammation^{(Reference Bae-Gartz, Janoschek and Kloppe48)} and β-cell dysfunction^{(Reference Zheng, Alves-Wagner and Stanford230)}. However, few studies have specifically investigated the effects of exercise intervention in obese pregnancy on offspring cardiovascular function^{(Reference Beeson, Blackmore and Carr128)}. In male mice it has been shown that maternal exercise prevents cardiac hypertrophy and dysfunction in offspring of obese dams, however there was no such protective effect seen on offspring vasculature with no reversal of increased systolic blood pressure or increased aortic diameter by maternal exercise intervention^{(Reference Beeson, Blackmore and Carr128)}.

Some mouse studies have suggested that the positive effects of maternal exercise intervention on obese pregnancies may be mediated via improvement of maternal hyperinsulinaemia, which may be sufficient to prevent offspring hyperinsulinaemia^{(Reference Fernandez-Twinn, Gascoin and Musial231)}, adipose tissue insulin resistance^{(Reference Fernandez-Twinn, Gascoin and Musial231)} and cardiac dysfunction^{(Reference Beeson, Blackmore and Carr128)}. However, as maternal exercise has not been shown to rescue the programming of offspring hypertension in rodents^{(Reference Beeson, Blackmore and Carr128)}, other programming factors may also be involved. One candidate for the programming of hypertension is maternal hyperleptinaemia, as this is not corrected by maternal exercise in rodents^{(Reference Vega, Reyes-Castro and Bautista222,Reference Fernandez-Twinn, Gascoin and Musial231)} .

Similar to the programming of the offspring cardiometabolic phenotype by maternal obesity discussed in previous sections, the effects of exercise intervention on early life also show some sexual dimorphism. Some studies have shown greater benefits to the more severely affected male rat pups^{(Reference Raipuria, Bahari and Morris223)}, while in contrast, in weaning mouse offspring, maternal exercise intervention has been shown to be more effective in females, with female-specific improved metabolic characteristics^{(Reference Zhu, Ma and Ye236)}. However, in other mouse studies the degree of metabolic improvement conferred to adult offspring by maternal exercise appears similar for both sexes^{(Reference Stanford, Lee and Getchell225,Reference Stanford, Takahashi and So226)} .

Thus, maternal exercise in obese pregnancy, while showing varied success in human trials, does appear to be an effective potential intervention to protect offspring from the long-term programming of cardiometabolic disease by maternal obesity. A greater number of high-quality human intervention studies, with better compliance and longer term follow-up, are required in order to validate these observations seen in animal models.