OCL 2020, 27, 15DOI: 10.1051/ocl/2020012© E.M. van der Beek and A. Oosting, Hosted by EDP Sciences, 2020

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Review

Nutritional programming in early life: the role of dietary lipid quality for future health☆

Programmation nutritionnelle en début de vie : le rôle de la qualité des lipides alimentaires pour la santé future

Eline M. van der Beek¹,2* and Annemarie Oosting¹

¹ Danone Nutricia Research, Utrecht, The Netherlands
² Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

* Correspondence: vanderbeek@danone.com

Received: 5 November 2019 Accepted: 10 March 2020 Published online: 3 April 2020

Abstract

Worldwide, overweight and obesity have increased dramatically, not only in high income countries. Clearly, unhealthy diets and sedentary lifestyle are important drivers of the increased obesity rates, but increasing evidence indicates that the vulnerability for later life non-communicable diseases is set during the first 1000 days, the period from conception until 2 years of age. The growth during this period is faster than during any other period in life. Dietary fats provide energy for growth, but also supply essential fatty acid (FA) precursors for long chain polyunsaturated FA that are building blocks and signals for adipose tissue development. Both epidemiological and experimental data support the notion that specific improvements in dietary fat quality, e.g. specific changes in the fatty acid composition as well as the structural organization of dietary lipids, may reduce the risk of obesity and other adverse outcomes in later life, but clinical evidence is limited and largely inconclusive. We anticipate that effects of such relatively small improvements in nutrient quality may be difficult to measure on the short term and have limited impact in healthy children. However, for children that already experience challenging conditions in the womb and have a higher risk profile based on deviations in birthweight and postnatal growth, the potential protective effects of improved dietary lipid quality in early life could be more substantial. Results from randomized clinical studies testing improved lipid quality concepts will help to develop specific strategies to adapt infant nutrition based on the need with the aim to improve long term outcomes.

Résumé

Au niveau mondial, la fréquence du surpoids et de l’obésité a augmenté de façon spectaculaire, et pas seulement dans les pays à hauts revenus. Il est clair que les régimes alimentaires déséquilibrés et la sédentarité sont des facteurs importants de ces augmentations, mais des preuves de plus en plus nombreuses indiquent que la vulnérabilité aux maladies non transmissibles à un âge plus avancé se détermine durant les 1000 premiers jours de la vie, c’est-à-dire la période allant de la conception à l’âge de 2 ans. La croissance pendant cette période est plus rapide que pendant toute autre période de la vie. Les graisses alimentaires fournissent l’énergie nécessaire à la croissance, mais aussi des précurseurs d’acides gras (AG) essentiels pour les AG polyinsaturés à longue chaîne qui sont des éléments constitutifs et des signaux pour le développement du tissu adipeux. Les données épidémiologiques et expérimentales confirment l’idée que des améliorations spécifiques de la qualité des graisses alimentaires, par exemple des modifications spécifiques de leur composition en acides gras ainsi que de leur organisation structurelle, peuvent réduire le risque d’obésité ainsi que d’autres effets néfastes pour la santé à un âge avancé, mais les preuves cliniques sont limitées et très peu concluantes. Il est à envisager que les effets de faible intensité de ces améliorations de la qualité des nutriments pourraient être difficiles à mesurer à court terme et donc avoir un impact limité sur les enfants en bonne santé. Toutefois, pour les enfants qui connaissent déjà des conditions difficiles in utero et qui peuvent présenter un profil de risque beaucoup plus élevé en raison des écarts de poids à la naissance et de croissance postnatale, les effets protecteurs potentiels d’une amélioration de la qualité des lipides alimentaires en début de vie pourraient être plus importants. Les résultats d’études cliniques randomisées testant les concepts d’une meilleure qualité lipidique aideront à développer des stratégies spécifiques pour adapter l’alimentation des nourrissons en fonction des besoins, dans l’objectif d’améliorer les résultats à long terme.

Key words: LA-ALA ratio / fatty acid composition / dietary fat structure / metabolic programming / obesity risk

Mots clés : rapport LA-ALA / composition en acides gras / structure des graisses alimentaires / programmation métabolique / risque d’obésité

☆

Contribution to the Topical Issue “Lipids and health / Lipides et santé”.

1 Early life, obesity & non-communicable disease

Obesity poses a global economic and health burden due to high medical costs, loss of productivity and loss of health-related quality of life (Wang et al., 2011; OECD report, 2019). Obesity increasingly emerges at an early age, and the prevalence of childhood obesity is increasing worldwide (Jackson-Leach and Lobstein, 2006). In 2010, 43 million children under the age of 5 were overweight or obese and numbers are expected to increase to 60 million by the year 2020 (De Onis et al., 2010; WHO Fact Sheet Obesity & Overweight, 2012; NCD Risk Factor Collaboration (NCD-RisC), 2017). This is particularly alarming because early onset obesity is strongly associated with adult obesity risk (Lobstein et al., 2004) and with early onset and more severe metabolic disease (Lobstein and Jackson-Leach, 2006).

Excess intake of energy-dense foods and sedentary lifestyle are considered the two most important contributors to the energy imbalance underlying obesity (Nishida et al., 2004, Crombie et al., 2009). However, neither contemporary lifestyle factors nor established genetic factors can fully explain the rapid increase in (childhood) obesity over the past few decades (Eisenmann, 2006; Crombie et al., 2009). Early life environmental factors have been suggested to contribute to (childhood) obesity including pharmaceutical agents, endocrine disruptors, reduced sleep duration and nutrition (McAllister et al., 2009). Since weight management programs show only moderate and short term effectiveness (Bond et al., 2009), prevention is key.

2 Programming later health

The Developmental Origins of Adult Health and Disease (DOHaD) concept originated from the “fetal origins of adult health” hypothesis. This notion was based on the observation that low birth weight, suggested as a proxy for impaired fetal growth, was associated with increased mortality due to ischemic heart disease at middle age (Barker et al., 1989). Since then, many epidemiological and experimental studies confirmed that nutritional disturbances during critical periods of early life development predispose to obesity and metabolic disease later in life (Barker et al., 1993; Uvena-Celebrezze et al., 2002; Ehrenberg et al., 2004; Gluckman et al., 2005, 2007; Lillycrop et al., 2005; Hernandez-Valencia and Patti, 2006; Lambin et al., 2007; Taylor and Poston, 2007; Godfrey et al., 2010; Schwarzenberg et al., 2018). Current thinking is that developmental adaptations to nutritional signals are a normal part of development in anticipation of the future (nutritional) environment. Consequently, a specific genotype can generate a variety of different phenotypes depending on environmental cues during critical periods of development, i.e. periods of developmental plasticity. Adaptation can only be induced during these critical periods and changes in phenotype are considered irreversible when the period of developmental plasticity ends (McMillen and Robinson, 2005).

It has become increasingly acknowledged that the window for programming extends into the (early) postnatal period (Singhal and Lucas, 2004; Guilloteau et al., 2009; Symonds et al., 2009). Observational studies investigating postnatal growth velocity provide evidence that the period after birth can be considered a critical window of plasticity, independent of the prenatal period. A meta-analysis of individual-level data of more than 47 thousand individuals from 10 cohort studies showed independent positive association of weight gain in the first year of life with childhood obesity (Druet et al., 2011). Postnatal growth velocity across all birth weight tertiles predicted abdominal adiposity at 2 years of age in a prospective birth cohort (Durmus et al., 2010) and enhanced postnatal weight gain rather than birth weight was strongly associated with abdominal fat mass in a pediatric obese population (Wells et al., 2011).

Although the timing of this critical period for individual organs is not fully clarified, the development of many (metabolic) organs including gastrointestinal tract (Le Huerou-Luron et al., 2010), brain (Alamy and Bengelloun, 2012), pancreas (Fowden and Hill, 2001) and adipose tissue (Symonds et al., 2010; Hauner et al., 2013) continues for a considerable time after birth.

Several mechanisms, including (irreversible) changes in organ and tissue structure, epigenetic regulation of gene expression, altered set-points for homeostatic neuroendocrine systems and changes in cellular mitochondrial capacity may contribute to these long term effects of early life nutritional programming (Godfrey et al., 2011; Waterland, 2014).

3 Breast feeding & obesity risk

Epidemiological studies indicate that breastfeeding is associated with a moderately reduced risk of later life obesity and metabolic disease (Fall et al., 1992; Owen et al., 2006, 2008; Ryan, 2007). Specifically longer duration (> 6 months) of breastfeeding is associated with a reduced risk of childhood obesity (Harder et al., 2005). It has been hypothesized that the reduced growth velocity of breastfed (BF) infants compared to formula fed (FF) infants might underlie the reduced obesity risk (Gale et al., 2012). The PIAMA birth cohort showed that infants who were BF for more than 16 weeks had a lower Body Mass Index (BMI) at 1 year of age, suggesting slower growth, compared to FF infants. BMI at 1 year of age was positively associated with BMI at 7 years of age (Scholtens et al., 2007). A systematic review and meta-analysis by Gale and colleagues showed that differences in weight gain between BF and FF were accompanied by differences in body composition trajectories (Gale et al., 2012). BF infants had lower lean body mass throughout infancy compared to FF infants, whereas fat mass was higher before 6 months of age but lower between 6 and 12 months of age. Additionally, breastfeeding for more than 4 months was associated with lower visceral adiposity at 2 years of age (Durmus et al., 2011). Long-term implications of these different growth trajectories remain to be elucidated, but the reduced growth velocity and altered lean and fat mass development are compatible with a better “quality of growth” in BF infants, resulting in less deposition of visceral adipose tissue.

Many other factors associated with infant feeding have been suggested to contribute to obesity risk, including milk volume and intake patterns, timing of weaning, energy density, protein content, n-6/n-3 PUFA content and bioactive compounds such as leptin, ghrelin and adiponectin (Bartok and Ventura, 2009; Thompson, 2012). It should be noted, however, that the contribution of these factors to obesity risk has often been extrapolated from their effects on early growth trajectories rather than clearly demonstrated through direct association with (childhood) obesity or through intervention studies. Clearly, since almost all of the studies examining the association between breast feeding and later outcomes are observational, there is a high risk of confounding by socioeconomic and other environmental circumstances. For instance, the choice to breast feed exclusively and/or for longer duration is strongly influenced by maternal education level.

4 Dietary lipids in early life

Human Milk (HM) lipid content and composition is affected by maternal diet and body composition, stage of lactation (colostrum, transitional or mature milk), interval between feeds during 24 h and volume ingested per feed, but even changes during a single feed (fore- versus hind-milk) (Emmett and Rogers, 1997; Mitoulas et al., 2002; Minda et al., 2004; Carlson and Colombo, 2016; van de Heijning et al., 2017).

The average lipid content of mature milk is 39 g/L, but can vary between 25 and 59 g/L. HM lipid globules comprise of a core consisting of triglycerides and cholesteryl-esters surrounded by a native biological membrane composed mainly of phospholipids, proteins and enzymes, free cholesterol and glycoproteins. The lipid globule size ranges between 1 and 10 μm. HM contains between 0.1 and 0.35 g/L cholesterol and between 0.1 and 0.4 g/L phospholipids (Koletzko et al., 2001, 2005; Michalski et al., 2005; Gallier et al., 2015). In contrast, the lipid composition in Infant Milk Formula (IMF) is maintained constant and uniform to adhere to (inter)national legislation (see EU Commission Directive, 2006) (Innis, 1992, 2007; Koletzko et al., 2005). IMF encompasses small lipid globules triglycerides with milk proteins adhering to the globule surface and the majority of the lipid content is comprised of triglycerides (Gallier et al., 2015; Bourlieu et al., 2017).

During the first 4–6 months of life, HM (or IMF) is the sole source of nutrition for the infant. Both provide 40–55% energy as fat. Dietary fats provide energy for growth, supply the essential fatty acids (EFA) linoleic acid (LA; C18:2 n-6) and α-linolenic acid (ALA; C18:3 n-3), and ensure adequate absorption of the fat-soluble vitamins required for a healthy growth and development. EFA play an important role in growth and development during the last months of gestation and the first months of postnatal life (Innis, 1991; Koletzko et al., 2008). Between 6 months and 2 years of age, the WHO recommends 30–40% energy from fat, although it has been suggested that the energy derived from fat should be gradually reduced to maximal 30% to better match energy requirements and reduce weight gain velocity according to new WHO reference growth standards (Uauy and Dangour, 2009).

The LA and ALA coming from the diet (Le et al., 2009) need to be converted to 20 to 22-carbon long chain polyunsaturated fatty acids (LC-PUFA) by (delta-5 and delta-6) desaturases and elongases (Guillou et al., 2009). Because LA and ALA compete for the same set of enzymes, the absolute amount of dietary EFA as well as the n-6/n-3 ratio determines the relative abundance of the LCPs arachidonic acid (ARA; C20:4 n-6) and docahexanoic acid (DHA, C22:6 n-3) and their incorporation in biological membranes (Jensen et al., 1997; Makrides et al., 2000), as well as the ARA and n-3 eicosapentaenoic acid (EPA; C22:6 n-3) derived eicosanoid metabolites (Broughton and Wade, 2002). LC-PUFAs can be considered conditionally essential during this period of rapid growth, because synthesis capacity may be too limited to obtain tissue LC-PUFA levels as high as found in infants fed preformed DHA and ARA (Salem et al., 1996; Fleith and Clandinin, 2005; Brenna et al., 2009).

The European Food Safety Authority (EFSA) set adequate nutrient intakes of LC-PUFA for infants from birth to 6 months at 100 mg DHA/day and 140 mg ARA/day (EFSA Scientific Opinion, 2013), supported by a systematic review of the available scientific evidence (Koletzko et al., 2014). However, according to the latest adopted European Union compositional requirements, all infant and follow-on formula should contain relatively high amounts of 20–50 mg DHA/100 kcal (approximately 0.5–1% of FA), but providing ARA is no longer considered necessary, thus allowing levels that are significantly deviating from levels typically found in human milk. To preserve in vivo conversion of the precursors LA and ALA to their respective LC-PUFAs, minimal LA addition levels were increased, whereas ALA addition levels were set lower resulting in a clearly higher LA/ALA ratio than before without a maximum (e.g. range n6/n3 set to 5–15 previously) (EFSA Scientific Opinion, 2014). These changes in the recommendations are a topic of fierce scientific debate based on the scarcity of data to support these directions (Delplanque et al., 2015; Koletzko et al., 2015). A recently published position paper of the European Academy of Paediatrics and Child Health Foundation strongly advocates addition of ARA to similar levels as DHA and highlights the need for well designed clinical studies to evaluate optimal intakes of DHA and AA based on relevant outcomes including safety (Koletzko et al., 2020).

As indicated earlier, the IMF recommendations are based on the composition of HM. However, changes in food processing, sourcing of dietary lipids and dietary intake patterns have resulted in a global contemporary increase in exposure to dietary LA and a decrease in n-3 LC-PUFA over the last decades (Sanders, 2000; Wolmarans, 2009; Blasbalg et al., 2011; Guyenet and Carlson, 2015; Wood et al., 2015) also considerably affecting HM FA composition (Ailhaud et al., 2006; Gibson et al., 2011). The net result is a higher dietary (and HM) n-6/n-3 ratio, which has been hypothesized to contribute to the pathogenesis of cardiovascular disease, cancer, inflammatory and auto-immune diseases (Hibbeln et al., 2006; Simopoulos, 2008; Ramsden et al., 2013).

5 Dietary lipid composition and adipose tissue development

Ailhaud and colleagues hypothesized that the contemporary high dietary LA intake and the concomitant increased n-6/n-3 ratio, is a key determinant in obesity development (Ailhaud and Guesnet, 2004; Ailhaud et al., 2006; Massiera et al., 2006, 2010). The proposed underlying mechanism includes the stimulatory effect of high ARA, synthesized from dietary LA, on adipose tissue expansion through enhanced adipogenesis and lipogenesis especially during early development (Massiera et al., 2003, 2006, 2010; Muhlhausler and Ailhaud, 2012).

Adipose tissue growth is regulated by the concerted actions of several transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ γ), which heterodimerizes upon activation with retinoid X receptor α (RXRα), and the CCAAT/enhancer binding protein (C/EBP) family members (Darlington et al., 1998; Berger and Moller, 2002). N-6 and n-3 polyunsaturated fatty acids (PUFA) and their eicosanoid metabolites act as endogenous PPAR ligands (Waku et al., 2009), enabling sensing of nutritional signals and translating these into a metabolic response to maintain homeostasis. ARA is a precursor of prostacyclin, a very potent adipogenic factor (Massiera et al., 2003). After its release from preadipocytes, prostacyclin binds to its receptor, which activates the protein kinase A pathway through cAMP production, thereby enhancing C/EBPβ and C/EBPδ expression (Madsen et al., 2005, 2008; Ailhaud et al., 2006). N-3 LCPs EPA and to a lesser extent DHA, inhibit ARA effects on cAMP production and can thereby counteract pro-adipogenic effects of ARA. Apart from adipogenesis, n-3 and n-6 LC-PUFAs have differential effects on transcription factors involved in white adipose tissue (WAT) lipogenesis with n-3 inhibiting and n-6 PUFA stimulating expression of lipogenic transcription factors (Muhlhausler et al., 2010a). Although PUFAs could exert their effects on WAT transcription factors throughout life, early life exposure may enhance their effects due to the high capacity of adipocyte precursors to proliferate and differentiate in this period (Hauner et al., 2013). Moreover, early LC-PUFA exposure may program lipogenic genes towards enhanced expression, for instance through modulation of DNA-methylation (Milagro et al., 2013).

6 Dietary FA composition in early life & later obesity risk

Based on the notion that a high dietary n-6/n-3 ratio may contribute to the current obesity incidence, changing dietary FA quality, reaching a level and composition closer to ancient diets (Kuipers et al., 2005; Muskiet et al., 2006), might decrease obesity risk. Preclinical studies in mice showed that early postnatal exposure to a diet containing identical levels of fat but containing either more n-3 LC-PUFA (5% of total fatty acid content) or a 50% reduction in LA content, both effectively decreasing the total n-6/n-3 ratio, protected against excessive fat accumulation in response to a mild western style diet challenge in adulthood (Oosting et al., 2010, 2015a). These two manipulations in early life in the dietary PUFA composition resulted in a comparable reduction in fat accumulation: 30% (n-3 LC-PUFA increase) and 27% (LA reduction) respectively. Possible effect size of such dietary manipulations may be very different in humans but warrant further research since a 5% reduction in body fat percentage already improves cardio-metabolic risk profile in obese children (Going et al., 2011).

Although these mouse studies demonstrated that both increased postnatal n-3 LC-PUFA or reduced LA decreased adult fat accumulation following an western diet challenge, the mechanisms by which these diets decreased adult obesity risk are likely different. Supplementation with the n-3 enriched diet resulted in reduced fat mass and smaller adipocytes (Oosting et al., 2010), supporting altered homeostatic control of lipid metabolism resulting in enhanced lipolysis or reduced lipogenesis (Kopecky et al., 2009). Lowering the relative contribution of n-6 LA to the diet, however, increased adipocyte size and showed a trend towards a lower adipocyte number (Oosting et al., 2015a), suggesting a reduction in preadipocyte differentiation (adipogenesis) and thereby decreasing longer term lipid storage capacity. In addition, other mechanisms may contribute to the observed effects. The reduced fat accumulation, despite enhanced adult food intake in mice fed the low LA diet (Oosting et al., 2015a), suggest programming effects on adult energy partitioning and feed efficiency. In line with this suggestion, a fat balance study in mice showed that LA tended towards enhanced energy storage in WAT and towards a lower energy expenditure compared to saturated fatty acids, n-3 PUFA or conjugated LA (Javadi et al., 2004). Additionally, altered hypothalamic regulation of energy homeostasis could also play a role, considering the lipid sensing ability of the hypothalamus (Pocai et al., 2006; Avram et al., 2007). Indeed, in a separate study we showed that both reducing LA and increasing n-3 LCP reduced the outgrowth of orexogenic and anorexogenic neuronal projections in the developing hypothalamus with potential consequences for the central regulation of satiety and energy (Schipper et al., 2013).

Our data suggest that the balance of n-6 and n-3 EFA and LC-PUFAs in the early postnatal diet is relevant for the observed programming effects on adult obesity development in mice and rats. The net balance of n-6 and n-3 PUFA in tissues is determined by dietary intake of LA and ALA and the respective LC-PUFAs produced, knowing that the enzymes for conversion of LA and ALA are shared, and dietary LC-PUFAs inhibit endogenous LC-PUFA synthesis. Consequently, supplementation of ALA to a high LA diet may have very limited effects on n-3 LC-PUFA status and metabolic health, because LA inhibits both n-3 LC-PUFA synthesis from ALA and its incorporation in biological membranes (Gibson et al., 2011, 2013). Apart from the n-6/n-3 balance, absolute amounts of LA and ALA are important, as high amounts of LA can inhibit ALA conversion to EPA irrespective of the relative dietary LA/ALA ratio (Goyens et al., 2006). In addition, the total dietary fat content modulates the PUFA effects. N-3 LC-PUFA concentrations ranging from 0 to 1.5%wt combined with fat content ranging from 5 to 20%wt of total diet under a constant LA concentration result in differential patterns of ARA derived eicosanoids in mice (Broughton and Wade, 2002). These data support the notion that adipogenic, lipogenic and proinflammatory effects of ARA and its eicosanoid metabolites are modulated by total fat content and n-3 LC-PUFA abundance (Broughton and Wade, 2002; Ailhaud et al., 2006; Muhlhausler et al., 2010a). Finally, also the macronutrient composition of the diet may modulate adipogenic effects of ARA during early development. The combination of high LA with high sucrose (43%wt) was pro-adipogenic, whereas the combination of high LA and high protein (50%wt) was anti-adipogenic in adult mice (Madsen et al., 2008).

Taken together, these data indicate that (programming) effects of early life PUFAs as demonstrated in rodent models depend on overall dietary EFA and LC-PUFA content and ratio, total dietary fat content and overall macronutrient composition, which may explain some of the ambiguous results from the few animal and human intervention studies that have investigated metabolic programming by dietary lipids.

7 Dietary physical lipid structure in early life & later obesity risk and metabolic health

Apart from FA composition, the physical structure of dietary lipids in HM can be considered a key feature of early life dietary lipid quality. We have shown that exposure of preweaning mice to a diet containing a physical lipid structure closer to that of HM, i.e. with an increased lipid droplet size and a phospholipid (PL) coating (Nuturis®, Gallier et al., 2015) protected against excessive fat mass accumulation in adolescence and young adulthood (Oosting et al., 2012, 2014; Baars et al., 2016) although effects may decrease and disappear after longer HFD exposure (Oosting et al., 2012; Ronda et al., 2019). The effect size of this programming diet on body composition was in fact comparable to those resulting from the adjustments in early life PUFA composition (Oosting et al., 2010, 2015a), namely 30% lower adult fat mass after feeding Nuturis® compared to a standard IMF based diet.

The underlying mechanism of this so called “lipid matrix” effect remains elusive to some extent. Postnatal exposure to the altered physical lipid structure had sustained effects on adipocyte size, indicating programming towards reduced lipid and storage. This notion was supported by reduced expression of lipogenic transcription factors in adulthood (Oosting et al., 2014) as well as enhanced gene and protein expression of specific mitochondrial oxidative capacity markers, indicative of increased substrate oxidation in white adipose tissue and skeletal muscle (Kodde et al., 2017). These results suggest that the physical lipid structure may have modulated the homeostatic set point of adipocyte lipid metabolism, thereby limiting lipid storage. Alternatively, as suggested for n-6 and n-3 PUFAs, lipid structure may have programmed adult energy partitioning and feed efficiency towards enhanced energy expenditure for instance due to higher basal metabolic rate or enhanced heat production. Indeed, experimental studies showed that physical properties of dietary lipids, including lipid droplet size and surface composition, modulate acute absorption and digestion kinetics as well as metabolic fate of lipids (Michalski et al., 2013; Bourlieu et al., 2017). For instance, small lipid droplets are hydrolyzed faster, but also delay gastric emptying compared to larger lipid droplets in healthy adults. In contrast, large lipid droplets with a native milk fat globule membrane (MFGM) on the lipid/water interface are hydrolyzed faster than small droplets with proteins on the interface in preterm infants. In adult rats, large MFGM coated lipid droplets decreased plasma triglyceride appearance and increased β-oxidation compared to small droplets with proteins at the interface (Michalski et al., 2013). Taken together, these data indicate that differences in lipid digestion and absorption may preferentially target lipids towards either β-oxidation or storage in WAT. However, data on in vivo lipid digestion and absorption kinetics are scarce and apart from the studies mentioned above, little is known about the effect of physical lipid structure on utilization of dietary lipids. Whether the effects found in human adults and adult rodents are applicable to infants is presently unknown since absorption and digestion kinetics differ between infants and adults due to immaturity of the infant digestive system (Armand et al., 1996; Abrahamse et al., 2012; Bourlieu et al., 2015; Baumgartner et al., 2017). An exploratory study in healthy 8-week old infants did indicate some distinct differences in postprandial kinetics between HM and IMF (Teller et al., 2017). If and how differences in absorption and digestion kinetics may contribute to the programming effects as observed in the mouse studies is topic of further research. It is tempting to speculate that differential postprandial FA kinetics and bioavailability due to the physical lipid structure modulates the functional development of metabolic organs during the postnatal period of plasticity, affecting later life obesity risk. Future studies dedicated to measurement of energy balance, nutrient partitioning and feed efficiency are pivotal to determine the potential value of these initial findings.

8 Critical periods in mice and men

The contribution of lipids in HM to later cardiometabolic outcomes has not been investigated in great depth apart from studies focusing on correlations between milk ARA and DHA content and body composition in (early) childhood. These studies have provided conflicting data on association between HM DHA and/or ARA and childhood adiposity (Muhlhausler et al., 2010a, b, 2016; Innis, 2011; Pedersen et al., 2012; van Rossem et al., 2012; Hauner et al., 2013). The few randomized clinical trials that have been performed, with focus on supplementing n-3 LC-PUFA during pregnancy and/or lactation, investigating later life body mass index and fat mass show inconsistent results (Muhlhausler et al., 2010a, b, 2016; Hauner et al., 2013; Vinding et al., 2018). These inconsistencies could be due to the focus on and differences in dose, timing and duration of n-3 LC-PUFA supplementation and background diet including LA and ALA intake levels and the n6/n3 ratio in case of maternal interventions and/or use of BMI as indirect growth variable rather than actual body composition measurements (Muhlhausler et al., 2010b; 2011; Rodriguez et al., 2012; Hauner et al., 2013; Vinding et al., 2018). Differences in sociodemographic variables, number of recruited subjects, different age at the time of measurement and the lack of precise techniques to measure body composition probably also limits the power of these studies. In addition, most of these studies were performed in healthy subjects who may be too resilient to current environmental challenges to have an increased disease risk and reveal any (in)adequate nutritional programming. Obviously, if the later life environment is relatively healthy and does not challenge the system, for instance by means of high fat feeding and/or sedentary lifestyle, adverse early life nutritional programming may not (yet) become manifest. Indeed, several experimental studies have shown that an adverse phenotype due to perinatal malnutrition only became apparent after exposure to an obesogenic adult environment (Bayol et al., 2005; Velkoska et al., 2005; Souza-Mello et al., 2007; Oosting et al., 2010, 2012).

Lipid quality in early life may be particularly critical in individuals with an increased obesity risk due to their prenatal environment. Prenatal factors predisposing to later life obesity include maternal obesity, unbalanced diet, smoking, gestational diabetes, gestational weight gain and psychosocial stress (Liao et al., 2019). Nutritional quality of the early postnatal diet could (partially) alleviate detrimental effects of an adverse prenatal environment. The few n-3 LC-PUFA programming studies performed in animal models (as reviewed in Muhlhausler et al., 2011) support the notion that n-3 LC-PUFA may ameliorate unfavorable metabolic outcome due to an adverse perinatal environment, i.e. fetal dexamethasone exposure or neonatal overfeeding (Wyrwoll et al., 2006; Hou et al., 2012; Hidaka et al., 2018; Kerling et al., 2019). Indeed, we recently showed that an early diet containing large, PL coated lipids droplets (Nuturis®, Gallier et al., 2015) in early life improved long term metabolic outcomes in growth restricted rats when challenged with a western style diet later in life (Teller et al., 2018). Clinical studies investigating the role of n-3 LC-PUFAs in growth and brain development also support this notion: n-3 LC-PUFA supplementation is consistently effective in preterm or small-for-gestational-age infants whereas effects in healthy term infants are less evident (Fleith and Clandinin, 2005; Makrides et al., 2011).

When extrapolating findings in mouse models to human development one needs to take into account that rodents are born relatively immature compared humans. Humans are born with a mature hypothalamus-pituitary-adrenal (HPA) axis, important in regulation of adipose tissue development, which starts in the third trimester of gestation (Kuzawa, 1998). In rodents, WAT development starts after birth and coincides with maturation of the HPA axis in the first two weeks of life (Schmitz and Ecker, 2008). Based on these species comparisons, it seems reasonable to assume that the PUFA interventions in our rodent studies starting at postnatal day (PN) 2 can correspond to a nutritional intervention during late gestation in humans continuing into early postnatal life as we extended the diet intervention even beyond weaning of the pups. Effectiveness of moderate FA composition changes for humans may therefore not only depend on postnatal but also on late fetal nutritional environment. Effectiveness of in particular reduced LA or enhanced n-3 LC-PUFA on body composition in human adult life might by enhanced when provided throughout (late) pregnancy and lactation and beyond. There are several arguments to support this approach: Firstly, it could potentially modulate fetal WAT development in the last trimester beneficially. The critical window for hyperplastic and hypertrophic WAT development in humans is not well defined, but it has been suggested that human preadipocytes have highest proliferation and differentiation capacity during the 1st year of life (Hauner et al., 2013), suggesting that the critical period for adipogenesis is still open during infancy and that nutritional signals could influence adipocyte development during this period. Secondly, it could increase the n-3 PUFA and decrease n-6 PUFA content in human milk, since experimental data indicate that only one-third of the milk DHA content is determined by dietary PUFA during lactation (Oosting et al., 2015b; Schipper et al., 2016) and the rest is derived from maternal fat depots.

In line with the reports that indicate that breastfeeding duration is associated with protective effects on (childhood) obesity (Harder et al., 2005), we could hypothesize that the protective effects of HM are (at least partially) mediated by the milk lipid structure. In our experimental studies, we simply extended exposure to the improved lipid structure (closer to that in mouse milk) beyond lactation into the early weaning period by providing a diet containing the large PL-coated lipid droplets (Oosting et al., 2012, 2014, Baars et al., 2016; Ronda et al., 2019). The observed reduction in adiposity in young adulthood following the western style diet challenge may indeed support the idea that the physical structure of HM lipids may explain some of the positive associations reported between the duration of BF and later overweight (Harder et al., 2005).

9 Health implications and future directions

Altogether the published preclinical data demonstrate that quality of nutrition during infancy, more specifically different aspects of lipid quality, such as FA composition and physical lipid structure, are important determinants for adult life metabolic health and disease risk. Since in humans mother’s milk or infant formula is the only source of food in early postnatal life, defining appropriate milk lipid composition and matrix is crucial for early development and adult health. That to date clinical data are limited and show positive, negative or no effects of intervention during pregnancy and/or lactation. These inconclusive outcomes could be related to a number of factors. Most studies focused on N3 LCPUFA supplementation but dose, duration and timing differ as well as the specific outcome measured and the timing of assessment differed considerably. In addition, most studies were performed in healthy term born infants. For these infants, such improvements in nutrient quality may only have small impact that is difficult to measure on the short term. Much of the risk profile may in fact be determined by later exposures as is also clear from the preclinical data that show that a challenge with a western style diet was often needed to show beneficial results of the early diet exposure. Yet, many children already experience challenging conditions in the womb that may impact their birth weight and/or postnatal growth and development in whom effects of such nutritional concepts could be more substantial. For instance, today, obesity among pregnant women is becoming one of the most important women’s health issues (NCD Risk Factor Collaboration, 2017; Poston et al., 2011). Maternal obesity is associated with higher birth weights and more body fat, forming a risk factor for unbalanced or faster growth and obesity later in life (Poston et al., 2011; Symonds et al., 2013). These effects may partly be related to the heightened risk of gestational diabetes (GDM). GDM is currently one of the most common medical complications in pregnancy affecting one in every seven births globally (Guariguata et al., 2014). Both the mothers and their offspring are at increased risk of short and of longer-term complications like development of type 2 diabetes (Silverman et al., 1998; Metzger et al., 2008). Although the evidence available currently favors actions directed at controlling pre-pregnancy weight and preventing obesity and GDM, adequate dietary guidance before and during pregnancy (Hanson et al., 2015), especially in the case of GDM diagnosis (Yamamoto et al., 2018), is crucial. Even more importantly, given the risk for accelerated adiposity development in the infants after birth (Logan et al., 2016, 2017), further research to optimize dietary support to secure balanced growth and to improve later outcomes for GDM offspring as a specific risk population is key.

Although HM lipids have been investigated intensively (Zeisel et al., 1986; Jensen, 1996; Mitoulas et al., 2002; Yuhas et al., 2006), many aspects have remained relatively unclear, such as the role of specific maternal factors and their interactions. Our preclinical results clearly indicate that maternal dietary PUFA content during lactation is readily translated to PUFA content in milk (Oosting et al., 2015b). In lactating women, dietary PUFA have been retrieved from HM within 6 h after intake (Hachey et al., 1987; Francois et al., 1998). The global increased LA and decreased n-3 LC-PUFA intake is reflected in mature milk (Ailhaud et al., 2006; Gibson et al., 2011). Current recommendations regarding n-3 and n-6 EFA and LC-PUFAs are based on HM composition and infant FA status and safety rather than on (long-term) health outcomes, due to lack of scientific proof in healthy term infants. It is tempting to speculate that specific subpopulations of infants at risk for obesity and NCD due to an adverse fetal environment (Vohr and Boney, 2008; Nelson et al., 2009) may benefit more clearly from increased n-3 LC-PUFA intake. Generally, however, rather than increasing n-3 LC-PUFA intake, reducing LA intake might ultimately prove to be more effective. In fact, Hibbeln and colleagues (Hibblen et al., 2006) argue that n-3 LC-PUFA recommendations could even be reduced to a tenth of current recommendations by reducing n-6 PUFA intake effectively.

As stated previously, current recommendations for EFA and LC-PUFAs in IMF are based on content in HM of Caucasian women, data on infant PUFA status and data on functional outcome such as growth and visual acuity (Uauy and Dangour, 2009). With the concerns of scientists and health care professionals about the imbalance between dietary n-6 and n-3 intake, recommendations based on contemporary HM originating from Caucasian women on a typical Western diet merits re-evaluation. Kuipers and others suggest IMF recommendations should be based on HM FA composition originating from ancient paleolithic diets rather than from our contemporary western diets (Kuipers et al., 2005). This ancient, paleolithic diet would entail a high n-3 PUFA (ALA), high n-3 LC-PUFA (DHA and EPA), high n-6 LC-PUFA (ARA) content and a low ARA/DHA ratio, but lower LA intake compared to our contemporary western diets. Such diets might protect against proinflammatory eicosanoid signaling, enhanced LDL oxidation, enhanced platelet aggregation and reduced incorporation of n-3-LC-PUFAs in membranes associated with high dietary n-6 PUFA intake and many chronic diseases (Simopoulos, 2006, 2008).

Yet, HM milk remains in many aspects superior to IMF due to reasons discussed in previous sections. It is now clear that dietary lipid structure can be added to the factors contributing to the potential long term health benefits of breastfeeding. It is impossible to exactly mimic all the characteristics of human milk in human milk substitutes, i.e. IMFs available if infants cannot be breastfed. However, our present studies suggest that we can further improve IMF lipid quality beyond FA composition by adjusting the lipid structure. This infant formula, containing large, PL-coated lipid droplets (Nuturis®, Gallier et al., 2015) supports equivalent growth in term born infants (Breij et al., 2019), and further clinical studies testing growth- and other developmental outcomes are ongoing.

10 Conclusion

Our experimental studies showed long term beneficial effects of FA composition and physical lipid structure in animal models. Future preclinical studies should at least investigate interaction between individual lipid aspects/compounds, because effects of individual compounds can be enhanced or abrogated when combined. As suggested for instance, high n-3 LC-PUFA supplementation may be more effective under a low LA background. The high n-6 PUFA recommendations may need to be addressed more specifically in future clinical studies given the proadipogenic properties as demonstrated in preclinical studies. Both the absolute amounts of dietary EFA and LC-PUFA as well as the ratio should be taken into account for a balanced n-6/n-3 status. Combining an optimized PUFA content and ratio with the altered lipid structure may be a promising strategy to further improve lipid quality of infant nutrition.

Randomized clinical trials are essential to generate solid data concerning safety and efficacy in infants and to test whether these promising results ultimately allow future implementation and improvement of IMF concepts that may improve long-term health. The changes in dietary lipids during infancy may especially benefit infants “at risk”, such as infants from women with GDM or obesity which are potentially exposed to fetal overnutrition, but also for small-for-gestational age infants that may have experienced fetal undernutrition and preterm infants which may have specific nutritional needs due to their immaturity at birth. Clinical studies in specific target populations will help to develop specific strategies to adapt infant nutrition based on the need with the aim to improve long term outcomes.

References

Abrahamse E, Minekus M, van Aken GA, et al. 2012. Development of the digestive system-experimental challenges and approaches of infant lipid digestion. Food Dig 3: 63–77.

Ailhaud G, Guesnet P. 2004. Fatty acid composition of fats is an early determinant of childhood obesity: a short review and an opinion. Obes Rev 5: 21–26.

Ailhaud G, Massiera F, Weill P, et al. 2006. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 45: 203–236.

Alamy M, Bengelloun WA. 2012. Malnutrition and brain development: an analysis of the effects of inadequate diet during different stages of life in rat. Neurosci Biobehav Rev 36: 1463–1480

Armand M, Hamosh M, Mehta NR, et al. 1996. Effect of human milk or formula on gastric function and fat digestion in the premature infant. Pediatr Res 40: 429–437.

Avram MM, Avram AS, James WD. 2007. Subcutaneous fat in normal and diseased states 3. Adipogenesis: from stem cell to fat cell. J Am Acad Dermatol 56: 472–492.

Baars A, Oosting A, Engels E, et al. 2016. MGFM coated large lipid droplets in the diet of young mice protect against excessive fat accumulation in adulthood. Br J Nutr 4: 1–8.

Barker DJ, Winter PD, Osmond C, et al. 1989. Weight in infancy and death from ischaemic heart disease. Lancet 2: 577–580.

Barker DJ, Hales CN, Fall CH, et al. 1993. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36: 62–67.

Bartok CJ, Ventura AK. 2009. Mechanisms underlying the association between breastfeeding and obesity. Int J Pediatr Obes 4: 196–204.

Baumgartner S, van de Heijning BJM, Acton D, Mensink RP. 2017. Infant milk fat droplet size and coating affect postprandial responses in healthy adult men: a proof-of-concept study. Eur J Clin Nutr 71: 1108–1113.

Bayol SA, Simbi BH, Stickland NC. 2005. A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning. J Physiol 567: 951–961.

Berger J, Moller DE. 2002. The mechanisms of action of PPARs. Annu Rev Med 53: 409–435.

Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR. 2011. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr 93(5): 950–62.

Bond M, Wyatt K, Lloyd J, et al. 2009. Systematic review of the effectiveness and cost-effectiveness of weight management schemes for the under fives: a short report. Health Technol Assess 13: 1–75.

Bourlieu C, Ménard O, De La Chevasnerie A, et al. 2015. The structure of infant formulas impacts their lipolysis, proteolysis and disintegration during in vitro gastric digestion. Food Chem 182: 224–35.

Bourlieu C, Deglaire A, de Oliveira SC, et al. 2017. Towards infant formula biomimetic of human milk structure and digestive behaviour. OCL 24: D206.

Brenna JT, Salem N, Jr., Sinclair AJ, et al. 2009. Alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot Essent Fatty Acids 80: 85–91.

Breij LM, Abrahamse-Berkeveld M, Vandenplas Y, et al. 2019. Mercurius Study Group. An infant formula with large, milk phospholipid-coated lipid droplets containing a mixture of dairy and vegetable lipids supports adequate growth and is well tolerated in healthy, term infants. Am J Clin Nutr 109: 586–596.

Broughton KS, Wade JW. 2002. Total fat and (n-3):(n-6) fat ratios influence eicosanoid production in mice. J Nutr 132: 88–94.

Carlson SE, Colombo J. 2016. Docosahexaenoic acid and arachidonic acid nutrition in early development. Adv Pediatr 63(1): 453–71.

Crombie IK, Irvine L, Elliott L, et al. 2009. Targets to tackle the obesity epidemic: a review of twelve developed countries. Public Health Nutr 12: 406–413.

Darlington GJ, Ross SE, MacDougald OA. 1998. The role of C/EBP genes in adipocyte differentiation. J Biol Chem 273: 30057–30060.

De Onis M, Blossner M, Borghi E. 2010. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 92: 1257–1264.

Delplanque B, Gibson R, Koletzko B, Lapillonne A, Strandvik B. 2015. Lipid quality in infant nutrition: current knowledge and future opportunities. J Pediatr Gastroenterol Nutr 61(1): 8–17.

Druet C, Stettler N, Desai M, Ross MG. 2011. Fetal programming of adipose tissue: effects of intrauterine growth restriction and maternal obesity/high-fat diet. Semin Reprod Med 29: 237–245.

Druet C, Stettler N, Sharp S, et al. 2012. Prediction of childhood obesity by infancy weight gain: an individual-level meta-analysis. Paediatr Perinat Epidemiol 26(1): 19–26.

Durmus B, Mook-Kanamori DO, Holzhauer S, et al. 2010. Growth in foetal life and infancy is associated with abdominal adiposity at the age of 2 years: the generation R study. Clin Endocrinol (Oxf) 72: 633–640.

Durmus B, Ay L, Duijts L, et al. 2011. Infant diet and subcutaneous fat mass in early childhood: The generation R study. Eur J Clin Nutr 66(2): 253–60.

Ehrenberg HM, Mercer BM, Catalano PM. 2004. The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol 191(3): 964–8.

Eisenmann JC. 2006. Insight into the causes of the recent secular trend in pediatric obesity: Common sense does not always prevail for complex, multi-factorial phenotypes. Prev Med 42: 329–335.

Emmett PM, Rogers IS. 1997. Properties of human milk and their relationship with maternal nutrition. Early Hum Dev 49(Suppl): S7–28.

EU Commission Directive 2006/141/EC. 2006. EU Commission Directive 2006/141/EC on infant formulae and follow-on formulae. Off J Eur Union 402: 1–32.

European Food Safety Authority (EFSA). 2013. Scientific opinion on nutrient requirements and dietary intakes of infants and young children in the European Union. EFSA J 11(10): 3408.

European Food Safety Authority (EFSA). 2014. Scientific opinion on the essential composition of infant and follow-on formulae. EFSA J 12(7): 3760.

Fall CH, Barker DJ, Osmond C, et al. 1992. Relation of infant feeding to adult serum cholesterol concentration and death from ischaemic heart disease. BMJ 304: 801–805.

Fleith M, Clandinin MT. 2005. Dietary PUFA for preterm and term infants: review of clinical studies. Crit Rev Food Sci Nutr 45: 205–229.

Fowden AL, Hill DJ. 2001. Intra-uterine programming of the endocrine pancreas. Br Med Bull 60: 123–142.

Francois CA, Connor SL, Wander RC, et al. 1998. Acute effects of dietary fatty acids on the fatty acids of human milk. Am J Clin Nutr 67: 301–308.

Gale C, Logan KM, Santhakumaran S, et al. 2012. Effect of breastfeeding compared with formula feeding on infant body composition: a systematic review and meta-analysis. Am J Clin Nutr 95: 656–669.

Gallier S, Vocking K, Post JA, et al. 2015. A novel infant milk formula concept: mimicking the human milk lipid structure. Colloids Surf B: Biointerfac 136: 129–139

Gibson RA, Muhlhausler B, Makrides M. 2011. Conversion of linoleic acid and alpha-linolenic acid to long-chain polyunsaturated fatty acids (LCPUFAs), with a focus on pregnancy, lactation and the first 2 years of life. Matern Child Nutr 7(Suppl 2): 17–26.

Gibson RA, Neumann MA, Lien EL, Boyd KA, Tu WC. 2013. Docosahexaenoic acid synthesis from alpha-linolenic acid is inhibited by diets high in polyunsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids 88: 139–46.

Gluckman PD, Cutfield W, Hofman P, et al. 2005. The fetal, neonatal, and infant environments-the long-term consequences for disease risk. Early Hum Dev 81: 51–59.

Gluckman PD, Lillycrop KA, Vickers MH, et al. 2007. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104: 12796–12800.

Godfrey KM, Gluckman PD, Hanson MA. 2010. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol Metab 21: 199–205.

Godfrey KM, Inskip HM, Hanson MA. 2011. The long-term effects of prenatal development on growth and metabolism. Semin Reprod Med 29: 257–265.

Going SB, Lohman TG, Cussler EC, et al. 2011. Percent body fat and chronic disease risk factors in U.S. children and youth. Am J Prev Med 41: S77–86.

Goyens PL, Spilker ME, Zock PL, et al. 2006. Conversion of alpha-linolenic acid in humans is influenced by the absolute amounts of alpha-linolenic acid and linoleic acid in the diet and not by their ratio. Am J Clin Nutr 84: 44–53.

Guariguata L, Linnenkamp U, Beagley J, Whiting DR, Cho NH. 2014. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract 103: 176–185

Guilloteau P, Zabielski R, Hammon HM, et al. 2009. Adverse effects of nutritional programming during prenatal and early postnatal life, some aspects of regulation and potential prevention and treatments. J Physiol Pharmacol 60(Suppl 3): 17–35.

Guillou H, Zadravec D, Martin PG, et al. 2009. The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. Prog Lipid Res 49: 186–199.

Guyenet SJ, Carlson SE. 2015. Increase in adipose tissue linoleic acid of US adults in the last half century. Adv Nutr 6(6): 660–4.

Hachey DL, Thomas MR, Emken EA, et al. 1987. Human lactation: maternal transfer of dietary triglycerides labeled with stable isotopes. J Lipid Res 28: 1185–1192.

Hanson MA, Bardsley A, De-Regil LM, et al. 2015. The International Federation of Gynecology and Obstetrics (FIGO) recommendations on adolescent, preconception, and maternal nutrition: “Think Nutrition First”. Int J Gynaecol Obstet 131(Suppl 4): S213–53.

Harder T, Bergmann R, Kallischnigg G, et al. 2005. Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol 162: 397–403.

Hauner H, Brunner S, Amann-Gassner U. 2013. The role of dietary fatty acids for early human adipose tissue growth. Am J Clin Nutr 98: 549S–555S.

Hernandez-Valencia M, Patti ME. 2006. A thin phenotype is protective for impaired glucose tolerance and related to low birth weight in mice. Arch Med Res 37: 813–817.

Hibbeln JR, Nieminen LR, Blasbalg TL, et al. 2006. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. Am J Clin Nutr 83: 1483S–1493S.

Hidaka BH, Thodosoff JM, Kerling EH, Hull HR, Colombo J, Carlson SE. 2018. Intrauterine DHA exposure and child body composition at 5 y: exploratory analysis of a randomized controlled trial of prenatal DHA supplementation. Am J Clin Nutr 07: 35–42.

Hou M, Ji C, Wang J, et al. 2012. The effects of dietary fatty acid composition in the post-sucking period on metabolic alterations in adulthood: can omega3 polyunsaturated fatty acids prevent adverse programming outcomes? J Endocrinol 215: 119–127.

Innis SM. 1991. Essential fatty acids in growth and development. Prog Lipid Res 30: 39–103.

Innis SM. 1992. Human milk and formula fatty acids. J Pediatr 120: S56–61.

Innis SM. 2007. Human milk: maternal dietary lipids and infant development. Proc Nutr Soc 66: 397–404.

Innis SM. 2011. Metabolic programming of long-term outcomes due to fatty acid nutrition in early life. Matern Child Nutr 7(Suppl 2): 112–123.

Jackson-Leach R, Lobstein T. 2006. Estimated burden of paediatric obesity and co-morbidities in Europe. Part 1. The increase in the prevalence of child obesity in Europe is itself increasing. Int J Pediatr Obes 1: 26–32.

Javadi M, Everts H, Hovenier R, et al. 2004. The effect of six different C18 fatty acids on body fat and energy metabolism in mice. Br J Nutr 92: 391–399.

Jensen RG. 1996. The lipids in human milk. Prog Lipid Res 35: 53–92.

Jensen CL, Prager TC, Fraley JK, et al. 1997. Effect of dietary linoleic/alpha-linolenic acid ratio on growth and visual function of term infants. J Pediatr 131: 200–209.

Kerling EH, Hilton JM, Thodosoff JM, Wick J, Colombo J, Carlson SE. 2019. Effect of prenatal docosahexaenoic acid supplementation on blood pressure in children with overweight condition or obesity: a secondary analysis of a randomized clinical trial. JAMA Netw Open 2: e190088.

Kodde A, van der Beek EM, Phielix E, Engels E, Schipper L, Oosting A. 2017. Supramolecular structure of dietary fat in early life modulates expression of markers for mitochondrial content and capacity in adipose tissue of adult mice. Nutr Metab (Lond) 12(14): 37.

Koletzko B, Rodriguez-Palmero M, Demmelmair H, et al. 2001. Physiological aspects of human milk lipids. Early Hum Dev 65(Suppl): S3–S18.

Koletzko B, Baker S, Cleghorn G, et al. 2005. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr 41: 584–599.

Koletzko B, Lien E, Agostoni C, et al. 2008. The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. J Perinat Med 36: 5–14.

Koletzko B, Boey CC, Campoy C, et al. 2014. Current information and Asian perspectives on long-chain polyunsaturated fatty acids in pregnancy, lactation, and infancy: systematic review and practice recommendations from an early nutrition academy workshop. Ann Nutr Metab 65: 49–80.

Koletzko B, Carlson SE, van Goudoever JB. 2015. Should infant formula provide both omega-3 dha and omega-6 arachidonic acid? Ann Nutr Metab 66: 137–8.

Koletzko B, Bergmann K, Brenna JT, et al. 2020. Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation. Am J Clin Nutr 111(1): 10–16.

Kopecky J, Rossmeisl M, Flachs P, et al. 2009. n-3 PUFA: bioavailability and modulation of adipose tissue function. Proc Nutr Soc 68: 361–369.

Kuipers RS, Fokkema MR, Smit EN, et al. 2005. High contents of both docosahexaenoic and arachidonic acids in milk of women consuming fish from lake Kitangiri (Tanzania): targets for infant formulae close to our ancient diet? Prostaglandins Leukot Essent Fatty Acids 72: 279–288.

Kuzawa CW. 1998. Adipose tissue in human infancy and childhood: an evolutionary perspective. Am J Phys Anthropol Suppl 27: 177–209.

Lambin S, van Bree R, Caluwaerts S, et al. 2007. Adipose tissue in offspring of Lepr(db/+) mice: early-life environment vs. genotype. Am J Physiol Endocrinol Metab 292: E262–271.

Le HD, Meisel JA, de Meijer VE, et al. 2009. The essentiality of arachidonic acid and docosahexaenoic acid. Prostaglandins Leukot Essent Fatty Acids 81: 165–170

Le Huerou-Luron I, Blat S, Boudry G. 2010. Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects. Nutr Res Rev 23: 23–36.

Liao XP, Yu Y, Marc I, et al. 2019. Prenatal determinanats of childhood obesity: a review of the risk factors. Can J Physiol Pharmacol 97: 147–157.

Lillycrop KA, Phillips ES, Jackson AA, et al. 2005. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135: 1382–1386.

Lobstein T, Jackson-Leach R. 2006. Estimated burden of paediatric obesity and co-morbidities in Europe. Part 2. Numbers of children with indicators of obesity-related disease. Int J Pediatr Obes 1: 33–41.

Lobstein T, Baur L, Uauy R. 2004. Obesity in children and young people: a crisis in public health. Obes Rev 5(Suppl 1): 4–104.

Logan KM, Emsley RJ, Jeffries S, et al. 2016. Development of early adiposity in infants of mothers with gestational diabetes mellitus. Diabetes Care 39: 1045–51.

Logan KM, Gale C, Hyde MJ, Santhakumaran S, Modi N. 2017. Diabetes in pregnancy and infant adiposity: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 102: F65– F72.

Madsen L, Petersen RK, Kristiansen K. 2005. Regulation of adipocyte differentiation and function by polyunsaturated fatty acids. Biochim Biophys Acta 1740: 266–286.

Madsen L, Pedersen LM, Liaset B, et al. 2008. cAMP-dependent signaling regulates the adipogenic effect of n-6 polyunsaturated fatty acids. J Biol Chem 283: 7196–7205.

Makrides M, Neumann MA, Jeffrey B, et al. 2000. A randomized trial of different ratios of linoleic to alpha-linolenic acid in the diet of term infants: effects on visual function and growth. Am J Clin Nutr 71: 120–129.

Makrides M, Collins CT, Gibson RA. 2011. Impact of fatty acid status on growth and neurobehavioural development in humans. Matern Child Nutr 7(Suppl 2): 80–88.

Massiera F, Saint-Marc P, Seydoux J, et al. 2003. Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern ? J Lipid Res 44: 271–279.

Massiera F, Guesnet P, Ailhaud G. 2006. The crucial role of dietary n-6 polyunsaturated fatty acids in excessive adipose tissue development: relationship to childhood obesity. Nestle Nutr Workshop Ser Pediatr Program 235-242: 243–235.

Massiera F, Barbry P, Guesnet P, et al. 2010. A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations. J Lipid Res 51: 2352–2361.

McAllister EJ, Dhurandhar NV, Keith SW, et al. 2009. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr 49: 868–913.

McMillen IC, Robinson JS. 2005. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85: 571–633.

Metzger BE, Lowe LP, Dyer AR, et al. 2008. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358: 1991–2002.

Michalski MC, Briard V, Michel F, et al. 2005. Size distribution of fat globules in human colostrum, breast milk, and infant formula. J Dairy Sci 88: 1927–1940.

Michalski MC, Genot C, Gayet C, et al. 2013. Multiscale structures of lipids in foods as parameters affecting fatty acid bioavailability and lipid metabolism. Prog Lipid Res 52: 354–373.

Milagro FI, Mansego ML, De Miguel C, et al. 2013. Dietary factors, epigenetic modifications and obesity outcomes: progresses and perspectives. Mol Aspects Med 34: 782–812.

Minda H, Kovacs A, Funke S, et al. 2004. Changes of fatty acid composition of human milk during the first month of lactation: a day-to-day approach in the first week. Ann Nutr Metab 48: 202.

Mitoulas LR, Kent JC, Cox DB, et al. 2002. Variation in fat, lactose and protein in human milk over 24 h and throughout the first year of lactation. Br J Nutr 88: 29–37.

Muhlhausler BS, Ailhaud GP. 2012. Omega-6 polyunsaturated fatty acids and the early origins of obesity. Curr Opin Endocrinol Diabetes Obes 20: 56–61.

Muhlhausler BS, Cook-Johnson R, James M, et al. 2010a. Opposing effects of omega-3 and omega-6 long chain polyunsaturated Fatty acids on the expression of lipogenic genes in omental and retroperitoneal adipose depots in the rat. J Nutr Metab 1–9.

Muhlhausler BS, Gibson RA, Makrides M. 2010b. Effect of long-chain polyunsaturated fatty acid supplementation during pregnancy or lactation on infant and child body composition: a systematic review. Am J Clin Nutr 92: 857–863.

Muhlhausler BS, Gibson RA, Makrides M. 2011. 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 85: 83–88.

Muhlhausler BS, Yelland LN, McDermott R, et al. 2016. DHA supplementation during pregnancy does not reduce BMI or body fat mass in children: follow-up of the DHA to Optimize Mother Infant Outcome randomized controlled trial. Am J Clin Nutr 103(6): 1489–96.

Muskiet FA, van Goor SA, Kuipers RS, et al. 2006. Long-chain polyunsaturated fatty acids in maternal and infant nutrition. Prostaglandins Leukot Essent Fatty Acids 75: 135–144.

NCD Risk Factor Collaboration (NCD-RisC). 2017. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128, 9 million children, adolescents, and adults. Lancet 390(10113): 2627–2642.

Nelson SM, Matthews P, Poston L. 2009. Maternal metabolism and obesity: modifiable determinants of pregnancy outcome. Hum Reprod Update 16(3): 255–75.

Nishida C, Uauy R, Kumanyika S, et al. 2004. The joint WHO/FAO expert consultation on diet, nutrition and the prevention of chronic diseases: process, product and policy implications. Public Health Nutr 7: 245–250.

OECD. 2019. The heavy burden of obesity: The economics of prevention, OECD Health Policy Studies, OECD Publishing, Paris, https://doi.org/10.1787/67450d67-en.

Oosting AO, Kegler D, Boehm G, Jansen H, van de Heijning BJM, van der Beek EM. 2010. N-3 Long-Chain Polyunsaturated Fatty Acids prevent excessive fat deposition in adulthood in a mouse model of postnatal nutritional programming. Pediatr Res 68: 494–499.

Oosting A, Kegler D, van de Heijning BJM, Wopereis H, Verkade HJ, van der Beek EM. 2012. Early feeding with a breast-milk like fat structure in a mouse model protects against adiposity in later life. Ped Res 72(4): 362–369.

Oosting A, van Vlies N, Kegler D, et al. 2014. Effect of dietary lipid structure in early postnatal life on mouse adipose tissue development and function in adulthood. Br J Nutr 28: 215–26.

Oosting A, Kegler D, van de Heijning BJM, Verkade HJ, van der Beek EM. 2015a. Dietary n-6 polyunsaturated fatty acids content in early life programs adult body composition and metabolic response to a western diet challenge in rodents. Nutr Res 35: 800–811.

Oosting A, Verkade HJ, Kegler D, van de Heijning BJ, van der Beek EM. 2015b. Rapid and selective manipulation of milk fatty acid composition in mice through the maternal diet during lactation. J Nutr Sci 4: e19.

Owen CG, Martin RM, Whincup PH, et al. 2006. Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr 84: 1043–1054.

Owen CG, Whincup PH, Kaye SJ, et al. 2008. Does initial breastfeeding lead to lower blood cholesterol in adult life? A quantitative review of the evidence. Am J Clin Nutr 88: 305–314.

Pedersen L, Lauritzen L, Brasholt M, et al. 2012. Polyunsaturated fatty acid content of mother’s milk is associated with childhood body composition. Pediatr Res 72(6): 631–6.

Pocai A, Lam TK, Obici S, et al. 2006. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest 116: 1081–1091.

Poston L, Harthoorn L, van der Beek EM. 2011. Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement. Pediatr Res 69: 175–180.

Ramsden CE, Zamora D, Leelarthaepin B, et al. 2013. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ 346: e8707.

Rodriguez G, Iglesia I, Bel-Serrat S, et al. 2012. Effect of n-3 long chain polyunsaturated fatty acids during the perinatal period on later body composition. Br J Nutr 107(Suppl 2): S117–128.

Ronda OAHO, van de Heijning BJM, de Bruin A, Jurdzinski A, Kuipers F, Verkade HJ. 2019. Programming effects of an early-life diet containing large phospholipid-coated lipid globules are transient under continuous exposure to a high-fat diet. Br J Nutr 23: 1–14.

Ryan AS. 2007. Breastfeeding and the risk of childhood obesity. Coll Antropol 31: 19–28.

Salem N, Jr., Wegher B, Mena P, et al. 1996. Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc Natl Acad Sci USA 93: 49–54.

Sanders TA. 2000. Polyunsaturated fatty acids in the food chain in Europe. Am J Clin Nutr 71: 176S–178S.

Schipper L, Bouyer K, Oosting A, et al. 2013. Postnatal dietary fatty acid composition permanently affects the structure of hypothalamic pathways controlling energy balance in mice. Am J Clin Nutr 98: 1395–1401.

Schipper L, Oosting A, Scheurink AJ, et al. 2016. Reducing dietary intake of linoleic acid of mouse dams during lactation increases offspring brain n-3 LCPUFA content. Prostaglandins Leukot Essent Fatty Acids 110: 8–15.

Schmitz G, Ecker J. 2008. The opposing effects of n-3 and n-6 fatty acids. Prog Lipid Res 47: 147–155.

Scholtens S, Gehring U, Brunekreef B, et al. 2007. Breastfeeding, weight gain in infancy, and overweight at seven years of age: the prevention and incidence of asthma and mite allergy birth cohort study. Am J Epidemiol 165: 919–926.

Schwarzenberg SJ, Georgieff MK, Committee on Nutrition. 2018. Advocacy for improving nutrition in the first 1000 days to support childhood development and adult health. Pediatrics 141(2)pii: e20173716.

Silverman BL, Rizzo TA, Cho NH, Metzger BE. 1998. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care 21(Suppl 2): B142–149.

Simopoulos AP. 2006. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 60: 502–507.

Simopoulos AP. 2008. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood) 233: 674–688.

Singhal A, Lucas A. 2004. Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet 363: 1642–1645.

Souza-Mello V, Mandarim-de-Lacerda CA, Aguila MB. 2007. Hepatic structural alteration in adult programmed offspring (severe maternal protein restriction) is aggravated by post-weaning high-fat diet. Br J Nutr 98: 1159–1169.

Symonds ME, Sebert SP, Hyatt MA, et al. 2009. Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol 5: 604–610.

Symonds ME, Budge H, Perkins AC, et al. 2010. Adipose tissue development – Impact of the early life environment. Prog Biophys Mol Biol 106(1): 300–6.

Symonds M, Mendez M, Meltzer HM, et al. 2013. Early life nutritional programming of obesity: mother-child cohort studies. Ann Nutr Metab 62: 137–145.

Taylor PD, Poston L. 2007. Developmental programming of obesity in mammals. Exp Physiol 92: 287–298.

Teller IC, Schoen S, van de Heijning B, van der Beek EM, Sauer PJ. 2017. Differences in postprandial lipid response to breast or formula-feeding in 8-week-old infants. J Pediatr Gastroenterol Nutr 64: 616–623.

Teller IC, Hoyer-Kuhn H, Brönneke H, et al. 2018. Complex lipid globules in early-life nutrition improve long-term metabolic phenotype in intra-uterine growth-restricted rats. Br J Nutr 120: 763–776.

Thompson AL. 2012. Developmental origins of obesity: early feeding environments, infant growth, and the intestinal microbiome. Am J Hum Biol 24: 350–360.

Uauy R, Dangour AD. 2009. Fat and fatty acid requirements and recommendations for infants of 0–2 years and children of 2–18 years. Ann Nutr Metab 55: 76–96.

Uvena-Celebrezze J, Fung C, Thomas AJ, et al. 2002. Relationship of neonatal body composition to maternal glucose control in women with gestational diabetes mellitus. J Matern Fetal Neonatal Med 12: 396–401.

van de Heijning BJM, Stahl B, van der Beek EM, Schaart M, Rings EHM, Mearin ML. 2017. Fatty acid and amino acid content of human milk over the course of lactation. J Human Lactation 4: 16–22.

van Rossem L, Wijga AH, de Jongste JC, et al. 2012. Blood pressure in 12-year-old children is associated with fatty acid composition of human milk: the prevention and incidence of asthma and mite allergy birth cohort. Hypertension 60: 1055–1060.

Velkoska E, Cole TJ, Morris MJ. 2005. Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers. Am J Physiol Endocrinol Metab 288: E1236–1243.

Vinding RK, Stokholm J, Sevelsted A, et al. 2018. Effect of fish oil supplementation in pregnancy on bone, lean, and fat mass at six years: randomised clinical trial. BMJ 362: k3312.

Vohr BR, Boney CM. 2008. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med 21: 149–157.

Waku T, Shiraki T, Oyama T, et al. 2009. Structural insight into PPARgamma activation through covalent modification with endogenous fatty acids. J Mol Biol 385: 188–199.

Wang YC, McPherson K, Marsh T, et al. 2011. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378: 815–825.

Waterland RA. 2014. Epigenetic mechanisms affecting regulation of energy balance: many questions, few answers. Annu Rev Nutr 34: 337–55.

Wells JC, Haroun D, Levene D, et al. 2011. Prenatal and postnatal programming of body composition in obese children and adolescents: evidence from anthropometry, DXA and the 4-component model. Int J Obes (Lond) 35: 534–540.

World Heath Orgaanization. 2012. Fact sheet: Obesity and overweight. http://www.who.int/mediacentre/factsheets/fs311/en/ (Updated June 2017 – Accessed 25 September 2019).

Wolmarans P. 2009. Background paper on global trends in food production, intake and composition. Ann Nutr Metab 55: 244–272.

Wood KE, Mantzioris E, Gibson RA, Ramsden CE, Muhlhausler BS. 2015. The effect of modifying dietary LA and ALA intakes on omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) status in human adults: a systematic review and commentary. Prostaglandins Leukot Essent Fatty Acids 95: 47–55.

Wyrwoll CS, Mark PJ, Mori TA, et al. 2006. Prevention of programmed hyperleptinemia and hypertension by postnatal dietary omega-3 fatty acids. Endocrinology 147: 599–606.

Yamamoto JM, Kellett JE, Balsells M, et al. 2018. Gestational Diabetes and Diet: A systematic review and meta-analysis of randomized controlled trials examining the impact of dietary intake on maternal glucose control and neonatal birthweight. Diabetes Care 41: 1346–1361.

Yuhas R, Pramuk K, Lien EL. 2006. Human milk fatty acid composition from nine countries varies most in DHA. Lipids 41: 851–858.

Zeisel SH, Char D, Sheard NF. 1986. Choline, phosphatidylcholine and sphingomyelin in human and bovine milk and infant formulas. J Nutr 116: 50–58.

Cite this article as: van der Beek EM, Oosting A. 2020. Nutritional programming in early life: the role of dietary lipid quality for future health. OCL 27: 15.