The cellularity of offspring's adipose tissue is programmed by maternal nutritional manipulations

Abstract

Epidemiological studies initially demonstrated that maternal undernutrition leads to low birth weight with increased risk of adult-onset obesity. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catch-up growth also predispose offspring to fat accumulation. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set-point. Adipose tissue is a key fuel storage unit mainly involved in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a gender- and depot-specific manner. This review summarizes the impact of maternal nutritional manipulations on cellularity (i.e., cell number, size, and type) of adipose tissue in programmed offspring. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Maternal nutritional manipulations result in increased adipogenesis and modified fat distribution and composition. Inflammation changes such as infiltration of macrophages and increased inflammatory markers are also observed. Overall, it may predispose offspring to fat accumulation and obesity. Inappropriate hormone levels, modified tissue sensitivity, and epigenetic mechanisms are key factors involved in the programming of adipose tissue's cellularity during the perinatal period.

Keywords:

• adipogenesis
• lipogenesis
• gestation
• lactation
• maternal nutrition
• epigenetics
• gene expression
• inflammation
• sympathetic activity
• adiposity

Introduction

It is now well accepted that adult-onset metabolic disorders may derive from events taking place during fetal and postnatal development. In particular, epidemiological studies demonstrated that intrauterine growth retardation (IUGR) and low birth weight are associated with higher adiposity in adulthood.¹ Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates and rapid catch-up growth also increase the risk of adult-onset obesity. These observations have participated in establishing the Developmental Origin of Health and Disease (DOHaD) hypothesis.² This concept states that an adverse environment in utero or during infancy, including dysnutrition, can program or imprint the development of several tissues, including the adipose tissue. It then may permanently determine physiological responses and ultimately produce energy balance dysfunction and diseases later in life. Numerous studies in animals have confirmed that perinatal nutritional manipulations can program adipose tissue in offspring.³

Three types of adipose tissue have been described, mostly composed of mature adipocytes (specialized fat-storing cells) and a stromal vascular fraction (preadipocytes, fibroblasts, endothelial cells, and immune cells). First, the white adipose tissue (WAT) is a specialized tissue that stores energy as triglycerides (TG) via lipogenic pathways. During period of negative energy balance, stored TG are hydrolyzed by lipolytic pathways, driven by the noradrenergic innervations (Fig. 1). The sympathetic system may also control fat cell number via inhibition of adipocyte proliferation.⁴ WAT expansion involves adipogenesis, a two-step process by which preadipocytes are first recruited from precursor cells and then differentiated into adipocytes. Adipogenesis is driven by the expression of adipogenic and lipogenic transcription factors including peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein (C/EBPα, β, γ), the sterol regulatory element-binding protein 1c (SREBP1c), as well as the expression of specific lipid-metabolizing enzymes such as fatty acid synthase (FAS). WAT expansion also relies on lipogenesis (i.e., conversion of fatty acids into TG) in pre-existing adipocyte (Fig. 1). Second, the brown adipose tissue (BAT) is specialized in the production of heat. Brown adipocytes are characterized by high expression of uncoupling protein 1 (UCP1), a BAT-specific marker, fatty-acid-activated transcription factor PPARα and PPARγ coactivator 1-α (PGC1-α). BAT also differs from WAT by its cell origin, using its own developmental transcription factor pathway.⁵ Third, brite adipocytes (brown-in-white) have been detected within some WAT depots. While brite adipocytes possess most of the characteristics of brown adipocytes, they have a distinct origin from brown adipocytes. In particular, activation of the WAT sympathetic system via β3-adrenoreceptor resulted in browning of white adipocytes (i.e, enhanced brite adipocytes) in rodents.⁶

Figure 1. Intracellular pathways of factors regulating adipogenesis, lipogenesis and lipolysis in the adipocyte. To simplify, only mechanisms that are primary targets of maternal nutrition manipulations have been represented. Triglycerides (TG) circulate in blood in the form of lipoproteins. Free fatty acids (FFA) that are released from lipoproteins, catalyzed by lipoprotein lipase (LPL), diffuse into the adipocyte. Intracellular FFA are converted to fatty acyl-CoA, and are then re-esterified to form TG using glycerol-3 phosphate (glycerol-3P) that is generated from glucose metabolism. FFAs may also originate from acetyl-CoA (de novo lipogenesis) driven by the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Lipolysis occurs via a cAMP-mediated cascade, which results in the phosphorylation of hormone-sensitive lipase (HSL), an enzyme which hydrolyzes TG into FFA and glycerol. These FFA are then free to diffuse into the blood. Leptin binding to its receptor (Ob-Rb) induces activation of Janus activated kinase 2 (JAK2), receptor dimerization, JAK2-mediated phosphorylation of intracellular part of Ob-Rb, phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Activated STAT3 dimerizes and translocates to the nucleus to transactivate target genes. Insulin binding to its receptor (InsR) induces receptor tyrosine autophosphorylation, activation of insulin receptor substrates (IRSs)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) signaling pathways. Leptin and insulin action is both linked to the common PI3K signaling pathway. Insulin enhances the storage of fat as TG by increasing LPL and lipogenic enzyme activities. It also facilitates the transport of glucose by stimulating GLUT4 glucose transporter. In addition, phosphorylation and activation of cyclic nucleotide phosphodiesterases 3B (PDE3B) is a key event in the antilipolytic action of insulin, decreasing cAMP level in adipocyte. In contrast, leptin presents anti-lipogenic effects by suppressing expression and activity of lipogenic enzymes (i.e., fatty acid synthase [FAS]). Both hormones may also activate adipogenesis. Adipogenesis is driven by the expression of adipogenic and lipogenic transcription factors including peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein (C/EBPα, β, γ), the sterol regulatory element-binding protein 1c (SREBP1c) as well as the expression of specific lipid-metabolizing enzymes such as FAS. Noradrenaline released from the sympathetic autonomic nervous system binds β-adrenoreceptor (β-AR) and activates lipolysis. Glucocorticoids (GC) bind intracellular glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) and can also modulate adipogenesis and/or lipogenesis. This may be due either to an increase in circulating GC and/or to an increase in adipose tissue 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity that amplifies local GC actions by converting inactive GC metabolites (11-dehydrocorticosterone, 11DHC) to active GC (corticosterone) (in rodents) or inactive cortisone to active cortisol (in humans). 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that degrades active GC to inactive metabolites is also found in adipose tissue.

As soon as 1962, it has been showed that rat epididymal fat pads exhibited a continual rise in DNA content from birth to 14 wk of age, suggesting modified WAT cellularity during this period. Once attained, the adipocyte number could not be changed. Thus, the timing of adipose tissue development determines the window of vulnerability to potential environmental insults, and this window markedly differs between species. In rodents, adipose tissue adipogenesis is particularly active during the perinatal period. In rats, these processes occur primarily during the last week of gestation, accelerate during early postnatal life (i.e., the lactation) until pups are completely weaned. Adolescence phase also constitutes a critical programming window for the development of adipose tissue.⁷ In contrast to rodent, adipogenesis essentially takes place before birth in bigger mammals such as sheep or primates.⁸ Despite this difference, altricial and precocial species share several mechanisms of offspring programming. This review summarizes the impact of maternal nutritional manipulations on cellularity (i.e., cell number, size, and type) of adipose tissue in programmed offspring.

Malnourished Offspring Display Altered Adipogenesis and Fat Accumulation

Intrauterine growth-restricted offspring

Two models of maternal undernutrition have been mainly described: maternal low-protein diet (8% instead of 20% protein) and global maternal food restriction ranging from 20% to 70% of control intake. Although both protocols usually produce IUGR, they result in different outcomes on the adult offspring's adipocyte size and number.

Rat offspring of low-protein diet (LP) fed-dams during gestation and lactation have persistent smaller adipocytes.⁹ Although exposure to a maternal low-protein diet did not affect the capacity of in vitro preadipocyte cultures to divide or store fat in perinatal period (fetuses, neonates, and weaning), adult offspring from LP dams exhibited increased rate of cultured preadipocyte proliferation.¹⁰ Consistent with these findings, the mRNA expression levels of C/EBPα and PPARγ were increased in the WAT of adult rat offspring from LP dams.¹¹ Adult rats from LP dams also exhibited increased adipose tissue expression of miRNA-483-3p, known to regulate early and late stages of in vitro differentiation and the capacity of adipocytes to store lipids. Thus, this may contribute to the inhibition of adipocyte hypertrophy (i.e., lipid storage) that would affect other tissues by promoting ectopic TG storage.⁹

In contrast to maternal LP procedure, low birth-weight rat offspring from 50% food-restricted dams (FR50) during gestation from day 10 to term¹² or from 70% food-restricted dams (FR70) throughout the gestation¹³ showed persistent hypertrophic adipocytes. As soon as postnatal day 1, IUGR offspring from FR50 dams exhibited enhanced PPARγ and its upstream regulatory transcriptional factors (C/EBPα, C/EBPβ, and C/EBPδ). Accordingly, at both postnatal day 1, primary cell cultures from IUGR neonates displayed increased preadipocyte proliferation and adipocyte TG accumulation.¹⁴ Increased adipocyte size was observed in offspring of FR50 dams as soon as weaning.¹² Prior to the onset of overt obesity, the increased expression of adipogenic factors was accompanied with elevated expression of lipogenic factors (SREBP1c, FAS, and leptin) in weanling pups¹² and adult offspring¹³ from FR dams.

Other animal models of IUGR have been developed. In particular, uterine artery ligation (mimicking uteroplacental insufficiency) in the pregnant dams leads to a gender- and depot-specific marked adiposity in adult rat offspring. As reported in offspring of undernourished rat dams, PPARγ mRNA expression levels were enhanced in WAT of juvenile offspring prior to the onset of overt obesity.¹⁵

The energy supply mismatch between overfeeding-induced postnatal catch-up growth and fetal nutrient restriction results in offspring with exacerbated fat accumulation. In agreement with these findings, cultured preadipocytes from overfed (i.e., reared in small litter increasing milk intake) juvenile rats from LP dams showed enhanced proliferation and differentiation.¹⁶ Overfed adult offspring from undernourished dams displayed marked adiposity with a global increase in adipogenic and lipogenic genes (SREBP1c, C/EBPα, PPARγ, FAS, and leptin) in a depot-specific manner.¹³ In addition, adult mice from LP dams cross-fostered to control lactating dams presented modified daily transcriptional profile of lipogenic and clock genes in WAT, suggesting an association between the disruption of the circadian clock and the programming of adiposity.¹⁷

In sheep, which have a similar profile of adipose tissue cell development as humans, a programmed effect on adipocyte development is implicated because of increased PPARγ. Indeed, PPARγ mRNA expression levels were lower within reduced fat depots in low birth-weight lamb. After a period of accelerated postnatal growth, adult offspring from undernourished dams during gestation presented overt obesity with increased PPARγ mRNA expression levels in WAT.⁸ Data obtained from altricial and precocial species suggest that undernourished offspring, especially when fed an obesogenic diet later in life, are vulnerable to adipogenesis and fat accumulation.

Maternal overfeeding

Models of maternal overnutrition and obesity rely on feeding the dams a high-fat (HF) or cafeteria (fat and sugar) diet before (preconceptional period) and/or during gestation and/or lactation. Offspring of obese animals are consistently prone to increased adiposity (i.e., hypertrophic adipocytes) in adulthood in a gender-dependent manner. Overnutrition during lactation and/or postweaning periods always worsens adipogenesis programming.¹⁸

A rat model of maternal obesity based on intragastric feeding of HF diet demonstrated that maternal obesity at conception programs increased adiposity in offspring despite normal birth weight. Indeed, a greater percentage of large adipocytes associated with elevated PPARγ were observed in adulthood suggesting enhanced adipogenesis.¹⁹ In agreement with these findings, fetuses from obese mice fed a cafeteria diet before mating and throughout gestation exhibited larger adipocytes.²⁰ A sheep model of maternal overfeeding during late gestation was also associated with higher WAT mass in the fetus with enhanced PPARγ mRNA expression levels sensitizing to postnatal adiposity.⁸

In a rat model of maternal obesity induced by HF diet before mating and during pregnancy, newborns had similar body weights than pups born from control diet-fed mothers.²¹ Maternal HF diet during lactation had a significant impact on adiposity of the offspring resulting in accelerated catch-up growth and early obesity, apparent at the end of the lactation period.²² In rodent models, offspring of obese dams consistently shows fat expansion suggesting enhanced adipogenesis which may be attributed, at least in part, to upregulated PPARγ¹⁸ associated with downregulated PPARγ corepressors (SIRT1, SMRT, NcoR [nuclear receptor corepressor]).²² In agreement with these findings, overweight adult offspring from obese mice fed a cafeteria diet before mating and throughout gestation displayed marked adiposity in a gender-dependent manner. The adipocyte hypertrophy, more pronounced in female, was accompanied by reduced lipolytic adrenoreceptors and elevated PPARγ mRNA expression levels.¹⁸

In adulthood, obese rat offspring of cafeteria-diet-fed dams during gestation and lactation presented an increase in adipose tissue TG content with elevated lipogenic enzyme activities (lipoprotein lipase [LPL]). They also had abnormalities in fatty acid composition.²³ Interestingly, a study showed that a mouse model of maternal gestational diabetes leads to overweight in adult offspring associated with larger adipocytes.²⁴ These findings indicate that perinatal exposure to a diabetic milieu characterized by increased glucose and/or insulin levels can program developmental processes such as adipogenesis (Fig. 1).

Altered feeding in the neonatal period

Because adipogenesis mostly takes place after birth in rodents, models based on postnatal dietary manipulations (i.e., postnatal over- [small litters] or undernutrition [large litters] of the nursing pups have been extensively used to investigate offspring adipose tissue programming.

Neonatally overfed offspring reared in small litters showed a long-lasting obese phenotype. Overfed rat offspring displayed increased body weight and plasma insulin as early as 10 d of age. They also presented higher preadipocyte and stromal cell numbers within WAT. At this age, adipose tissue expansion arose only from adipocyte hypertrophy (i.e., enhanced LPL activity), since hyperplasia occurred only at 15 d of age. In later life, higher fat mass and hypertrophic adipocytes are associated with a depot-specific elevation of lipogenic gene expression, especially the glucocorticoid (GC) system²⁵ (Fig. 1). Interestingly, obesity-prone rat offspring artificially raised by intragastric canula (“pup in the cup” model) under a high-carbohydrate milk formula (in contrast to rat milk wherein the major source of calories is fat) exhibited hyperinsulinemia, hypertrophied adipocytes with enhanced lipogenic enzyme activities.²⁶ On the contrary, neonatally underfed offspring reared in large litters presented persistent lower adiposity and small adipocytes. Consistent with these findings, adult offspring from FR30 dams only during suckling period exhibited decreased expression of adiponenic genes associated with a long-term protective effect providing resistance to diet-induced obesity.²⁷

Perinatal Malnutrition Programs Modifications in Adipose Tissue Noradrenergic Innervation in Offspring

Several studies have shown that maternal nutrient restriction impairs sympathetic activity in WAT offspring. Weanling rats from FR50 dams during the last week of gestation and lactation exhibited elevated circulating norepinephrine level that could participate, via chronic β-adrenergic stimulation, to the remodeling of WAT into a thermogenically active BAT. Indeed, a marked increase in UCP1, PGC1α, and PPARα mRNA expression levels, markers of brown adipocytes and/or adaptive thermogenesis were observed in fat pads of offspring. These observations suggest a delay in the maturation of offspring WAT, favoring the acquisition of brite adipocytes in WAT and increased thermogenesis.²⁸ Adult rat offspring from FR20 dams during the first 12 d of pregnancy exhibited a gender-dependent reduction of noradrenergic innervation to WAT and BAT as well as modified adrenoreceptor subtypes ratio. These modifications are associated with greater adiposity, enhanced adipocyte hyperplasia and hypertrophy²⁹. In addition, adult rats reared in small litters exhibited reduced BAT mass and thermogenesis (i.e., lower UCP1 mRNA expression levels), modified lipolytic adrenoreceptor subtypes ratio and impaired sympathetic outflow activity that might affect lipolysis.³⁰

Offspring of Malnourished Dams Exhibit Increased Circulating and Adipose Tissue Pro-Inflammatory Mediators Levels

Perinatal nutritional manipulations influence the circulating levels of several adipocytokines (i.e., tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]) in obesity-prone offspring. Chronic inflammation of adipose tissue is viewed as a hallmark of obesity and metabolic syndrome. In particular, inflammation has detrimental effects on insulin secretion, insulin sensitivity, and lipid metabolism. It may reflect either a modification of the cell composition (i.e., immune cell infiltration), and/or an increase in pro-inflammatory markers mRNA gene expression in the WAT. Consistent with this notion, adipose tissue of prenatally undernourished adult sheep exhibited upregulation of key pro-inflammatory genes accompanied by a recruitment of macrophage within WAT.³¹ Interestingly, uteroplacental insufficiency resulting in IUGR is also associated with enhanced inflammatory mediators in WAT prior to the onset of overt obesity.¹⁵ In addition, fetuses of obese mice fed a cafeteria diet before mating and throughout gestation exhibited an increase in several pro-inflammatory markers in WAT, suggesting macrophage infiltration.²⁰ Similarly, enlarged adipocytes of rat offspring reared in small litters displayed a postnatal induction of pro-inflammatory cytokines (i.e., TNF-α and IL-6) mRNA expression levels that were exacerbated under HF diet.²⁵

Programming mechanisms

Different opposite paradigms (undernutrition vs. overfeeding) have been used to study the long-term effects of nutritional manipulations in the perinatal period, and both protocol result in similar outcomes on the adult offspring's adipose tissue. Thus, the perturbation of circulating factor levels as well as adipose tissue local factor levels, other than nutrients, induced by nutrition during neonate development may account for long-lasting adipose tissue cellularity perturbations.

Circulating and local factors

Several studies support the notion that inappropriate neonatal leptin levels lead to fat expansion by programming the hypothalamus adipose-axis.³² First, leptin displays marked in vivo and in vitro neurotrophic effects.³³ Second, perinatal leptin manipulations have long-term detrimental effects resulting in an increase in adiposity in adulthood.³² Third, leptin directly activates adipogenesis by promoting differentiation of preadipocytes¹⁶ whereas it shows antilipogenic effects on mature adipocytes³⁴ (Fig. 1). Increased insulin levels might also be a key factor of fat accumulation. Similarly, insulin exhibited in vivo and in vitro programming effects on the hypothalamus adipose-axis.³² In particular, insulin directly activates adipogenesis and lipogenesis whereas it inhibits lipolysis in mature adipocytes³⁵ (Fig. 1).

On the one hand, persistent modified GC circulating levels might contribute to the susceptibility of obesity in adulthood. In line with these findings, maternal nutritional manipulations coincide with elevated perinatal circulating GC levels. Thus, it may lead to long-lasting disturbed HPA axis feedback with permanent hypercorticosteronemia. Chronic GC exposure activates adipogenesis primarily by regulating key adipogenic transcription factors (i.e., C/EBPα, PPARγ) (Fig. 1). It may also induce the expression of pro-inflammatory genes, favoring macrophage infiltration and providing the environmental conditions for inflammation.^13,25

On the other hand, the predisposition of increased adiposity may be due to local adipose tissue GC metabolism (i.e., modified GR, MR, 11β-HSD11, 1β-HSD2 expression levels), rather than systemic GC status (Fig. 1). Indeed, perinatal nutritional manipulations program the local adipose tissue GC sensitivity in a sex-specific manner. A primate model of maternal nutrient reduction in which offspring develop increased adiposity in adulthood was associated with elevated mRNA expression levels of glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), enzyme that amplifies local GC actions by converting inactive GC metabolites to active GC in fetal adipose tissue in a sex-specific manner.³⁶

Low birth weight lamb with reduced fat deposition from undernourished dams during gestation, exhibits changes in potential GC sensitivity directly related to the increase in postnatal WAT mass. Indeed, adipose tissue GR and 11β-HSD1 mRNA expression levels displayed a progressive postnatal increase that parallels active catch-up growth and fat expansion. In contrast, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that degrades active GC to inactive metabolites was reduced.³⁷

Similarly, hypertrophied WAT of overfed offspring reared in small litters displayed a postnatal induction of WAT GR and 11β-HSD1 mRNA expression levels. Postweaning HF diet exacerbated this profile. Interestingly, adult rat offspring from diabetic dams also showed an increase in 11β-HSD1 mRNA expression levels prior to the onset of overt obesity.²⁵ As reported during postnatal catch-up growth in undernourished lamb,³⁷ these observations emphasize the pivotal role of the GC WAT environment during the perinatal period on the subsequent development of obesity.

Finally, the ratio between adipose tissue 11β-HSD1 and 11β-HSD2 expression were modified in adult rat offspring from FR70 dams throughout the gestation and, thus, the local tissue ratios between active and inactive GC. In response to HF diet, the depot-specific upregulation of 11β-HSD2 mRNA, while 11β-HSD1 expression remains stable, might limit corticosterone concentration within its local environment, thus, diminishing responsiveness to GC. This may represent an adaptive mechanism that may counteract excess fat storage and adipocyte hypertrophy.¹³

Epigenetic and Transgenerational Mechanisms

Nutritional manipulations during the perinatal period are now considered as transient environmental challenges that can permanently imprint the offspring genome to exert their metabolic effect in adulthood. Indeed, maternal (and/or paternal) perinatal food manipulations can cause epigenetic modifications such as gene promoter region methylation (i.e., the CpG sites), chromatin histone acetylation/methylation and changes in miRNA expression levels in offspring.³⁸ These nutritionally-induced epigenetic modifications may persistently affect transcriptional levels of key genes involved in adipogenesis³⁹ (especially GR, C/EBPα, and PPARγ) and/or in inflammation⁴⁰ to program long-term WAT cellularity. To our knowledge, only few studies have reported epigenetic modulations associated with programmed adipose tissue induced by maternal nutritional manipulations.^9,19,41,42 However, these findings suggest a close link between maternal nutritional manipulations and programmed adipose tissue's cellularity via epigenetics mechanisms.

Jousse et al.⁴¹ showed that adult mice from LP dams presented hypomethylation of the leptin promoter in WAT with lower leptin contents. Ferland-McCollough et al.⁹ showed that rat offspring from LP mothers exhibited an increase in miRNA-483-3p expression levels in WAT with a decrease in GDF3 (a member of the BMP/TGF-β family) protein content, a factor that impairs late stages of adipocyte differentiation. Masuyama et al.⁴² reported that exposure to a HF diet in utero causes an increase in leptin and adiponectin mRNA expression levels associated with epigenetic modifications in WAT of mouse offspring. In particular, lower acetylation and higher methylation levels of histone H3 at lysine 9 of the promoter of adiponectin were evidenced whereas higher methylation of histone 4 at lysine 20 in the leptin promoter was observed in obesity-prone offspring. Borengasser et al.¹⁹ showed that obesity-prone weanling rat from obese dams induced by intragastric feeding of HF diet presented greater ex vivo adipocyte differentiation associated with increased mRNA expression levels of key adipogenic and lipogenic transcription factors (PPARγ, C/EBPβ) and specific alterations in DNA methylation of CpG sites.

Nutritional manipulations in the perinatal period can predispose to obesity and imprint adipose tissue's cellularity in offspring in a gender-dependent manner. For example, the consumption of HF diet during pregnancy appears to directly influence placental methylation and placental gene expression patterns only in female mice offspring.⁴³ Thus, sex-specific differences in term of epigenetic modulations are associated with developmentally programmed phenotypes in animal models. Finally, although underlying mechanisms remain unclear, it appears that the transmission of epigenetic alterations might extend beyond the malnourished first generation resulting in the transgenerational inheritance of obesity. Thus, acute programming of somatic tissues can result in long-term health outcomes in the first generation. In addition, germ cells, which contribute genetic and epigenetic information to the second generation, undergo reprogramming during embryonic development.⁴⁴ In mice, it has been shown that both male and female offspring showed increased body weight and adiposity over generations under multigenerational HF diet feeding. In particular, DNA hypomethylation on promoters on several inflammatory genes result in epigenetically increased expression across generations, which may contribute to persistent inflammation in adipose tissue.⁴⁵ Data from the Dutch Famine Study reveal that starvation during pregnancy can also have transgenerational consequences wherein second generation offspring have increased neonatal adiposity.⁴⁶

Conclusion

The periods of gestation and lactation appear to be particularly sensitive time windows for the developmental programming of adiposity. During these periods, plasma levels of circulating factors as well as adipose tissue hormone sensitivity show perturbations in offspring of malnourished dams resulting in long-lasting adipose tissue programming (i.e., modified cellularity) (Fig. 1). Epigenetic mechanisms (especially involving GR, C/EBPα, PPARγ, as well as mediators of inflammation) might also be responsible for adipose tissue's cellularity programming induced by maternal nutritional manipulations. Thus, in the future, a better knowledge of the epigenome changes in response to maternal malnutrition raises the exciting possibility that dietary supplementation (i.e., folic acid, taurine, glycine, vitamin D, and n-3 fatty acid) may provide a therapeutic option using specific regimen for reversing adverse programming of adipose tissue in humans.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

This work was supported by grants from the French Ministry of Education and grants of the Conseil Régional du Nord-Pas de Calais.