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Am J Physiol Endocrinol Metab 292: E1318-E1324, 2007. First published January 9, 2007; doi:10.1152/ajpendo.00526.2006
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Sucrose feeding during pregnancy and lactation elicits distinct metabolic response in offspring of an inbred genetic model of metabolic syndrome

Lucie Sedová,1,3 Ondrej Seda,1,2,3 Ludmila Kazdová,2 Blanka Chylíková,1 Pavel Hamet,3 Johanne Tremblay,3 Vladimír Kren,1 and Drahomíra Krenová1

1Institute of Biology and Medical Genetics of the First Faculty of Medicine of Charles University and the General Teaching Hospital; 2Department of Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; and 3Centre de Recherche, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Submitted 27 September 2006 ; accepted in final form 7 January 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The importance of early environment, including maternal diet during pregnancy, is suspected to play a major role in pathogenesis of metabolic syndrome and related conditions. One of the proposed mechanisms is a mismatch between the prenatal and postnatal environments, leading to misprogramming of the metabolic and signaling pathways of the developing fetus. We assessed whether the exposure to high-sucrose diet (HSD) alleviates the detrimental effects of sucrose feeding in later life (predictive adaptive hypothesis) in a highly inbred model of metabolic syndrome, the PD/Cub rat. Rat dams were continuously fed either standard or HSD (70% calories as sucrose) starting 1 wk before breeding, throughout pregnancy, at birth, and until weaning of the offspring. After weaning, all male offspring were fed HSD until the age of 20 wk, when detailed metabolic and morphometric profiles were ascertained. The early life exposure to a sucrose-rich diet resulted in distinct responses to longtime postnatal HSD feeding. Offspring of the sucrose-fed mothers displayed higher adiposity and substantial increases in triglyceride liver content together with unfavorable distribution of cholesterol into lipoprotein subfractions. On the other hand, their adiponectin concentrations were significantly higher, and insulin sensitivity of skeletal muscle was enhanced compared with the offspring of standard diet-fed mothers. Triglycerides, free fatty acids, overall glucose tolerance, and the insulin sensitivity of adipose tissue were comparable in both groups. In the genetically identical animals, maternal HSD feeding elicited a variety of subtle effects but did not lead to predictive adaptive protection from most HSD-induced metabolic derangements.

developmental plasticity; animal model; PD/Cub; maternal diet

GROWING EVIDENCE SUGGESTS that fetal and early life environment are determinants of disease in adult life, including dyslipidemia, insulin resistance, obesity, and hypertension (1, 26). The "thrifty phenotype" hypothesis (2) confronted the 30-yr-older "thrifty genotype" concept (28), which linked the manifestations of cardiovascular disease, insulin resistance, and diabetes in adulthood with fetal malnutrition rather than with modulation of metabolic and signaling pathways by environmental factors. Apart from the responses of the developing embryo or fetus to survive an immediate environmental challenge, the current view of developmental plasticity recognizes a class of predictive adaptive responses (PARs) (12, 13). Although their advantage may not be immediately apparent, PARs are thought to represent strategies for maximizing the chances of postnatal survival based on the "expectation" or "anticipation" of a particular adult environment. According to the PAR hypothesis, mismatched early and adult environments (e.g., poor maternal nutrition, placental disease, or maternal stress followed by relative nutritional overabundance) increase the risk of adult disease. By definition, metabolic programming does not change DNA sequence and thereby produce distinct phenotypes. Rather, gene expression is altered by epigenomic changes such as DNA methylation, histone acetylation/methylation/phosphorylation/sumoylation patterning, chromatin remodeling, or irreversible alterations of differentiation and organogenesis (11, 27). Nevertheless, some genetic component in the epigenetically-induced effects cannot be ruled out. Different genotypes, when exposed to distinct environmental challenges, may generate specific outcomes (6), even in terms of the thrifty phenotype. This phenomenon has been already described, e.g., in relation to the effects of the peroxisome proliferator-activated receptor-{gamma}2 gene on insulin sensitivity (8), and a genetic component of predisposition toward a thrifty phenotype associated with decreased placental weight and restricted fetal growth has recently been proposed (4).

Thus, metabolic programming may be viewed as a form of complex gene-environment interaction. As such, a detailed analysis of metabolic programming encounters obstacles common to the study of all multifactorial traits. These studies may be aided by using defined animal models that facilitate the search for causative allelic variants. Most studies (1, 12, 23, 24, 26) of developmental plasticity used various models of fetal nutritional deprivation. Addressing the current sweeping pandemics of metabolic syndrome-related conditions, several studies have examined maternal and early-life fat overfeeding (3, 15, 19, 20, 21, 39, 40), but high-carbohydrate diets have received much less attention (14). A combined analysis of overfeeding and malnutrition manipulations revealed a U-shaped curve that defines the point of departure from the normal range of fetal nutritional conditions that result in increased rates of adult disease. Only a handful of studies directly testing the predictive adaptive hypothesis have been performed (20), usually with an experimental design that involves switching offspring to standard dietary conditions after the stimulus had been applied. Furthermore, outbred model strains of rats and mice are often used in studies of developmental plasticity. Although their genetic heterogeneity somewhat mimics that of the general human population, individual specific genome-environment interactions may confound the effect of the programming stimulus (9).

In this study, we tested the predictive adaptive hypothesis of developmental plasticity in a highly inbred PD/Cub rat, an established model of insulin resistance and dyslipidemia (36, 38, 47), to preclude possible effects of genetic heterogeneity. We assessed whether the exposure to high-sucrose diet (HSD) during pregnancy and lactation programs the offspring toward an improved metabolic response to sucrose-rich postweaning diet compared with prepartum unexposed, yet genetically identical, rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental protocol. All experiments were performed in agreement with the Animal Protection Law of the Czech Republic (311/1997), which is in compliance with the European Community Council recommendations for the use of laboratory animals (86/609/ECC), and were approved by the Ethics Committee of the First Faculty of Medicine of the Charles University. Animals were held under temperature- and humidity-controlled conditions on a 12:12-h light-dark cycle. At all times, the animals had free access to food and water. The polydactylous rat [PD/Cub, Rat Genome Database (42) ID 728161] is a highly inbred (F>90) (22) established model of metabolic syndrome, repeatedly evaluated for sensitivity to sucrose diet-induced dyslipidemia and insulin resistance (36, 38, 47). A total of 16 virgin PD/Cub rat dams were continuously fed either standard diet (STD, n = 7) or HSD (n = 10) starting 1 wk before breeding, throughout pregnancy, at birth, and until weaning of the offspring. The diets differed in the carbohydrate fraction only (starch in STD vs. sucrose in HSD); otherwise they were isocaloric and contained equal amounts of proteins (19.6 cal%), fat (10.4 cal%), carbohydrates (70 cal%), and balanced levels of micronutrients. Two STD-fed dams and one HSD-fed dam failed to conceive. At delivery of the offspring, the litter size did not vary significantly between individual litters or between HSD and STD-fed groups (8.3 ± 1.2 vs. 8.5 ± 0.4). The male offspring from litters of two STD-fed dams and two HSD-fed dams (n = 5 and n = 7, respectively) were weighed, assessed for glucose, insulin, triglyceride (TG), free fatty acid (FFA), and adiponectin concentrations, and killed at birth. At weaning (21 days of age for all litters), 5 and 11 male rats were randomly selected from the three and six litters of STD- and HSD-fed dams, respectively, to undergo the identical procedure as described for the newborn group. The remaining males (n = 5 and n = 9, respectively) were all transferred to HSD until they reached 20 wk of age. Then, oral glucose tolerance test was performed after overnight fast. The rats were killed in a postprandial state, and the weights of heart, liver, kidneys, adrenals, soleus muscle, and epididymal and retroperitoneal fat pads were determined. The soleus and gastrocnemius muscles and adipose tissues were used for in vitro assessment of insulin sensitivity and analyses of their TG and cholesterol contents.

Metabolic measurements in adult rats. During the oral glucose tolerance test, blood for glycemia determination was drawn from the tail at intervals of 0, 30, 60, and 120 min after intragastric glucose administration to conscious rats (3 g/kg body wt, 30% aqueous solution). The serum concentrations of postprandial TG, cholesterol, FFA, insulin, and glucose were determined as described previously (38). In short, commercially available analytical kits were employed to determine plasma glucose and serum TG concentrations (Pliva-Lachema, Brno, Czech Republic). Serum FFAs were determined using an acyl-CoA oxidase-based colorimetric kit (Roche Diagnostics, Mannheim, Germany). Serum insulin concentration was determined using an ELISA kit for rat insulin assay (Mercodia, Uppsala, Sweden). Serum levels of adiponectin were determined using Rat Adiponectin ELISA kit (B-Bridge International). Plasma lipoproteins from fasting samples were analyzed using an on-line dual enzymatic method for simultaneous quantification of cholesterol and TG by HPLC at Skylight Biotech (Akita, Japan) according to the procedure described previously (37, 43).

TG and cholesterol content of hepatic and muscle tissues. For determination of TGs and cholesterol in liver and gastrocnemius muscle, tissues were powdered under liquid N2 and extracted for 16 h in chloroform:methanol, after which 2% KH2PO4 was added and the solution centrifuged. The organic phase was removed and evaporated under N2. The resulting pellet was dissolved in isopropyl alcohol, and TG and cholesterol contents were determined by enzymatic assay as described above (Pliva-Lachema).

Insulin-stimulated glycogen synthesis. Basal and insulin-stimulated glucose incorporation into glycogen (conversion of [14C]glucose to [14C]glycogen) was determined in isolated soleus muscle, as described previously (34, 44, 46).

Insulin-stimulated lipogenesis. Basal and insulin-stimulated incorporation of [14C]glucose into total lipids of rat adipose tissue in vitro (lipogenesis) was determined. In short, after decapitation, distal parts of the epididymal adipose tissue (200 mg) were incubated in Krebs-Ringer bicarbonate buffer, as described previously (34, 44, 46). Total adipose tissue lipids were extracted according to Folch et al. (10), and the radioactivity was determined as described previously (44).

Statistical analysis. All results are expressed as means ± SE. Statistical analysis was performed using general linear model ANOVA with maternal diet and litter of origin as main factors, followed by Fisher's least significance difference post hoc test. The null hypothesis was rejected whenever P < 0.05.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Newborns and weanlings. No differences occurred in maternal body weight or food intake for the dams of the STD and the HSD groups throughout pregnancy and lactation (data not shown). Prior to pregnancy, the HSD-fed dams displayed lower glucose tolerance compared with their STD-fed counterparts (AUC0–120 min 917 ± 18 vs. 828 ± 19, P = 0.005). The maternal dietary regimens had no effect on litter sizes or on survival rates. The newborn male offspring of HSD-fed mothers (MHSD) were slightly heavier than the male offspring of STD-fed mothers (MSTD) (MHSD: 5.5 ± 0.1 vs. MSTD: 5.2 ± 0.1 g, P = 0.05), but this difference disappeared by weaning. At birth, MHSD showed significantly lower glycemia (MHSD: 108 ± 5 vs. MSTD: 148 ± 7 mg/dl, P = 0.03) while maintaining similar insulin concentrations as MSTD, but by weaning, both glucose and insulin levels were comparable between the groups. Neither FFA nor TG displayed significant differences between MHSD and MSTD in either newborns or weanlings (data not shown). A steep rise in adiponectin levels occurred in the first 3 wk of life, reaching significantly higher values in the weanling MHSD group (Fig. 1).


Figure 1
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  		Fig. 1. The adiponectin levels in offspring of standard diet- (MSTD; open bars) vs. high-sucrose diet-fed (MHSD; closed bars) PD/Cub mothers is shown for newborn (n = 5 and n = 7) and weaning (n = 5 and n = 11) male rats. Only the significant levels of differences between the groups differing in maternal diets are shown for Fisher's least significant difference (LSD) post hoc test of general linear model ANOVA with maternal diet and litter of origin as main factors (*P < 0.05). Data are shown as means ± SE.

 
Morphometric profile and lipid depots in adult offspring. We observed no differences in either body weight or the organ weights in the 20-wk-old offspring groups, except for the adipose tissue (Table 1). Significantly higher weights of both epididymal (visceral) and retroperitoneal fat pads in MHSD were accompanied by substantially increased levels of TGs in liver (MHSD: 9.95 ± 0.51 vs. MSTD: 6.01 ± 0.55 µmol/g, P = 0.006). The muscle TG (MHSD: 5.08 ± 0.40 vs. MSTD: 5.83 ± 0.46 µmol/g, P = 0.25) and liver cholesterol concentrations (MHSD: 7.05 ± 0.20 vs. MSTD: 6.67 ± 0.36 µmol/g, P = 0.35) were similar in both groups.


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  		Table 1. Morphometric comparison between adult offspring of standard and high-sucrose diet-fed mothers

 
Glucose tolerance and insulin sensitivity of muscle and adipose tissues of adult offspring. MHSD and MSTD demonstrated almost identical patterns in response to the oral glucose load (Fig. 2), resulting in similar areas under the glycemic curves (MHSD: 930 ± 46 vs. MSTD: 947 ± 48 mg·dl–1·120 min–1, P = 0.44). Insulin concentrations also did not vary under either fasting (MHSD: 0.42 ± 0.05 vs. MSTD: 0.38 ± 0.05 nmol/l, P = 0.65) or postprandial conditions (data not shown). Whereas the insulin sensitivity of visceral adipose tissue did not differ between MHSD and MSTD groups, a significant elevation in both basal and insulin-stimulated glycogenesis in skeletal muscle occurred in MHSD (Fig. 3).


Figure 2
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  		Fig. 2. The glucose tolerance MSTD ({lozenge}, n = 5) vs. MHSD ({blacklozenge}, n = 9) PD/Cub mothers is depicted. Data are shown as means ± SE. There were no significant differences between the 2 groups in any of the time points.

 

Figure 3
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  		Fig. 3. Insulin sensitivity of skeletal muscle and visceral adipose tissues in MSTD (open bars, n = 5) and MHSD (closed bars, n = 9) PD/Cub mothers. Basal (INS –) and insulin-stimulated (INS +) glucose incorporation into glycogen of m. soleus (A) and into total lipids of epididymal (visceral) adipose tissue (B) is shown. Statistical significance levels (Fisher's LSD post hoc test of general linear model ANOVA, with maternal diet and litter of origin as main factors) are indicated as **P < 0.01.

 
Lipid profile of adult offspring. The fasting TG and cholesterol concentrations in the major lipoprotein subfractions in 20-wk-old rats are shown in Table 2. No significant difference in either total TG concentration (both fasting and postprandial) or in any TG levels of the 20 lipoprotein subfractions between MHSD and MSTD were observed (Fig. 4). On the other hand, MHSD displayed higher LDL cholesterol concentrations despite similar total cholesterol concentrations under both fasting (Table 2) and postprandial conditions (MHSD: 70.6 ± 3.1 vs. MSTD: 95.2 ± 7.4 mg/dl, P = 0.09). The lipoprotein classes accounting for these differences were the very small LDL (diameter 20.7 nm) and HDL of medium to small size (diameter 8–16 nm) (Fig. 3). The size of VLDL, LDL, and HDL particles did not vary significantly between the two groups (Table 3). Neither fasting nor postprandial concentrations of FFA showed differences between the two groups of adult offspring (MHSD: 1.34 ± 0.05 vs. MSTD: 1.36 ± 0.04 mmol/l, P = 0.82; and MHSD: 0.86 ± 0.04 vs. MSTD: 0.73 ± 0.02 mmol/l, P = 0.08, respectively). However, as with 3-wk-old animals, adiponectin levels were significantly higher in adult MHSD (MHSD: 7.75 ± 0.31 vs. MSTD: 6.27 ± 0.19 µg/ml, P = 0.02).


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  		Table 2. Major TG, cholesterol subfractions, and free glycerol comparison between MSTD and MHSD

 

Figure 4
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  		Fig. 4. The triglyceride and cholesterol content in 20 lipoprotein subfractions in MSTD (open bars, n = 5) and MHSD (closed bars, n = 9) PD/Cub mothers. Within the graph, the significance levels of comparison between the groups differing in maternal diets (Fisher's LSD post hoc test of general linear model ANOVA, with maternal diet and litter of origin as main factors) are shown as follows; *P < 0.05. The allocation of individual lipoprotein subfractions to major lipoprotein classes is shown in order of the particle's decreasing size from left to right. CM, chylomicron.

 

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  		Table 3. Lipoprotein particle size comparison between MSTD and MHSD

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We have tested the potential of a HSD to elicit predictive adaptive responses, allowing the exposed individuals to cope better with the detrimental effects of HSD feeding in the postnatal life. To rule out confounding factors of genetic heterogeneity, we (38, 36, 47) utilized the PD/Cub rat strain with history of more than 90 generations of inbreeding and with repeated confirmation of sucrose-induced derangements of carbohydrate and lipid metabolism. To further assure homogeneity of the experimental groups, we confined this study to only male offspring even though this precluded us from evaluating the sex specificity of the programming effects observed in other studies (1, 19, 23).

The PAR is predicated upon the mismatch of environmental (particularly nutritional) factors before and after birth (12, 13). Although this notion was deduced almost exclusively from the data on restricted intrauterine growth followed by relative overabundance of nutrients in later life, several studies (3, 15, 19, 20, 21, 39, 40) have shown that the converse relation (mismatch between early energy overabundance vs. lack of it after birth) was also relevant. Given the current worldwide shift toward Westernized lifestyle, there is an urgent need to address the relation between excess macronutrient intake during pregnancy and the metabolic fate of the offspring (11). One of the few studies directly testing matched prenatal and postnatal high-fat diet feeding (20) revealed that, although the PARs were not able to reverse the development of hypertension, the exposed pups showed reduced heart rate and endothelial dysfunction. For the present study, the PAR hypothesis predicts that the rats whose mothers were fed HSD should display a more favorable metabolic profile in the presence of HSD in their adult life. However, a maternal HSD had no significant effect on many of the parameters we evaluated (Table 4). After being fed HSD for 5 mo, the "programmed" offspring displayed a seemingly disparate mixture of metabolic features. The capacity to store excess TG in liver and adipose tissue was enhanced in MHSD, consistent with observations in offspring of high-fat diet-fed rat dams (3, 15). We also observed substantial increases in the insulin sensitivity of skeletal muscle together with higher concentrations of adiponectin. Low levels of adiponectin are commonly associated with obesity, insulin resistance (17), and nonalcoholic fatty liver disease (41). However, a recently revealed facet of adiponectin biology postulated the existence of a muscle-specific reaction to circulating adiponectin and even of adiponectin expression directly in muscle tissue (7, 18). We can speculate that the metabolic adaptation in MHSD involves shunting TG away from the muscle, a crucial organ for the whole body insulin sensitivity (25), and toward the liver and adipose tissue. Hence, at the expense of increased adiposity and fatty liver, the overall glucose tolerance is preserved and, in the case of muscle, even enhanced. Although the mechanisms are not clear, adiponectin may confer part of the observed effect. Our observation of an early adulthood increase in insulin sensitivity is similar to that observed in studies of maternal protein restriction and undernutrition (30, 48).


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  		Table 4. Predictive adaptive responses

 
Clearly, the relationships between pre- and postnatal nutrition and their metabolic consequences are complex and extend beyond a mechanistic mismatch paradigm. Recently, a similarly complicated picture (24) was described for the effects of maternal protein restriction and low birth weight on longevity. Contrary to observations in high-fat diet-fed dams, the present study reveals no reduction in litter size or increased weight gain throughout the pregnancy. The HSD-fed mothers gave birth to slightly bigger pups showing reduced glycemia; both traits are most likely attributable to elevated maternal insulin, since these differences ceased by weaning. The HSD-induced maternal insulin resistance may be an underlying mechanism for the distinct metabolic features seen in MHSD, because perinatal hyperinsulinemia has been demonstrated as a potent programming stimulus (31, 39). However, other facets of the metabolic milieu could be involved; e.g., the lipotoxic action of excess free fatty acids can affect the developing organism or can modulate the expression of target genes. Lipoprotein lipase could play a role since a HSD downregulated its activity in adipose tissue and upregulated it in muscle (33, 45). The predictive adaptive response may have prevented this modulation of lipase activity, resulting in decreased accumulation of TG in muscle and increased TG in adipose tissue. As in the case of high-fat diet and several human studies (29), detailed phenotyping is necessary since some of the changes are subtle and virtually impossible to detect with global biochemical and metabolic measures. Even employing 20 discrete lipoprotein fractions, we did not observe any effects of early HSD administration on TG distribution and saw only a mild shift towards higher LDL/lower HDL cholesterol profile in MHSD.

Altogether, maternal HSD feeding appears to amplify several detrimental effects commonly described in postnatal exposure in a way similar to that of HSD-fed offspring of dams fed a high-fat diet (39). The outcomes of the current study indicate a cumulative effect of HSD feeding throughout early development; the identification of the specific stages most sensitive to HSD programming effects (24) is yet to be pursued. One of the questions still unanswered is whether the observed effect is specific to our inbred model of metabolic syndrome or whether the effect would be modulated depending on the particular genotype. The resolution of a possible genomic component together with identification of the responsible molecular pathways could be achieved in a genetical genomics study (35) utilizing comprehensive model sets like the recombinant-inbred (32) or consomic (5) strain panels. In summary, maternal HSD feeding elicited a variety of subtle effects in the genetically identical animals but did not lead to predictive adaptive protection from most HSD-induced metabolic derangements.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by the following grants: GAAV CR KJB5105401 from Grant Agency of the Academy of Sciences of the Czech Republic, NR-7888 from the Internal Grant Agency of the Ministry of Health of Czech Republic, GEI-53958 "CardioGEN" and TACTICS (to L.Sedová) from the Canadian Institutes of Health Research, and the Research Project MSM 0021620807 (Ministry of Education, Youth, and Sport of the Czech Republic).


   ACKNOWLEDGMENTS
 
We thank Michaela Janku, Zdenka Kopecká, and Marie Uxová for their excellent technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: L. Sedová, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Albertov 4, 12800 Prague 2, Czech Republic (e-mail: lsedo{at}lf1.cuni.cz)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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