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Am J Physiol Endocrinol Metab 292: E1095-E1100, 2007. First published December 12, 2006; doi:10.1152/ajpendo.00390.2006
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Resistance to high-fat diet in the female progeny of obese mice fed a control diet during the periconceptual, gestation, and lactation periods

Catherine Gallou-Kabani,1 Alexandre Vigé,1 Marie-Sylvie Gross,1 Catherine Boileau,1,2 Jean-Pierre Rabes,1,2 Jamilla Fruchart-Najib,3 Jean-Philippe Jais,4 and Claudine Junien1,2

1Institut National de la Santé et de la Recherche Médicale, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, Faculté de Médecine, Hôpital Necker-Enfants Malades, 4Service de Biostatistique et Informatique Médicale, Paris; 2Assistance Publique-Hopitaux de Paris, Faculté de Médecine Paris Ile-de-France-Ouest, Université Versailles-Saint-Quentin-en-Yvelines, Laboratoire de biochimie, Hôpital Ambroise Paré, Boulogne; and 3Institut National de la Santé et de la Recherche Médicale, Université de Lille 2, Département d'Athérosclérose, Loos, France

Submitted 3 August 2006 ; accepted in final form 5 December 2006


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
With the worldwide epidemic of metabolic syndrome (MetS), the proportion of women that are overweight/obese and overfed during pregnancy has increased. The resulting abnormal uterine environment may have deleterious effects on fetal metabolic programming and lead to MetS in adulthood. A balanced/restricted diet and/or physical exercise often improve metabolic abnormalities in individuals with obesity and type 2 diabetes mellitus (T2D). We investigated whether reducing fat intake during the periconceptual/gestation/lactation period in mothers with high-fat diet (HFD)-induced obesity could be used to modify fetal/neonatal MetS programming positively, thereby preventing MetS. First generation (F1) C57BL/6J female mice with HFD-induced obesity and T2D were crossed with F1 males on control diet (CD). These F1 females were switched to a CD during the periconceptual/gestation/lactation period. At weaning, both male and female second generation (F2) mice were fed a HFD. Weight, caloric intake, lipid parameters, glucose, and insulin sensitivity were assessed. Sensitivity/resistance to the HFD differed significantly between generations and sexes. A similar proportion of the F1 and F2 males (80%) developed hyperphagia, obesity, and T2D. In contrast, a significantly higher proportion of the F2 females (43%) than of the previous F1 generation (17%) were resistant (P < 0.01). Despite having free access to the HFD, these female mice were no longer hyperphagic and remained lean, with normal insulin sensitivity and glycemia but mild hypercholesterolemia and glucose intolerance, thus displaying a "satiety phenotype." This suggests that an appropriate dietary fatty acid profile and intake during the periconceptual/gestation/lactation period helps the female offspring to cope with deleterious intrauterine conditions.

epigenetics; nutrition; metabolic syndrome; fetal programming

THE WORLDWIDE EPIDEMIC of metabolic syndrome (MetS), combining disturbances in glucose and insulin metabolism, excess weight distributed predominantly around the abdomen, mild dyslipidemia, and hypertension, leading to obesity, type 2 diabetes mellitus (T2D), and cardiovascular disease, has become a major health concern (6). Like obesity and T2D, MetS is occurring earlier in childhood and worsening from generation to generation. It has been estimated that ~24% of US adults now present MetS (6). An increasing number of women are overweight and consuming a calorific or fat-rich diet before and during pregnancy and lactation. Human epidemiological studies and appropriate dietary interventions in animal models (3) have provided evidence to suggest that maternal nutritional imbalance and metabolic disturbances during critical developmental time windows may have a persistent effect on the health of the offspring and may even be transmitted to the next generation. According to the "predictive adaptive response" hypothesis (12, 13, 17), the rodent fetus makes adaptations in utero and/or in the early postnatal period on the basis of the predicted postnatal environment. Evidence has accumulated (11) to suggest that epigenetic regulation is responsible for this inheritance pattern.

Most studies on developmental programming (1) have examined the consequences of protein restriction during gestation in rodents, which do not entirely match the features of the current epidemic of MetS. A few studies in rodents (2) have dealt with the consequences of a high-carbohydrate or fat-rich diet, which better correspond to the features of the current MetS epidemic in humans. However, it remains difficult to determine whether, how, and when MetS can be reliably induced by dietary intervention, due to differences between protocols, diets (e.g., type of fatty acids), dose and duration of exposure to the nutritional factor, sex, and the periods examined (1).

It has been shown (18) that MetS features in the adult offspring of fat-fed rats can be acquired both antenatally and during suckling. However, in these experiments the animals were fed a fat-rich diet during gestation/lactation but not before pregnancy. Pregnant mothers were therefore not overweight and did not display metabolic disturbances that were capable of interfering with fetal/postnatal programming (7). These data, therefore, only partly reflect the features of MetS.

Obesity during pregnancy is clearly a threat to the health and well being of the offspring, even into adulthood. Research is lacking in this area, and the mechanisms underlying this phenomenon are unknown, because few studies using animal models of obesity during pregnancy (2) have been published.

Because T2D is theoretically preventable, even in individuals at high risk, it should be possible to revert the vicious cycle of intergenerationnal transmission by modifying the diet of the mother during the periconceptual/gestation/lactation period. Thus, rather than feeding pregnant mothers a high-fat diet (HFD), as previously described (2, 14), we investigated whether reducing fat intake during the periconceptual/gestation/lactation period in mothers with HFD-induced obesity before pregnancy could be used to modify fetal/neonatal MetS programming positively, thereby preventing MetS.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals and diets. All experiments on animals were conducted following ethics review, under French government license for three generations: 1) F0 generation (founders): male and female C57BL/6J mice were obtained from Harlan at 4 wk of age. After 1 wk of adaptation, the animals were housed in individual cages in a controlled-temperature room with a 12:12-h light-dark cycle. The mice were allowed ad libitum access to water and chow diet. 2) First generation (F1): at 6 mo of age, F0 males and F0 females were mated. Males were removed once the females were pregnant. The day after delivery, all F1 litters were randomly reduced to four or five pups. After being weaned, each mouse was transferred to an individual cage and randomly assigned to the control diet (CD) or HFD. Mice of both sexes were fed a CD ad libitum with 10% of calories from fat, the typical fat content of regular mouse chow, and the others were fed a HFD (60% of calories from fat) for 20 wk. 3) Second generation (F2): at 6 mo of age, F1 female mice on the HFD were crossed with F1 male mice on the CD. The pregnant F1 females were maintained on the CD from mating until the end of lactation, and all of the F2 male and female offspring were maintained on the HFD for 20 wk after being weaned (Fig. 1A). In parallel F1 female mice on the CD were crossed with F1 male mice on the CD to generate F2 control mice fed the CD (Fig. 1A, left). To ensure reproducibility, three independent experiments with contemporaneous controls were carried out.


Figure 1
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  		Fig. 1. A: crossing and diet scheme. Gray bars, control diet (CD; 10% fat); black bars, high-fat diet (HFD; 60% fat). F, female; M, male. The number below M and F is the number of mice analyzed in each group. F0, founders; F1, first generation; F2, second generation. Three independent experiments with contemporaneous controls (left) were carried out (no. of animals = 543). B: F2 female resistance to a HFD. The percentages of obese and lean females are the percentage of animals weighing more or less than the cutoff value, mean weight of F1N + 2 standard deviations (SD). Weight and cumulative food intake were determined for females (C and E) and males (D and F) of the F1 and F2 generations after 24 wk on the CD or HFD (n = 20–158). C and E: downward hatched bars, F1 and F2 mice on CD (F-CD); black bars, F1-HFD; upward hatched bars, F2 "resistant" females on HFD (F2-HFD-R); white bars, F2 "sensitive" females on HFD (F2-HFD-S). D and F: downward hatched bars, F-CD; black bars, F1-HFD; upward hatched bars, F2-HFD-S. Data are means ± SE. *P < 0.05; ***P < 0.001.

 
Diets were supplied in pellet form by Research Diets (New Brunswick, NJ). For the CD, 10% of calories were in the form of fat, 20% were in the form of protein, and 70% were in the form of carbohydrates. The carbohydrates present were corn starch (45%), maltodextrin (5%), and sucrose (50%). The proportions of the various types of fatty acid, corresponding to 10% of the kilocalories and 4 g/100 g, were, for 4 g: 1.0 g (25.1%) saturated fatty acids (SFAs), 1.3 g (34.7%) monounsaturated fatty acids (MUFAs), and 1.6 g (40.2%) polyunsaturated fatty acids (PUFAs). For the HFD, 60% of calories were in the form of fat, 20% were in the form of protein, and 20% were in the form of carbohydrates. The carbohydrates present were maltodextrin (65%) and sucrose (35%). The proportions of the various types of fatty acid, corresponding to 60% of the kilocalories and 35 g/100 g, were, for 35 g: 12.25 g (35.0%) SFAs, 15.19 g (43.4%) MUFAs, and 5.6 g (15.9%) PUFAs. The CD and HFD contained 18 and 300 mg cholesterol/kg and 0.3 and 4.2 g of arachidonic acid/4,057 kcal, respectively.

Food consumption measurement. Each mouse was weighed twice weekly (Tuesday and Friday). Diet and water were weighed once per week (Tuesday). Food consumption was estimated by subtracting the amount of food left on the grid from initial food weight. Energy intakes were calculated on the basis of 3.8 kcal/g for the CD diet and 5.2 kcal/g for the HFD. Food spilled on the floor of the cage was not weighed, but spillage was minimal because the diet was supplied as pellets. Feed efficiency (FE) was calculated as (grams of body weight gain per kilocalorie of food consumed per animal) x 1,000.

Plasma lipid analysis. Blood was collected at 8, 16, and 24 wk of age. The animals were fasted for 5–6 h, and blood samples were collected via retroorbital sinus puncture in unanesthetized animals. Plasma triglyceride, total cholesterol (tC), and high-density lipoprotein cholesterol (HDL-C) concentrations were determined using a Beckman CX7. Plasma lipoproteins from pooled mouse plasma were separated by gel filtration chromatography, using a Superose 6HR 10/30 column (Pharmacia LKB Biotechnology), as previously described (9). The elution fraction numbers of the plasma lipoproteins separated by fast-protein liquid chromatography (FPLC) were VLDL, 20–30; IDL/LDL, 35–45; and HDL, 45–60.

Metabolic studies. Plasma insulin levels were measured with the Ultra-Sensitive Rat Insulin ELISA kit using the mouse standard, reference 90090 (Crystal Chem, Downers Grove, IL). Oral glucose tolerance tests (OGTTs) and intraperitoneal insulin tolerance tests (IPITTs) were performed after 4.5 mo on the HFD. Glucose (2 g/kg) was administered orally and insulin (0.5 units/kg, Actrapid; Novo Nordisk, Bagsvaerd, Denmark) intraperitoneally at time 0. Tail blood was collected at –20, 20, 40, 60, 80, and 120 min for OGTT and at –15, 15, 30, 45, 60, 90, and 120 min for IPITT. Blood glucose concentration was determined with a glucometer (Accu-Chek Active; Roche Diagnostics). Mice were fasted for 14 h (OGTT) or 4 h (IPITT). The area under the curve (mM/min) was calculated manually.

Statistical analysis. Computations were carried out with the SAS System 8.2 (SAS Institute, Cary, NC). Data are expressed as means ± SE for quantitative variables, except for weight, which is expressed as means ± 2 SD. Mixed analyses of variance (SAS Proc Mixed) (21), modeling litter effect by a random component, were used to test differences between generations and diets. Pairwise comparisons between groups were adjusted by the Bonferroni method. A generalized estimating equations regression approach (SAS Proc Genmod) (15) defining the litter as a cluster variable was used for comparisons of qualitative data. Differences were considered to be significant if P < 0.05.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
HFD-induced obesity in F1. We fed 352 male and female C57BL/6J mice a HFD or a CD for 5 mo after weaning (Fig. 1A). HFD-fed mice became hyperphagic and obese. At 6 mo of age, a significant proportion of HFD-fed F1 females (83%; 29.3 ± 5.4 g, n = 87) and HFD-fed F1 males (80%; 37.6 ± 6.3 g, n = 60) were more than two standard deviations (SD) above mean "normal" weight estimated from the CD-fed mice (21.2 ± 1.3 and 27.6 ± 2.2 g for females and males, respectively; Fig. 1, A and B).

Sex-specific resistance/sensitivity to HFD-induced obesity in the progeny. Given the increasing incidence of obesity and T2D, we investigated whether dietary intervention during pregnancy/lactation could slow the progression of obesity and T2D in the next generation. We crossed our first generation of obese F1-HFD females (28.5 ± 5.3 g) with normal males (27.6 ± 2.2 g) and fed them the CD from mating until the end of lactation (Fig. 1A). At birth, litter size was adjusted to four to five pups of both sexes by random culling of the pups to prevent bias due to litter size. At 1 mo of age, pups were weaned onto the HFD. Male F2 mice (80%; 36.4 ± 5.6 g, n = 35), like those of the F1 (80%), became obese (Fig. 1D), hyperglycemic, and hypercholesterolemic by 6 mo of age. Thus there was no statistically significant difference in resistance to the HFD between F1 and F2 males. In contrast, a significantly higher proportion of the female offspring (F2-HFD) of obese mothers than of F1-HFD females (43%, n = 47, vs. 17%, n = 87) showed resistance to the HFD and had a weight <2 SD above the mean at 6 mo (Fig. 1, B and C), with this difference being statistically significant (P < 0.01) for females only. We defined this subpopulation of F2 females as "resistant" (F2-HFD-R) to the obesity-inducing effects of the HFD, with females above this cutoff defined as "sensitive" (F2-HFD-S). As the weights and biological parameters of F1 and F2 mice on CD were not statistically different, we pooled the results into one control group, F-CD (F1 and F2 mice on CD), for each sex.

Caloric intake and FE: lack of hyperphagia in resistant females on the HFD. Cumulative food intake and FE were determined for females and males of the F1 and F2 generations after 24 wk on the CD or HFD (n = 20–158). F1 mice females on the HFD ate more than those on the CD, with mean global intakes of 1,592 ± 41 and 1,275 ± 9 kcal/5 mo (25%, P < 0.001) and 1,540 ± 23 and 1,386 ± 7 kcal/5 mo (11%, P < 0.001) for females and males, respectively (Fig. 1, E and F). F2-HFD males were also hyperphagic and had the same FE as F1-HFD males.

Conversely, F2-HFD-R females had a caloric intake similar to that of F-CD females but significantly lower than that of their F1-HFD obese mothers and the F2-HFD-S females (F2-HFD-R: 1,314 ± 26; F-CD: 1,275 ± 9; F1-HFD: 1,592 ± 41; F2-HFD-S: 1,515 ± 42 kcal/5 mo; Fig. 1E). FE was significantly higher in HFD-fed F1 and F2 females (F1-HFD and F2-HFD-S) showing diet-induced obesity. By contrast, FE was identical for F-CD females and F2-HFD-R females. F1-HFD, F2-HFD-S, and F2-HFD-R weighed 38, 39, and 1% more, respectively, than F-CD females.

Lipid metabolic response to diet. As previously reported for diet-induced obesity in mice, triglyceride levels determined at 8, 16, and 24 wk were not significantly affected (data not shown). High-fat feeding led to significant increases in plasma tC concentration (Fig. 2, A and B), mostly due to HDL-C (Fig. 2, C and D). However, the time course of this increase and final plasma tC and HDL-C concentrations differed between the groups of mice at 24 wk. All HFD mice displayed a significant increase in plasma tC concentration at 16 wk (Fig. 2, A and B). HDL-C levels gradually increased between weeks 8 and 24 in F1-HFD females (Fig. 2C). In F2-HFD females, HDL-C concentration increased between 8 and 16 wk and reached a plateau at 24 wk (Fig. 2C). In F2-HFD-R and F2-HFD-S mice, HDL-C concentration was intermediate between those for F-CD females and obese F1-HFD females, but the latter did not reach significance (Fig. 2C).


Figure 2
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  		Fig. 2. Total cholesterol (A and B) and HDL cholesterol (HDL-C; C and D) levels were determined for females and males of the F1 and F2 generations after 8, 16, or 24 wk on the CD or HFD (n = 8–47). A and C: downward hatched bars, F-CD; black bars, F1-HFD; upward hatched bars, F2-HFD-R; white bars, F2HFD-S; B and D: downward hatched bars, F-CD; black bars, F1-HFD; upward hatched bars, F2-HFD-S. Lipoprotein analysis. Sera were also subjected to fast-protein liquid chromatography, and the cholesterol content of the eluted fractions was determined for females (E) and males (F) (n = 5–6). Data are means ± SE. *P < 0.05; **P < 0.01; ***P < 0.001. {circ}, F-CD; bullet, F1-HFD; {blacktriangleup}, F2HFD-S; {triangleup}, F2-HFD-R.

 
FPLC analysis revealed that the excess cholesterol was mostly associated with the HDL fraction, although a smaller increase in LDL cholesterol concentration was also observed, mostly in males (Fig. 2, E and F) (4). However, in the F1 generation, LDL and HDL cholesterol levels were higher in obese males than in obese females. This difference was even more pronounced in the F2 generation, and the mild hypercholesterolemia in resistant females was due to an increase in HDL-C levels only. In F1-HFD males and, to a lesser extent, females, the significant increase in HDL-C levels was associated with the appearance of a second species of HDL in the plasma. In sensitive F2-HFD males and females, HDL-C levels fell (Fig. 2, E and F). Thus hypercholesterolemia profiles differed in F1 and F2 animals. Although F2 HFD males were not resistant to diet-induced obesity, their lipid profiles were also qualitatively and quantitatively different (Fig. 2, B and F). Cholesterol levels and profiles and the time course were intermediate between F1-HFD males and CD males.

Effect of diet on glucose tolerance and insulin sensitivity. Glucose homeostasis was impaired by high-fat feeding in F1 males and females. By contrast, weight gain, glycemia, and insulinemia were similar in F2-HFD-R females and in F1 and F2 mice fed the CD (F-CD; Fig. 3, A and C).


Figure 3
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  		Fig. 3. Blood glucose levels and plasma insulin concentrations were determined for females (A and C) and males (B and D) of the F1 and F2 generations after 8, 16, or 24 wk on the CD or HFD (n = 7–46). Note that, due to differences in insulin levels between females (C) and males (D), different x-axes were used for the two sexes. Data are means ± SE. *P < 0.05; **P < 0.01; ***P < 0.001. A and C: downward hatched bars, F-CD; black bars, F1-HFD; upward hatched bars, F2-HFD-R; white bars, F2HFD-S; B and D: downward hatched bars, F-CD; black bars, F1-HFD; upward hatched bars, F2-HFD-S.

 
F1-HFD mice (females and males) were hyperglycemic and hyperinsulinemic, F2-HFD-S female mice were hyperinsulinemic but not hyperglycemic, and F2-HFD-R female mice were normoglycemic and normoinsulinemic at 24 wk (Fig. 3, A and C). Plasma insulin levels steadily increased over time in F1-HFD mice (females and males) and, to a lesser extent, in F2-HFD-S female mice (Fig. 3C). By contrast, F2-HFD-R female mice displayed a slight increase in insulinemia after 4 wk of HFD, slowly decreasing to the level for CD-fed mice at 24 wk.

OGTTs were performed in 48 conscious, overnight-fasted female mice after 4.5 mo of HFD. Oral glucose (2 g/kg) administration resulted in more rapid glucose clearance from the peripheral circulation in CD-fed mice than in F1 and F2 HFD-fed mice. Glucose intolerance was particularly marked in F2-HFD-R females (Fig. 4A). By contrast, following the intraperitoneal administration of insulin, F1-HFD and F2-HFD-S females displayed insulin resistance (P < 0.05 and P < 0.001, respectively), whereas the response to insulin of F2-HFD-R females was similar to that of CD-fed normal control mice (F-CD) (Fig. 4B).


Figure 4
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  		Fig. 4. A: oral glucose tolerance test (OGTT). Plasma glucose concentrations during OGTT were determined in females fed the CD or HFD (n = 3–30). B: intraperitoneal insulin tolerance test (IPITT). Plasma glucose concentrations during IPITT were also determined in females fed a CD or HFD (n = 3–30). Data are means ± SE. {circ}, F-CD; bullet, F1-HFD; {blacktriangleup}, F2HFD-S; {triangleup}, F2-HFD-R.

 
We studied the effects of shifting from a HFD to a CD in F1 obese nonpregnant females over a period of 8 wk (corresponding to the duration of gestation and lactation) so as not to stress pregnant mice. Caloric intake fell dramatically on the first week on the CD, resulting in 12.7 ± 1.36% weight loss. Insulinemia and glycemia decreased substantially, reaching control levels. Unfortunately, we could not determine when these mice became normoglycaemic/normoinsulinemic since we could not collect more blood between 0 and 3 wk for ethical and physiological reasons. After 1 wk on the CD, these mice were no longer hyperphagic. However, mice remained overweight (25.53 ± 0.67 g) and hypercholesterolemic (3.05 ± 0.37 mm/l) until the end of the experiment at 8 mo (unpublished observations).


   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Adult health is largely determined by the conditions in which the organism develops in the womb and milk yield and composition during suckling (28). In human populations, the increasing number of women who are overweight and consuming a high-calorie or fat-rich diet before and during pregnancy and lactation therefore represent a major threat for future generations. Here, we show that a CD during the periconceptual/gestation/lactation period may thwart the deleterious effects of excess maternal weight, but only in female offspring. The nutritional trajectory included 1) diet-induced (HFD) obesity and diabetes in mothers just before pregnancy, 2) a shift from the HFD to the CD during the periconceptual/gestation/lactation period in the mothers, and 3) postweaning HFD for 5 mo in the offspring. One-half the female offspring, but far fewer males, became resistant to the HFD. This sequence led to the sex-specific "normalization" of most metabolic parameters. Thus the use of a recommended diet during the periconceptual/gestation/lactation period in overweight female mice formerly fed a HFD (60%) interfered with early MetS programming in the offspring in a positive way. In the F2 generation, resistant (females) and sensitive (males and females) animals were observed in the same litter (n = 18). Thus resistance was not mother specific.

Although we cannot exclude the possibility that other mechanisms of energy homeostasis regulation remained altered, this adaptation may result from changes in satiety threshold or interference with hyperphagia for highly palatable food. F1 mice on the HFD ate more than mice on the CD, with a mean increase in calorie intake of 25% for females and 11% for males. F2 males fed the HFD diet were also hyperphagic. By contrast, F2-HFD-R females had a calorie intake similar to that of F-CD females (+3%) but significantly lower than that of their obese F1-HFD mothers and the F2-HFD-S females (–21 and –23%, respectively). Thus female F2-HFD-R mice displayed a satiety or satiation phenotype (5). The exact mechanisms by which HFD maintenance decreases sensitivity to satiation signals, such as CCK and nutrients, are unknown (23). Palatable food, which is rich in fat and sugar, upregulates the expression of hunger signals and satiety signals while it blunts the response to satiety signals and activates the reward system. Palatable food, therefore, offsets normal appetite regulation, potentially accounting for the increasing problem of obesity worldwide (8). Interestingly, in F2-HFD-R females and in normal F-CD females, repletion or satiety was attained with the same number of calories for each diet despite very different fat contents (10 vs. 60% fat). This suggests that hunger signals may not be upregulated or that the high palatability of the HFD is no longer perceived and/or transduced as a signal to the central nervous system circuitry (24, 27). Indirect calorimetry experiments may reveal whether the reduction in caloric intake results from a lower intake during meals, from fewer meals, or both.

We observed that the switch from a 60%-fat to a 10%-fat diet around the time of conception led to moderate weight loss in pregnant females, who remained significantly overweight with respect to normal CD females. However, because we could not measure several metabolic parameters without stressing the animals, we carried out parallel experiments on F1 obese mice not subsequently crossed with males. The duration of this experiment was the same as that of the periconceptual/gestation/lactation period (8 wk). Although the F1-HFD mice that gave birth to F2-HFD-R or -S females became pregnant after this weight loss, we can assume that they remained overweight during pregnancy and lactation (8 mo), just as in these control experiments. To compare the effects of the CD with the HFD during pregnancy, additional control experiments were carried out with obese F1 females maintained on the HFD throughout the periconceptual/gestation/lactation period. Unfortunately, for unknown reasons, most of the offspring of these females did not survive the perinatal period.

Glucose homeostasis was impaired by high-fat feeding in the F1 generation and in F2-HFD-S mice. F1-HFD mice were hyperglycemic and hyperinsulinemic, whereas F2-HFD-S mice were hyperinsulinemic but not hyperglycemic, and F2-HFD-R were normoglycemic and normoinsulinemic at 24 wk. Glycemia and insulinemia were thus similar in lean F2-HFD-R females and in control F1 and F2 mice fed the CD (F-CD). The normoglycemia of F2-HFD-S and F2-HFD-R mice results from an active compensatory mechanism. For F2-HFD-R mice, this could be accounted for by normal sensitivity to insulin despite marked glucose intolerance. For F2-HFD-S mice, glucose intolerance was probably temporarily blunted by high insulin levels at 6 mo, possibly indicating some latency with respect to F1-HFD-S mice. It has been shown (26) that insulin sensitivity and glucose tolerance can be affected independently in HFD-fed mice.

The profile of obesity-associated hypercholesterolemia differed between F1 and F2 animals for both sexes (25). In F2-HFD-R females, we observed complete protection against obesity, hyperglycemia, and hyperinsulinemia but incomplete protection against hypercholesterolemia. In contrast, sensitive mice (F2-HFD-S females) are insulin resistant. In F2-HFD males, we observed no protection against obesity and hyperglycemia, but cholesterol levels and profiles and time courses were intermediate between F1-HFD males and CD males. The intermediate levels in both F2 groups and in both sexes on the HFD suggest that these differences in lipid homeostasis may result from adaptive programming by the uterine environment, i.e., an overweight mother on the CD during the periconceptual/gestation/lactation period (13).

We observed a sex-specific satiety phenotype limited to female F2 mice. Only males are studied in most protocols, and ours is one of very few reporting results for both sexes. Some studies have reported such differences to be specific to developmental time windows (28) or to specific traits, such as plasma glucose and adiponectin levels, blood pressure, endothelial function, and visceral and subcutaneous fat deposits (1, 20, 22). As previously suggested for rats (10, 16, 19, 28), female sex hormones may protect against the development of insulin resistance and associated disorders. In our experiments, the differences in adaptive programming between the two sexes apply to glucose and insulin, but not to lipids.

An appropriate dietary fatty acid profile and intake during the periconceptual/gestation/lactation period may therefore help female offspring to cope with deleterious maternal milieu conditions. These results in rodents demonstrate the need for epidemiological studies on qualitative and quantitative recommendations for pregnant and lactating women who are overweight or obese. They also suggest that making overweight pregnant women more aware of the real needs of their babies could help to slow the alarming progression of MetS. They also clearly establish that nutritional experience in early development may affect adult-onset diseases in the same and subsequent generations. We are currently trying to determine which of these periods are important for programming resistance to HFD. With the increasing incidence of obesity, hyperinsulinemia, insulin resistance accompanied by nutritional imbalance, and complications associated with such pregnancies and with drastic hypocaloric diets and bariatric surgery are also likely to become more frequent. Given the limitations on human experimentation, this mouse model, which is based on diet-induced obesity and diabetes, is more suitable for studying the periconceptual/fetal/postnatal origins of adult diseases associated with hyperinsulinemic/obese pregnancy than rodent models associated with monogenic disorders and better reflects the human situation.


   GRANTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by Nestlé Fondation pour la Recherche Médicale and Association Française d'Etudes et de Recherche sur l'Obesité studentships awarded to A. Vigé, a Fournier-Pharma studentship awarded to C. Gallou-Kabani, and grants from Institut National de la Recherche Agronomique, Institut National de la Santé et de la Recherche Médicale (Actions Thématiques Concertées-Nutrition, Programme Recherche Nutrition Humaine), Association Française des Diabétiques, and Institut Benjamin Delessert.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. Junien, Inserm Unit 781, Clinique Maurice Lamy, porte 15, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris, France (e-mail: junien{at}necker.fr)

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
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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