Energy Intake Equalization During Pregnancy of Obese Mothers: Efects on the Maternal Energy Balance and Fetal Development

doi:10.21203/rs.3.rs-2580054/v1

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Energy Intake Equalization During Pregnancy of Obese Mothers: Efects on the Maternal Energy Balance and Fetal Development

https://doi.org/10.21203/rs.3.rs-2580054/v1

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OBJECTIVE: The effects of maternal obesity on fetal development are controversial. Our aim was to evaluate the effects of energy intake equalization during pregnancy on the maternal energy balance and fetal development.

METHODS: Female rats were mated 30 days following the bilateral lesion of ventromedial hypothalamus (VMH) divided into three groups: CONTROL (C) – false lesionated (sham) fed ad libitum; OBESE (OB) - lesionated fed ad libitum; OBESE PAIR-FED (OBP) - lesionated fed on the equalized C ingestion. Cesarean was made on the 20th day of pregnancy. Maternal and pups carcass, feces and food were submitted to calorimetric measurement for energy balance determination. Body composition and plasmatic levels of hormones and lipids were determined. Body weight, food intake and fat content were increased in obese animals following experimental lesion of the VMH.

RESULTS: During pregnancy, obese animals showed higher metabolizable energy intake and energy expenditure compared to the control and pair-fed animals, in which food-equalization reduced net body weight gain, metabolizable energy intake, energy gain, and gross food efficiency, compared to control and obese animals. Maternal obesity did not alter hormone and lipid profiles, body weight, energy content and body composition of the offspring, except for a reduction of lipid content in OBP newborns.

CONCLUSION: The results suggest that at birth the fetuses were preserved of deleterious effects of maternal obesity. Hence, unlike the expected, caloric equalization imposed during the gestational period to previously obese pregnant seems to exert negative effects on the offspring.

maternal obesity

fetal development

energy balance

body composition

pregnancy

The global obesity epidemic has led to an increasing number of obese women in the reproductive phase. Estimates suggest that by 2025 more than 21% of the total number of women in the world will be obese [1].

With the increasing prevalence of obesity in the world, maternal obesity has become one of the most common high-risk obstetric conditions [2] whereas preconceptional obesity and excessive gestational weight gain increasing risks for both mother and child [3]. Among the risks, we can mention: gestational diabetes mellitus (GDM) [4, 5], preeclampsia and other hypertensive diseases [6, 7] spontaneous abortion [8], congenital malformations [9, 10], late fetal death [11], macrosomia and preterm and cesarean delivery [2, 12, 13].

Moreover, the effects resulting from maternal obesity have been observed in early birth [14] and in late adulthood as a metabolic syndrome (i.e. obesity, hypertension, glucose intolerance and dyslipidemia) [15]. Shankar et al. [16] suggested that maternal obesity can be responsible for a fetal programming, resulting in late obesity. We have previously reported that maternal obesity altered the response of adult rats to the effects of hypercaloric diets [17].

Weight gain during pregnancy has usually been neglected in obesity researches due to the relatively short period of gestation compared to total lifetime [18]. In 2009, the Institutes of Medicine (IOM) reviewed the gestational weight gain guidelines, recommending that obese women should have a gestational weight gain between 5 and 9 kg. Several authors have criticized the IOM, and recommended very limited, no weight gain, or even weight loss during pregnancy in order to reduce the risks for mother and infant [19, 20]. However, others studies had found that obese women who lose weight or gain less than 5 kg during pregnancy had neonates who - in addition to an increase in small-for-gestational-age (SGA) - had a significant decrease in lean body mass and fat mass as compared with obese women who gain greater than 5 kg weight during pregnancy [21]. The potential long-term consequences for the offspring of this difference in lean body mass (decreases in both head circumference and length) is unclear but could be associated with further increased metabolic and cognitive risk for the child [22].

Thus, it is essential to better understand the effect of interventions on the diet and lifestyle of pregnant women [23]. All types of intervention aimed at preventing excess weight gain during pregnancy or reducing related complications should be considered, and low energy diet is one of them [24]. Equalizing the level of caloric intake of obese pregnant women based on the intake of non-obese pregnant women can be a preventive strategy.

Thus, the aim of this study was to evaluate the effects of equalization on food intake levels during the gestational period on energy balance of obese mothers and their offsprings.

Animals

The experimental protocol was approved by the Ethical Committee of Universidade Federal de São Paulo (UNIFESP) (n. 0594/07) and it is in accordance with the NIH guidelines for care and use of animals.

During the entire experiment the animals were maintained under a 12-hour light-dark cycle (lights on at 07.00 h) in a room kept at constant temperature (23 ± 1°C).

Female rats Wistar EPM-1, aged 60 days, underwent to stereotactic surgery for obesity induction by electrolytic lesion of ventromedial hypothalamic (VMH) neurons, related to the control of satiety [25]. The animals were anesthetized by halothane inhalation and the electrodes were introduced in ventromedial hypothalamus at the following coordinates: 2.5 mm posterior to Bregma, 0.5 mm lateral to Bregma and 9.5 mm ventral to the dorsal surface. The intensity of stimulation to the injury was 1mA for 30 seconds. The coordinates were obtained in a stereotactic atlas [26] and adapted to the size of female rats.

After the surgery, the animals received food and water ad libitum containing analgesic solution (2 days) and had their food intake and body weight measured for 30 days (evaluation period). On the 30th day after surgery, female rats were mated with adult males and the day of pregnancy was determined by the presence of spermatozoa in the vaginal smear.

During the whole gestational period (20 days) pregnant rats were kept in individual metabolic cages and distributed in three main groups: CONTROL (C) - animals with false hypothalamic lesion (sham) that were fed ad libitum during pregnancy; OBESE (OB) - animals with hypothalamic lesions that were fed ad libitum during pregnancy; OBESE PAIR-FED (OBPF) - animals with hypothalamic lesions that was submitted to an energy intake equalization (they receive the same amount of food ingested by control animals)

Energy balance

At the end of the gestational period (20 days) animals were anesthetized with sodium pentobarbital (60mg/kg, intraperitoneally) and sacrificed by decapitation between 10.00 and 11.00h.

The abdominal cavity was opened and the uterine contents were extracted and separated into male and female pups. The gut was removed, emptied and put back in the carcass. The carcass was then weighed (net weight) and after softening of hard tissues, homogenized in a blender with equal water volume. Male and female pups from each dam were separately homogenized after recording the number and weight. The homogenized material was dried to constant weight in oven at 60°C until a constant weight was reached (dry weight) and the resulting powder was re-homogenized before a sample was burnt in an adiabatic calorimeter (IKA C-5000). The water percentage was obtained by calculating the difference between the net and dry weight of the carcass. Samples of homogenate were collected for determination of fat and protein.

During the whole pregnancy period, feces were collected and dried in the same way as the carcasses and after dry homogenization to powder, the energy content was determined.

Body weight and food intake were recorded daily and samples of pellets were analyzed in the calorimeter in order to obtain the energy content (kJ) per gram of diet. The energy intake was calculated by multiplying the total amount ingested (g) by the energy content of the diet (16.362 kJ/g).

Absorbed energy was calculated as energy intake minus energy in the feces. Metabolizable energy intake was considered as 96% of the absorbed energy [27]. Body energy gain was considered the difference between energy in the carcass and the initial body energy. It was determined from a baseline group of both rat groups (control; n = 21 and obese; n = 11) killed on the first day of the experiment (day of copulation). A regression of body weight vs body energy was calculated. The initial body energy of experimental animals was calculated from their initial body weight using the regression equation calculated earlier. Energy expenditure over 20-day pregnancy period was calculated as metabolizable energy intake minus body energy gain. Gross food efficiency was calculated as body energy gain divided by the metabolizable energy intake and expressed as percentage. To calculate energy expenditure and gross food efficiency, the offspring energy was added to the maternal body energy gain.

Body composition

Carcass fat and protein contents were determined in fresh samples of homogenized carcasses using the chloroform-methanol [28] and Lowry [29] methods, respectively.

Plasma measurements

After decapitation the blood was collected in tubes containing EDTA (6%). The blood samples were centrifuged at 3500rpm for 10 min and the plasma was collected and kept at -4°C. Plasma cholesterol, high density lipoprotein (HDL), triglycerides and glucose concentrations were evaluated by the colorimetric method (kit, Labtest, Brazil). Plasma T3, T4 (ALPCO Diagnostics, USA), insulin (Crystal Chem. Inc, USA) and leptin (Immuno-Biological Laboratories Inc, USA) were determined by ELISA, according to the manufacturer’s instructions.

Statistical analysis

All data are presented as means with their standard error. Statistical analysis was carried out using two-tail Student’s unpaired t test to compare two independent groups or one-way ANOVA followed by post hoc Tukey test. The level of significance to reject the null hypothesis was 5%.

Table 1 shows the values for body weight, food intake and fat content in control and obese animals during the evaluation period (30 days following surgery). All variables increased in obese animals (p < 0.05), following experimental lesion of VMH.

Table 1

Body weight gain (g), total food intake (g) and fat content in the carcasses (mg/g) of control (C) and obese (OB) animals during the evaluation period (30 days following surgery). (Mean values with their standard errors)
	Body weight gain (g)	Total food intake (g)	Fat content (mg/g)
	n Mean SEM	n Mean SEM	n Mean SEM
C	39 33.74 2.22	39 481.51 6.05	21 151.41 7.60
OB	39 69.13* 5.11	30 554.17* 11.33	11 269.10* 24.28
* vs C p < 0.05

Table 2 shows the parameters of energy balance as well as gross food efficiency and absorbed energy determined in the control, obese, and pair-fed obese animals. Obese animals showed higher metabolizable energy intake and energy expenditure in comparison to control and pair-fed animals (p < 0.05). In pair-fed animals, food-equalization reduced net body weight gain, energy gain and gross food efficiency compared to control and obese animals (p < 0.05). As expected, metabolizable energy intake was similar between control and pair-fed animals (p > 0.05).

Table 2

Parameters of energy balance (kJ/20 days), gross-food efficiency and absorbed energy in control (C), obese (OB) and obese pair-fed (OBPF) pregnant animals. (Mean values with their standard errors, n 9–13)
		C		OB		OBPF
		Mean	SEM	Mean	SEM	Mean	SEM
BWG (g)	Total	111.23	5.55	122.44	8.18	103.78	6.54
BWG (g)	Net	66.64	3.53	75.00	5.29	47.72 *°	5.24
MEI (kJ)		6686.78	211.28	7722.38 *	303.87	6408.46 °	91.56
AEN (%)		81.91	0.42	81,68	0.38	81,82	0.55
EG (kJ)		920.76	87.85	684.62	159.68	54.57 *°	57.49
EE (kJ)		5766.05	251.78	7037.77 *	279.80	6353.99	52.15
GFE (%)		14.11	1.60	8.74	1.99	0.76 *°	0.95
BWG = body weight gain; MEI = metabolizable energy intake; AEN = absorbed energy; EG = energy gain; EE = energy expenditure; GFE = gross food efficiency. Net body-weight gain corresponds to the total body weight gain of pregnant rats minus the weight of the conceptuses
* vs C º vs OB p < 0.05

The body composition in pregnant rats (Table 3) was affected by obesity as well as by food-equalization (p < 0.05). In the carcasses, obese animals showed significant increase (p < 0.05) in fat content and decrease (p < 0.05) in protein content and percentage of water, compared to control. Obese pair-fed animals presented lower fat content and higher percentage of water in comparison to control and obese animals (p < 0.05).

Table 3

Body composition in control (C), obese (OB) and obese pair-fed (OBPF) pregnant animals. (Mean values with their standard errors, n 9–13)
	C		OB		OBPF
	Mean	SEM	Mean	SEM	Mean	SEM
Protein (mg/g)	170.02	6.57	130.53 *	7.14	159.97	13.30
Fat (mg/g)	209.63	10.69	259.85 *	20.52	142.34 *°	7.30
Water (%)	60.05	0.01	57.37 *	0.01	62.66 *°	0.01
* vs C º vs OB p < 0.05

The comparison of body composition for control and obese offspring shows no significant differences (p > 0.05), except for an increase in water percentage (p < 0.05). In contrast, fat carcass was significantly reduced in offspring from obese pair-fed pregnant rats (p < 0.05) (Table 4).

Table 4

Body weight, body energy and body composition at birth of offspring from control (C), obese (OB) and obese pair-fed (OBPF) pregnant rats. (Mean values with their standard errors, n 9–13)
	C		OB		OBPF
	Mean	SEM	Mean	SEM	Mean	SEM
Pups per litter	9.62	0.77	10.11	0.82	12.33 *	0.41
Body weight (g)	3.92	0.09	3.94	0.08	4.03	0.20
Body energy (kJ/g)	8.61	0.31	7.78	0.45	8.65	0.25
Protein (mg/g)	110.42	5.18	112.97	2.47	111.17	9.98
Fat (mg/g)	20.00	0.28	20.04	0.36	16.84 *°	1.04
Water (%)	86.89	0.004	87.77 *	0.006	87.65 *°	0.001
* vs C º vs OB p < 0,05

As shown in Table 5, no significant differences were observed in the lipid plasma profile and glucose levels of obese and obese pair-fed pregnant rats, except for decreased HDL levels in obese animals (p < 0.05). Similar results were obtained for offspring, in which the only difference detected was a raise in triglycerides levels of OBPF pups (p < 0.05).

Table 5

Plasma levels of glucose, triglycerides, total cholesterol and HDL cholesterol in control (C), obese (OB) and obese pair-fed (OBPF) pregnant animals and respective offspring. (Mean values with their standard errors, n 7–13)
	C		OB		OBPF
	Mean	SEM	Mean	SEM	Mean	SEM
PREGNANT
Glucose (mg/dL)	111.89 5.37		118.33 4.72		101.98 6.20
Triglycerides (mg/dL)	2.75 0.30		2.95 0.30		2.58 0.29
Cholesterol (mg/dL)	2.44 0.24		2.42 0.16		2.85 0.30
HDL cholesterol (mg/dL)	11.88 1.64		6.73 * 1.22		8.46 1.06
OFFSPRING
Glucose (mg/dL)	87.21 10.92		86.01 9.50		94.03 11.35
Triglycerides (mg/dL)	0.57 0.07		0.63 0.03		0.84 *° 0.05
Cholesterol (mg/dL)	2.15 0.24		1.95 0.12		2.76 0.32
HDL cholesterol (mg/dL)	12.77 3.96		4.32 1.28		8.01 3.36
* vs C º vs OB p < 0,05

Insulinemia of pregnant animals and their offspring were affected neither by maternal obesity nor by maternal food-equalization (p < 0.05) (Table 6).

Table 6

Plasma levels of insulin, leptin and thyroid hormones (T₃ and T₄) in control (C), obese (OB) and obese pair-fed (OBPF) pregnant animals and respective offspring. (Mean values with their standard errors, n 7–13)
	C	OB	OBPF
	Mean SEM	Mean SEM	Mean SEM
PREGNANT
Insulin (ng/ml)	1.77 0.27	1.31 0.20	2.06 0.33
Leptin (ng/ml)	4.49 0.44	5.01 0.48	2.49 *° 0.34
T3 (ng/ml)	2.63 0.19	2.96 0.22	3.43 * 0.17
T4 (ng/ml)	149.97 5.52	152.35 4.82	142.91 3.78
OFFSPRING
Insulin (ng/ml)	7.12 1.39	8.04 0.99	4.86 0.56
Leptin (ng/ml)	6.18 0.78	4.82 0.47	4.51 0.53
T3 (ng/ml)	3.53 0.12	3.63 0.09	3.85 0.21
T4 (ng/ml)	119.20 2.20	124.50 16.02	130.81 3.32
* vs C º vs OB p < 0,05

Plasma leptin levels were reduced by food-restriction imposed to obese pregnant animals (p < 0.05) without effect in offspring (p > 0.05). Thyroid hormones (T3 and T4) of the offspring were not affected by obesity (p > 0.05). However, food-equalization imposed to obese pregnant animals led to increase in maternal T3 levels (p < 0.05) (Table 6).

The model of animal obesity by electrolytic lesion of hypothalamic ventromedial nucleus (VMH) is largely described in the literature [30]. As expected, the present study showed that during evaluation period (30 days following the surgery) animals exhibited higher body weight (≈ 105%), food intake (≈ 15%) and body fat content (≈ 78%) than the control ones and they were considered obese.

During the pregnancy period, the higher values of food intake were reflected in higher values of metabolizable energy intake showed by obese animals, since there are not significant differences in the percentage of absorbed energy, suggesting that the absorptive capacity of these animals was not affected by the obesity. Similar results were found by Soares et al. [31]. On the other hand, Mozes et al. [32, 33] have demonstrated increased alkaline phosphatase activity in the small intestine of rats subjected to early postnatal overfeeding for monosodium glutamate administration.

Hyperphagia is a characteristic of the experimental model of obesity induced by electrolytic lesion of VMH [30]. Although the higher caloric intake, obese animals showed similar body weight and body energy gain than control animals since they presented increased energy expenditure. It is well known that hyperphagia usually leads to increased energy expenditure, as a natural mechanism to maintain the energy balance, described as diet-induced thermogenesis [34, 35]. It is interesting to note that despite pair-fed obese animal (OBPF) showed similar values of energy expenditure to the control animals; they presented lower values of energy gain, probably due to a significant reduction in gross food efficiency. Similar results were obtained before for non-obese pregnant food-restricted rats [36, 37]. The alterations of body composition in the present study were due to obesity and food equalization. As expected, obesity leads to increased fat content before and during the pregnancy period. The reduction in the fat percentage increase for obese animals before and the end of pregnancy period is due to the natural rise in fat depots that occurs in control animals during this period. Goldman et al. [38] have described that VMH lesions led to body weight gain by increase in fat depots, basically by adipocytes hypertrophy. Increasing in fat depots naturally lead to reduced water content, as verified in obese animals and previously reported by Chlouverakis et al. [39].

In corroboration to Shankar et al. [16] we observed reduction in protein content in obese animals. Hansen et al. [40] have suggested that this reduction could be due to some increase in protein catabolism verified in obese animals by VHM lesions.

It is well known that food restriction induced body fat loss as a consequence of higher mobilization of fat sources [41, 42] and increased body water content [43]. According to the expected, obese pair-fed (OBPF) animals increased the water percent in the carcass and reduced the fat content in relation to the obese animals (OB). Surprisingly the fat content of OBPF animals was lower than control ones, which could be the reason for the lower energy gain observed in these animals. These results are in accordance with the impaired leptin and increased T3 levels showed by OBPF animals compared to both obese and control animals.

Usually, obesity leads to increased insulin levels, as demonstrated in different experimental models [44, 45]. However, our results did not show significant differences for plasmatic insulin and glucose levels. Similarly, no difference was observed in lipid profile, except for HDL of OB pregnant rats, which was lower than control animals as expected. Apparently, food equalization did not improve HDL levels for OBPF animals, since the values were similar to the OB group.

Similar results were recently published by Akyol et al. [46]. These authors studied pregnant rats obese by cafeteria diet that during the gestational period were kept under cafeteria diet or received standard diet. They have found no significant differences among groups in relation to plasma glucose, cholesterol and triglycerides. Other studies in rats suggest resistance to the development of hypercholesterolemia, unless they are fed on hyperlipidic diets rich in cholesterol [47, 48]. The literature is controversial regarding the maternal obesity reflexes on the offspring. Some studies point to the fact that obese women are more likely to have the largest placenta and babies [49] while others did not show alteration in the body weight of newborns at birth [16] or intrauterine growth restriction [2].

In the present study the analysis of the newborns did not show differences between the groups C and OB for number, weight and body energy. We believe that this observation occurs because the maternal body is trying to protect the offspring of metabolic changes which it is submitted. It could also be justified by the similarity of protein and lipid content of pups of OB and C groups. Different results were found by Akyol et al. [46] on newborns of rats with obesity induced by cafeteria diet before pregnancy, which ones were smaller than control groups. On the other hand, different authors have reported increased neonatal fat mass associated with maternal obesity [50,51]. Surprisingly, OBP newborns had lower levels of body lipid content than control animals which may be due to the reduction in the maternal fat storages presented in this group.

The determination of hormonal and lipid profiles of newborns showed no differences among the groups studied, what seems naturally reflect the results obtained for their respective mothers, in which also no differences were found for these parameters, except for the OBP pups that showed increased triglyceride levels.

In conclusion, our results indicate that the energy intake equalization imposed to obese pregnant animals not only did not bring benefits, but seems to have exerted negative effects on maternal and pup organisms.

Ethical Approval

Competing interests

The authors declare no conflict of interest.

Authors' contributions

SILVA, NR. performed experimental and surgical trials, helped to draft the manuscript and contributed to analysis and data interpretation.

NEJM, MB. performed experimental and surgical trials

SILVA S.M.A. performed experimental and surgical trials

CRAVO, SLD. was responsible for the standardization and support of surgical procedure

LUZ J. was the main investigator, designed the study and searched for grant funding. Oversaw all aspects of study and assisted with data collection and analyses and prepared the manuscript

Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #07/58488-8). Nejm, MB and Ribeiro-Silva, N were granted for the undergraduate fellowship by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Acknowledgements

We are thankful to Dr. Vânia D’Almeida for her aid with hormonal determinations and Dr. Willian S. Korim for his participation in the standardization of surgical procedure.

Grants: This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #07/58488-8). Nejm, MB and Ribeiro-Silva, N were granted for the undergraduate fellowship by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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No competing interests reported.

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Energy Intake Equalization During Pregnancy of Obese Mothers: Efects on the Maternal Energy Balance and Fetal Development

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Abstract

Introduction

Material And Methods

Animals

Energy balance

Body composition

Plasma measurements

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

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