Elsevier

Metabolism

Volume 56, Issue 10, October 2007, Pages 1431-1438
Metabolism

Diet-induced obesity in gravid rats engenders early hyperadiposity in the offspring

https://doi.org/10.1016/j.metabol.2007.06.007Get rights and content

Abstract

Exposure to a dysmetabolic in utero environment may be one of the mechanisms to explain why individuals with high birth weight are more likely to remain overweight. We explored this hypothesis in an animal model of diet-induced obesity (DIO). We studied adipose tissue development and glucose tolerance in the offspring of rat dams fed a diet rich in milk and sugar from early adulthood until day (d) 2 postpartum. This diet promoted body weight (BW) gain and was previously shown to produce insulin resistance and gestational glucose intolerance. The DIO offspring showed a higher BW in early life (between d7 and d35), with a maximum of 1 SD above the mean BW of controls; however, BW in DIO offspring after d35 was comparable with that of controls. Neonatal DIO offspring also showed larger fat depots, adipocyte hypertrophy (P ≤ .001), and more than 2-fold increased tumor necrosis factor α messenger RNA levels in subcutaneous adipose tissue (P < .05). In addition, they displayed a higher peak glucose response to a glucose challenge (P < .05). In postpubertal (d56) and adult (d98) offspring, we found differences in fat mass and distribution and glucose tolerance relating to the offspring's sex but not the maternal diet. In conclusion, DIO during pregnancy results in hyperadiposity and reduced glucose tolerance only in their neonatal/weanling but not postpubertal offspring. Future research should disclose whether these early-life effects are reactivated in conditions of heightened insulin resistance.

Introduction

The body mass index (BMI) of adolescents and young adults tracks with parental BMI and size at birth [1]. Both genetic and behavioral factors explain the robust correlation between parental and offspring BMI; in addition, the intrauterine environment may play a role. It is now fairly well documented that the risk of obesity is elevated at the low and high end of the birth weight spectrum [2]. At the high end, exposure in utero to a glucose-intolerant or diabetic environment is thought to reset metabolic pathways that facilitate fat accumulation and perturb glucose handling in postnatal life. Indeed, the BMI of children of mothers with gestational glucose intolerance was related to several measures of glycemic control during pregnancy (eg, postprandial glycemia, amniotic fluid insulin) [3], [4].

Studies in animal models may help unravel the contribution of the intrauterine environment to the risk of obesity. Holemans et al [5] studied the metabolic effects of diet-induced obesity (DIO) in gravid rats; the obesogenic diet was a highly palatable semisolid mixture of chow, condensed milk, and sugar [6]. This diet was commenced on day (d) 70 (early adulthood). The DIO rats gained more body weight (BW) and fat mass than did the rats fed the standard chow, and they were insulin resistant as shown by hyperinsulinemic clamps. Gestation had an additively negative effect on insulin sensitivity, leading to glucose intolerance in late gestation: the area under the glucose curve (AUCglucose) was 41% higher in DIO dams than that in controls. Total litter weight (albeit not individual fetal weight) was increased by 25%. Thus, an advantage of the DIO model compared with the frequently used streptozotocin-induced diabetes model is the absence of fetal hypotrophy [7], [8].

In the current study, we used this DIO model to examine the effects of in utero exposure to an obesogenic diet on adipose tissue (AT) development and glucose tolerance at 3 ages (neonatal period, adolescence, and young adulthood). Adipose tissue development was assessed by weighing the various fat depots, measuring the number and size of adipocytes in 2 fat depots, and assaying the messenger RNA (mRNA) levels of peroxisome proliferator–activated receptor (PPAR) γ, a pivotal transcriptional regulator of adipocyte differentiation [9], and several adipokines—leptin, adiponectin, resistin, and tumor necrosis factor (TNF) α—in the fat depots.

Section snippets

Animals, diets, and procedures

The protocol was approved by the ethical committee for animal procedures. Thirty-six female (9 weeks old) and 6 male (12 weeks) Wistar rats were purchased from Charles River (Wilmington, MA) and housed in standard conditions. They had free access to tap water and a standard laboratory rat chow (Trouw, Gent, Belgium) (Table 1). One week after arrival, the female rats were randomly assigned to the control chow (n = 18) or an experimental diet (n = 18), both available ad libitum. The experimental

BW of dams and offspring

The DIO rats weighed significantly more than the controls 1 week after diet randomization (Fig. 1), and the mean BW difference with control dams widened to approximately 32 g before mating. The DIO dams also weighed more than control dams during gestation, but gestational BW gain was comparable (P = .50). The DIO dams were returned to the control chow on d2 postpartum; by d7, there was no longer a significant difference in BW between DIO and control dams.

Litter size was 10.1 ± 0.56 in DIO rats

Discussion

The experimental diet rich in milk and sugar caused prompt and sustained weight gain, confirming our previous findings; this DIO model was also shown to provoke glucose intolerance at the end of gestation [5]. In the present study, we were interested in the short- and long-term metabolic effects of exposure in utero to such environment. Although BW on postnatal d2 was normal in DIO offspring, their BW was increased between d7 and d35, as was their fat mass and adipocyte size. These results

Acknowledgments

SC, SL, and this project were supported by grants from the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Belgium), grant G.0221.03, and the Katholieke Universiteit Leuven (OT/02/48).

The authors thank L Vercruysse for her help with the image analysis program, and C Luyten and E Van Herck for their assistance with the analyses.

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