Diet-induced obesity in gravid rats engenders early hyperadiposity in the offspring
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.
References (35)
- et al.
Diet-induced obesity in the rat: a model for gestational diabetes mellitus
Am J Obstet Gynecol
(2004) - et al.
The mechanisms by which heterozygous peroxisome proliferator–activated receptor γ (PPARγ)deficiency and PPARγ agonist improve insulin resistance
J Biol Chem
(2001) Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis
J Biol Chem
(1964)- et al.
Prenatal protein restriction does not affect the proliferation and differentiation of rat preadipocytes
J Nutr
(2004) - et al.
High-fat diet induces increased tissue expression of TNF-α
Life Sci
(2005) - et al.
Comparison of two methods for determining human adipose cell size
J Lipid Res
(1972) - et al.
Altered body composition and metabolism in the male offspring of high fat–fed rats
Metabolism
(2005) - et al.
Pregnancy and lactation in the obese rat: effects on maternal and pup weights
Physiol Behav
(1982) - et al.
High-fat feeding during pregnancy and lactation affects offspring metabolism in rats
Physiol Behav
(1995) - et al.
Dietary fat, genetic predisposition, and obesity: lessons from animal models
Am J Clin Nutr
(1998)