Toward an animal model of childhood-onset obesity: follow-up of OLETF rats during pregnancy and lactation

Abstract

A. Toward an animal model of childhood-onset obesity: follow-up of OLETF rats during pregnancy and lactation. Am J Physiol Regul Integr Comp Physiol 296: R224 -R232, 2009. First published November 26, 2008 doi:10.1152/ajpregu.90697.2008.-The Otsuka LongEvans Tokushima Fatty (OLETF) rat model of obesity (a spontaneous CCK1 receptor knockout) has been extensively studied as model of hyperphagia-induced obesity. In previous studies, young OLETF rats presented abnormal eating patterns [compared with Long-Evans Tokushima Otsuka (LETO) controls] in a variety of independent ingestion and nursing tests during the suckling period. The aim of the present study was to characterize the early emergence of abnormal adiposity in the pups. Moreover, because both the dams and the pups present the genetic mutation, a close follow-up of the dams' body weight and intake during pregnancy and lactation was performed to examine the circumstances that contribute to build up the pups' early adiposity. Compared with controls, OLETF pups presented higher fat levels, larger adipocytes, and increased waist circumference as early as postnatal day 7 and this profile persisted to the age of weaning. While LETO dams gained weight throughout pregnancy and lactation, OLETF dams were obese and hyperphagic during pregnancy but lost weight during lactation, probably as a result of rearing hyperphagic pups. Current and previous results suggest a possible influence of the dams' obesity during gestation and a high investment in nursing time during lactation on the pups' obesity levels during childhood. This, combined with the innate hyperphagia repeatedly observed in the pups at these early ages, makes the OLETF strain a useful tool in the research of childhood-onset obesity.overeating; animal models; gestation; feeding OBESITY IS A GROWING PUBLIC health concern that has reached epidemic proportions in Western societies in the last few decades (27). Although much research has already been conducted on obesity by using animal models, investigations have usually focused on adult males, leaving a gap regarding childhood and female obesity. In many cases, early symptoms can be detected during "preobese" stages, where interventions could be more successful in reaching perdurable outcomes. Given the permanent upward resetting of body weight set point that takes place when genetically predisposed individuals become obese, the identification of the early factors that can help understand and prevent obesity might be the key to control the spread of the obesity epidemic (1,5,6,33,36).Maternal obesity during pregnancy and lactation have been found to influence the offspring in the long term, predisposing them to develop larger fat pads and higher leptin and glucose levels later in life, especially in the presence of a genetic tendency (23, 30). Maternal obesity can also predispose offspring to obesity for generations to come (15,47). In a study on mice, females fed a palatable obesogenic diet throughout pregnancy and lactation produced obese offspring presenting...

Development of obesity in the Otsuka Long-Evans Tokushima Fatty rat

“…We have previously demonstrated that OLETF males and females are born heavier and present more white fat soon after birth (46). The developmental follow-up conducted here has exposed an abrupt change during and after the period of sexual maturation (PND 90 in the males and PND 120 in the females), especially in the males, where body weight, fats, and adipocyte area sharply increased.…”

“…We have recently reported that females present a significantly higher level of adipocyte cell increase in the preweaning period, compared with the males (46). Here, the first weeks postweaning appeared to be a continuation of this pattern, with females presenting more fat cells than males until PND 48; from then on, the cell number in the females remained constant.…”

“…Still, sexual maturation precedes the explicit obesity observed from PND 65-120, and while the transitory "normalization" observed on PND 38 appears less dramatic than in the males, it might still be a sensitive point for the females too. It may be the case that interventions during that period of time may help normalize OLETF's otherwise "abnormal" (compared to LETO controls) estrous cycle, which might have some relation to the OLETF females' well-known fertility problems (46,53).…”

“…Briefly, OLETF males and females are heavier from birth (47), hyperphagic in independent ingestion tests as early as PND 2 (12), consume more milk during the nursing episodes (45), initiate more nursing bouts (44), and present increased % body fat, larger adipocytes, and increased waist circumference as early as PND 7 compared with LETO controls (46). Altogether, these developmental findings have led us to conclude that obesity in this strain starts developing very early in life (maybe even during gestation), as a result of life-long abnormalities in eating behavior.…”

Feeding and reward: Ontogenetic changes in an animal model of obesity

“…OLETF rats exhibit hyperphagia and eventually become obese, an effect primarily due to the lack of CCK-1 receptors on their genotypic background. OLETF rats show pre-obese characteristics from infancy and sex-differences in patterns of obesity emergence (Schroeder et al, 2009a; Schroeder et al, 2009b). Research has showed that adult OLETF rats demonstrate high avidity for sucrose (De Jonghe et al, 2005; Hajnal et al, 2005), greater dopamine (DA) response to cocaine and amphetamine in the Nucleus accumbens (Nac) region (Feifel et al, 2003) and low D2R function and binding in the Nac shell area (Hajnal et al, 2008).…”