New evidence from animal models. Giblin KA(1), Blumenfeld H. Author information: (1)Department of Neurology, Yale University School of Medicine, New. Evidence from Animal Models: Is a Restricted or Conventional Intestinal Microbiota Composition Predisposing to Risk for High-LET Radiation. Evidence from animal models on the pathogenesis of PCOS. Walters KA(1), Bertoldo MJ(2), Handelsman DJ(3). Author information: (1)Fertility.
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Serotonin in obsessive-compulsive disorder: Although an obesogenic nutritional environment and increasingly sedentary lifestyle contribute to our risk of developing obesity, a growing body of evidence links early life nutritional adversity to the development of long-term metabolic disorders. In particular, the increasing prevalence of maternal obesity and excess maternal weight gain has been associated with a heightened risk of obesity development in offspring in addition to an increased risk of pregnancy-related complications.
The mechanisms that link maternal obesity to obesity in offspring and the level of gene-environment interactions are not well understood, but the early life environment may represent a critical window for which intervention strategies could be developed to curb the current obesity epidemic. This paper will discuss the various animal models of maternal overnutrition and their importance in our understanding of the mechanisms underlying altered obesity risk in offspring.
The current epidemic of obesity and related metabolic disorders has been seen as a symptom of affluence with the primary cause relating to the development of an obesogenic environment and ease of access to highly calorific foods and reduced energy expenditure in work and leisure activities [ 1 ].
The metabolic syndrome is characterised by the clustering of cardiovascular risk factors including diabetes, obesity, hyperlipidaemia, and hypertension and is likely the result of complex interactions between genes, dietary intake, physical activity, and the environment. Within the cluster of risk traits for the metabolic syndrome, insulin resistance and visceral obesity have been recognized as the most important causal factors [ 2 ].
A number of genes have been identified that are associated with obesity and metabolic syndrome in humans [ 1 , 3 ], but the genetic component of this condition cannot account for the marked increases in the prevalence of obesity and metabolic syndrome in recent years. In this context, the developmental origins of health and disease DOHaD hypothesis has highlighted the link between the periconceptual, fetal, and early infant phases of life and subsequent development of adult obesity and the metabolic syndrome [ 4 — 6 ].
The mechanisms underpinning the developmental programming framework and the role of genetic versus environmental factors remain speculative. One general thesis is that in response to an adverse intrauterine environment the fetus adapts its physiological development to maximize its immediate chances for survival. These adaptations may include resetting metabolic homeostasis set points, endocrine systems, and downregulating of growth, commonly manifest in an altered birth phenotype.
Thus, it is thought that whilst adaptive changes in fetal physiology may be beneficial for short-term survival in utero, they may be maladaptive in later life, contributing to adverse health outcomes when offspring are exposed to catch-up growth, diet-induced obesity, and other factors [ 8 , 9 ]. Animal models have been extensively used to study the basic physiological principles underlying the DOHaD hypothesis and are essential to the search for the mechanistic links between prenatal and postnatal influences and risk for developing the metabolic syndrome in later life.
Epidemiological data suggest that developmental programming occurs within the normal range of birth size [ 10 , 11 ], but most early experimental work has focused on fetal growth restriction in the assumption that insults impairing fetal growth are likely to be those triggering developmental programming. However, over recent years there has been an increasing focus on developing models of maternal obesity. Obesity in pregnancy and gestational diabetes represent a special problem, not only as a result of their immediate adverse effects on maternal health and pregnancy outcome, but also because of growing evidence for their persistent and deleterious effects on the developing offspring [ 12 ].
However, in obese women, it is difficult to discern between genetic and environmental contributions in offspring disease risk.
Several obesogenic animal models, primarily performed in the rodent, show a relatively common phenotype of metabolic disorders in offspring, but the magnitude of effects differs with the timing of the nutritional challenge and diet composition [ 13 ]. A recent systematic review by Ainge et al. This paper will provide a current summary of animal models of maternal obesity including model species, nature and timing of dietary manipulations, phenotypic outcomes in offspring, possible mechanisms, and the potential role of epigenetics.
The rodent is the most commonly used model species for investigation of developmental programming via a maternal obesogenic nutritional environment.
A maternal cafeteria or high-fat HF diet has been shown to induce obesity, insulin and leptin resistance [ 15 — 17 ], hypertension [ 18 — 21 ], fatty pancreas disease [ 22 ], hepatic steatosis, and nonalcoholic fatty liver disease in offspring [ 23 — 26 ] Figure 1.
It has also been reported that maternal adiposity, and not dietary fat per se , induces hyperleptinemia and insulin resistance in offspring, as well as an increased body weight that persists into adulthood [ 27 ]. Even mild maternal overnutrition has been shown to induce increased adiposity, glucose intolerance, and altered brain appetite regulators in offspring [ 28 ]. Our own previous work has shown that a moderate maternal HF diet results in significant obesity and hyperinsulinemia in male and female offspring, independent of the level of preconceptional obesity [ 29 ] Figure 2.
Both approaches have been extensively utilised over recent years and have provided important insights into disease development, particularly in relation to the development of the metabolic syndrome. There has been some recent debate as to which dietary approach is more closely aligned to the human setting. A purified HF diet normally utilises a modification of a single fat source, for example, lard, in order to induce excess weight gain. A cafeteria diet, a mix of foods typified in the human setting such as highly processed snack food, mimics a more western style diet.
However, interpretation of specific macronutrient effects is very difficult due to the widely varied macronutrient sources across the added foods and the dietary interaction across the varied fat, protein, and carbohydrate backgrounds.
Further, there is some evidence that specific components utilised in the cafeteria diet may have deleterious effects such as those related to dairy intake in the rodent [ 34 , 35 ] and oxidative stress [ 36 ]. Recent work by Sampey et al. Both diets resulted in increased adiposity and hepatosteatosis but cafeteria-fed rats displayed increased inflammation in white fat, brown fat, and liver compared to HF and control groups [ 37 ].
Interestingly, the review by Ainge et al. Sheep models are less studied than the rodent, but there is strong evidence from ovine models that maternal obesity predisposes to altered growth and metabolic sequelae in offspring, data that closely parallels that observed in the small animal models.
In a study by Zhang et al. Maternal obesity and increased nutrient intake before and during gestation in the ewe is known to result in altered growth, adiposity, and glucose tolerance in adult offspring [ 39 ]. As with the rodent studies, different levels of overnutrition and weight gain during pregnancy have differential effects on fetal growth and organ development [ 40 ].
Exposure to maternal overnutrition during the periconceptional period alone, however, was shown to result in an increase in total body fat mass only in female lambs with a dominant effect on visceral fat depots. In contrast to the rodent literature, where maternal obesity has been shown to result in an amplified and prolonged neonatal leptin surge [ 41 ], data in the sheep has shown that maternal obesity eliminates the neonatal lamb plasma leptin peak [ 39 ].
These differences may be explained via the relative immaturity of the rat at birth compared to the lamb, with the newborn lamb being born at a more advanced level of maturity equivalent to humans [ 39 ]. The extensive body of evidence in small animal models and those undertaken in the sheep linking a maternal HF diet to disease risk has been supported by studies, albeit limited, in the nonhuman primate. One of the earliest, in the baboon, showed that overfeeding in the preweaning period permanently increased adiposity in offspring through fat cell hypertrophy, a gender-dependent effect in the females only [ 42 ].
Maternal HF diet triggers lipotoxicity in the fetal liver of macaques [ 43 ] and predisposes the offspring to develop nonalcoholic fatty liver disease in adulthood. Data by Farley and colleagues demonstrated that for normal weight offspring of obese baboons, placental, and fetal phenotypes were consistent with those described for large-for-gestational age human fetuses [ 44 ]. Recent work in the macaque by Grayson et al. Third-trimester fetuses from mothers on HF showed increases in proopiomelanocortin mRNA expression, whereas agouti-related protein mRNA and peptide levels were decreased in comparison with control fetuses.
In this study, a subgroup of adult HF animals was switched to a control diet during pregnancy diet reversal. Although at the time of conception the diet reversal animals remained significantly obese and insulin resistant compared to controls, the offspring displayed normal melanocortin levels. These data suggest that chronic consumption of an HF diet during pregnancy, independent of maternal obesity and diabetes, can lead to widespread activation of proinflammatory cytokines that may alter the development of the melanocortin system.
This aligns with the work in the rat by Howie et al. It has also recently been shown that chronic consumption of an HF diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring [ 46 ].
In the Japanese macaque, consumption of an HF diet, independent of maternal obesity, increased placental inflammatory cytokines and the expression of Toll-like receptor 4 [ 47 ]. HF diet consumption also reduced volume blood flow on the fetal side of the placenta and significantly increased the frequency of both placental infarctions and stillbirth. These results suggest that an HF diet, independent of obesity, decreases uterine volume blood flow with maternal obesity and insulin resistance further exacerbating placental dysfunction and resulting in an increased frequency of stillbirth [ 47 ].
This aligns with the rodent data whereby a maternal HF diet has been shown to result in reduced fetal and placental junctional zone weights [ 48 ]. The mechanisms underpinning maternal obesity and programming of obesity risk in offspring are not well defined. Limited data to date highlight the role of altered leptin production and regulation and changes in the hypothalamic regulation of key genes involved in appetite control and energy balance.
There is also evidence of altered skeletal muscle metabolism and maternal HF diet-induced effects on placental structure and function. One of the most studied and consistent observations is hyperphagia and altered energy intake [ 49 ]. Early data suggested a change in food preference with maternal HF offspring displaying a preference for junk food over chow [ 50 ] and more recent studies demonstrate hyperphagia in chow-fed offspring of obese mothers [ 41 , 51 ].
Programmed resistance to the adipokine leptin is as a prime candidate for the mechanism predisposing towards an altered energy balance. The leptin surge has been well characterised in the rodent; it appears to be neonatal in origin and is associated with an upregulation in leptin mRNA expression in adipose tissue over the same time course [ 41 , 52 ]. Maternal obesity has been shown to result in an amplified and prolonged leptin surge in neonatal rat offspring [ 41 ].
In the rat, the leptin surge is seen as a consequence of elevated maternal serum leptin during the early postnatal period leading to elevated milk leptin concentrations and hyperleptinemia in suckling offspring. However, there are some inconsistencies across studies—milk from HF dams has been shown to have significantly higher fat content compared to controls associated with increased insulin but not leptin concentrations [ 53 ].
It must be noted, however, that although the leptin surge in the rodent has been well described, the precise timing and characteristics of the neonatal leptin peak have not been well defined in offspring of either normal or obese mothers in any precocial species. Further studies have described lactational failure and increased neonatal mortality in offspring of HF fed mothers [ 54 ]. It has also recently been reported that obese mothers spend significantly more time nursing their young which could manifest as programming changes in the HPA via altered maternal care as described by Meaney and colleagues [ 55 , 56 ].
Journal of Diabetes Research
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