Prenatal Stress or High-Fat Diet Increases Susceptibility to Diet-Induced Obesity in Rat Offspring

OBJECTIVE

Perturbations to the prenatal environment have been associated with the development of adult chronic disease, findings that gave rise to the “Barker Hypothesis” or the “developmental origins of adult disease” concept. In this study, we used an animal model to determine the metabolic consequences of maternal prenatal stress and high-fat feeding on the developing offspring.

RESEARCH DESIGN AND METHODS

Pregnant female Sprague-Dawley rats were maintained on standard chow or 60% high-fat diet throughout gestation and lactation. Half of each group were exposed to a novel variable stress paradigm during the 3rd week of gestation, whereas control dams were left undisturbed. Body weight, body composition, glucose tolerance, and endocrine parameters were measured in offspring through early adulthood.

RESULTS

Male and female pups from dams that experienced prenatal stress and/or were on a high-fat diet weighed more beginning on postnatal day 7 compared with standard chow–control pups. Access to high-fat diet at weaning increased the body weight effect through early adulthood and was attributable to greater adiposity. Pups weaned onto standard chow diet showed no significant difference in glucose clearance or insulin secretion. However, pups weaned onto high-fat diet had impaired glucose tolerance if their dams were on a high-fat diet, experienced prenatal stress, or both.

CONCLUSIONS

Our data demonstrate that prenatal stress and/or high-fat diet during the intrauterine or postnatal environment affects offspring in a manner that increases their susceptibility to diet-induced obesity and leads to secondary adverse metabolic consequences.Obesity is a worldwide public health problem and a major contributor to the increased incidence of coronary artery disease, hypertension, and type 2 diabetes (1,2). In addition, and perhaps more disturbing, there is an escalating prevalence of overweight and obesity among infants and children worldwide (3–5). The trend toward greater obesity in the young raises concern because infant or childhood obesity alone significantly increases susceptibility to adult chronic diseases, including cardiovascular disease, hypertension, and diabetes (6). Although it is recognized that genetics plays a role in the development of obesity, genetic factors alone cannot account for the tripling in the prevalence of overweight and obesity over the past 3 decades (7).The intrauterine environment has a significant influence on the health of offspring, and exposure to suboptimal in utero conditions can predispose offspring to adult chronic disease. This concept, originally termed the “Barker Hypothesis,“ derives from human and animal studies demonstrating that, for example, exposure to limited resources in utero produces offspring who show maladaptive responses to the ample postnatal nutritional environment and will develop obesity and diabetes (8). Poor maternal nutrition during the Dutch famine resulted in an increased incidence of obesity in men (9). Although undernutrition and growth restriction caused by famine is not a health issue in modern Western societies, these conditions do occur with hyperemesis gravidarum, high-altitude pregnancy, and pregnancy in women with eating disorders. Based on this, models of low birth weight or IUGR (intrauterine growth restriction) have been studied and are now well characterized (10,11). Animal models of altered nutritional conditions in dams during pregnancy (e.g., caloric restriction, low-protein diet, and gestational diabetes) result in low birth weights and eventually lead to adult conditions such as obesity, hypertension, and diabetes reminiscent of observations reported in human epidemiological studies, particularly when exposed to a high-energy diet after birth (12). The mismatched prenatal versus postnatal nutritional environments result in adverse consequences for the offspring as proposed by the “predictive adaptive hypothesis” (13).Undernutrition and growth restriction are not the only conditions that impact the long-term health of the offspring. Maternal diets have changed such that dietary fat intake among pregnant mothers has increased in the U.S. (14). Alterations in maternal diet have led to a twofold increase in the incidence of maternal overweight and obesity over the last 20 years. Overnutrition or consumption of Western diets that contain a high amount of dietary fat during pregnancy can also result in metabolic syndrome in offspring (15,16).Another aspect of the maternal environment that may have significant effects on the developing fetus is stress arising from socioeconomic or psychosocial factors. Psychosocial and socioeconomic challenges activate the hypothalamic-pituitary-adrenal (HPA) axis, causing hypersecretion of cortisol, and this in turn has been associated with the development of obesity-related conditions including excessive visceral fat deposition, insulin resistance, dyslipidemia, hypertension, and cardiovascular disease in humans (17). Increased glucocorticoid levels and its associated conditions during pregnancy can have significant long-term effects on the developing fetus. Prenatal stress in rodent and primate models has been implicated in altered stress responsivity (18), increased anxiety-like behavior (19), schizophrenia (20,21), cognitive impairments (20), and reduced neurogenesis (22). Although exogenous glucocorticoid administration to pregnant rats during gestation has been linked to later development of hypertension, hyperglycemia, and features of the metabolic syndrome (23,24), there are a limited number of studies that have directly examined the consequences of prenatal stress on energy homeostasis (25–27).The neural pathways that regulate stress responses are also involved in maintaining metabolic homeostasis, and the available literature strongly suggests interactions between the two systems (28). In light of the current dietary and stress environment that many humans live in, it is important to address whether prenatal stress, in addition to a high-fat diet, may exacerbate the effects of the high-fat diet alone. Animal models provide the ability to study the long-term consequences of maternal diet or prenatal stress on offspring while allowing for control over variables that human studies do not afford. We hypothesize that prenatal stress or maternal high-fat diet consumption will predispose offspring to metabolic side effects that will be exacerbated by weaning on to a high-fat diet.     

Zinc chromate induces chromosome instability and DNA double strand breaks in human lung cells

Hexavalent chromium Cr(VI) is a respiratory toxicant and carcinogen, with solubility playing an important role in its carcinogenic potential. Zinc chromate, a water insoluble or ‘particulate’ Cr(VI) compound, has been shown to be carcinogenic in epidemiology studies and to induce tumors in experimental animals, but its genotoxicity is poorly understood. Our study shows that zinc chromate induced concentration-dependent increases in cytotoxicity, chromosome damage and DNA double strand breaks in human lung cells. In response to zinc chromate-induced breaks, MRE11 expression was increased and ATM and ATR were phosphorylated, indicating that the DNA double strand break repair system was initiated in the cells. In addition, our data show that zinc chromate-induced double strand breaks were only observed in the G2/M phase population, with no significant amount of double strand breaks observed in G1 and S phase cells. These data will aid in understanding the mechanisms of zinc chromate toxicity and carcinogenesis.     

Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice

Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE-/- mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.     

Epidermolysis bullosa simplex Dowling-Meara due to an arginine to cysteine substitution in exon 1 of keratin 14

Epidermolysis bullosa simplex (EBS) is a blistering disorder affecting the basal layer of the epidermis usually inherited in an autosomal dominant fashion. Most cases are caused by mutations in the genes encoding keratin 5 (K5) and keratin 14 (K14) and are characterized by cytolysis within the basal layer of the epidermis. We report a patient manifesting the Dowling-Meara variant of EBS in whom we characterized a cytosine to thymine transition at codon 125 (R125C) in K14. This missense mutation is located at the amino terminus of the helical rod domain of the keratin 14 molecule, resulting in defective pairing with K5, thereby disrupting keratin tonofibril integrity.     

Computed tomography angiography to evaluate thoracic outlet neurovascular compression

The objective was to evaluate the efficacy of computed tomography angiography with upper extremity hyperabduction to diagnose thoracic outlet syndrome. Over 5 years, 21 patients were treated surgically for neurogenic symptoms of thoracic outlet syndrome. For patients whose diagnosis was unclear after history and physical examination, adjunctive tests (duplex, magnetic resonance angiography, or computed tomography angiography) were performed to help establish the diagnosis. Five of the 6 computed tomography angiograms were positive. The sixth computed tomography was deemed to be an incomplete study. With mean follow-up of 9.4 months, 95% (n = 19) of patients with a positive hyperabduction test on physical examination were free of symptoms postoperatively. All patients with a positive computed tomography angiogram, with their neurovascular compression localized to the thoracic outlet, had successful operative decompression. Computed tomography angiogram with abduction of the arm can be used as an adjunct to confirm the diagnosis of neurovascular compression and then predict successful operative decompression.