The obese and diabetic intrauterine environment: long-term metabolic or cardiovascular consequences in the offspring.

It has long been recognized that the intrauterine environment can have profound effects on the development and health of the fetus. Alterations in maternal nutritional status resulting from caloric or protein restrictions as well as specific micronutrient deficiencies have been shown to impact fetal development. Maternal undernutrition can lead to intrauterine growth retardation and has been shown to increase the risk of metabolic disorders such as diabetes, hypertension, and cardiovascular disease in the offspring.

Emerging evidence suggests that maternal over-nutrition may have similar long-term metabolic consequences in the offspring as those seen with undernutrition. Recent animal studies suggest that the pups of obese dams develop obesity and gain more weight than offspring of normal-weight rats. In rodents, maternal high-fat or cholesterol overfeeding during pregnancy results in offspring with elevated risk factors for cardiovascular disease such as increased blood pressure, abnormal lipid profiles and abnormal glucose homeostasis. Fat-rich diets have also been shown to produce endothelial dysfunction in the offspring. In humans, the reported increases in prepregnancy body mass index and increased weight gain during pregnancy, particularly in obese women, are associated with increases in neonatal weight and body adiposity. Furthermore, several studies have shown that fetuses and children born of hypercholesterolemic mothers have an increased incidence of fatty streaks in the aorta. Recent studies in the Pima Indian Population indicate that intrauterine exposure to diabetes significantly increases systolic blood pressure (SBP) and hemoglobin A1c (HbA1c) during childhood. Evidence also exists that increased birth weight is positively correlated with subsequent risk of cancer. As infant and childhood obesity can predict obesity in the adult, these data suggest that maternal obesity may exacerbate an already alarming incidence of obesity and potentially Type II diabetes in the general population. Understanding the mechanisms by which the obese and diabetic maternal intrauterine environment elicits permanent metabolic and cardiovascular disease in the fetus will provide a basis for future interventional studies in humans.

Maternal insulin resistance as observed in obese women and women with gestational diabetes has been associated with increased fetal fat mass. Leptin, elevated in obesity, has been shown to alter placental gene transcription and cell proliferation and it is possible that other cytokines, also increased in obesity, may play a role as well. The adipose tissue also secretes factors that are implicated in inflammatory processes, blood pressure, coagulation and fibrinolysis that can influence the development of cardiovascular disease. In addition, islet cell or adipocyte development and morphology may be altered. However, the exact mechanisms by which maternal obesity increases the risk of metabolic and cardiovascular disease in the offspring have not been established. Potentially permanent changes may be occurring at the genetic, cellular, or tissue level, either peripherally or at the level of the central nervous system.

Neural pathways regulating food intake, body weight, and the cardiovascular system may be particularly vulnerable to the metabolic status of the obese or diabetic mother. Leptin, through direct central effects, can affect the sympathetic nervous system and lead to hypertension and/or heart disorders. Recent studies demonstrate that leptin exerts a trophic effect on hypothalamic neurons and that the pathways involved in feeding regulation exhibit extensive neuroplasticity in response to metabolic perturbations, even during the postnatal period. However, the role of postnatal nutrition in the development of metabolic, cardiovascular disease, or cancer in the offspring of obese mothers is not clear. Maternal undernutrition in both animal and population-based studies indicate that the detrimental effects are primarily manifested when postnatal nutrition is excessive relative to the intrauterine environment but therapeutic windows with respect to the consequences of maternal obesity have not been identified or defined.

The objective of this RFA is to support mechanistic research investigating the effects of maternal obesity, gestarional diabetes, or diabetes on the development of obesity, and other metabolic and cardiovascular diseases, or cancer in the offspring. This is a new and burgeoning area with important clinical implications. Thus, the applications solicited by this RFA should not only elucidate factors involved in the etiology of obesity in the offspring of obese mothers but in addition, should provide the scientific basis whereby future prevention and intervention studies in humans can be developed. Proposed studies in murine, rat, and large animal models, like sheep and nonhuman primates, should be focused on identifying the potential mechanisms mediating the proposed long-term consequences of maternal obesity or diabetes on the offspring. Outcome variables should not be limited solely to the weight of the offspring but should also include specific measurement of biological endpoints in appropriate tissues such as the brain, adipocyte, heart, and vasculature, placenta, endothelium, mammary gland or pancreatic islet. Pilot studies demonstrating the feasibility of conducting ethical and appropriate studies in humans will also be considered. Studies conducted in nonhuman primates and where possible, in humans, are encouraged.

Potential research topics include, but are not limited to: 1) Defining critical periods of plasticity and/or susceptibility to metabolic perturbations in the maternal environment for neural pathways involved in the regulation of food intake, motivation, body adiposity, and the cardiovascular system in the rodent and nonhuman primates. 2) Development of appropriate animal models to facilitate determination of the relative roles of the genetic, maternal in utero environment, and postnatal environment. 3) Brain imaging studies to study development of neural pathways involved in regulation of food intake and motivational pathways associated with food intake in humans and nonhuman primates. 4) Imaging of the adipocyte, heart and vasculature, placenta, pancreatic b-cell, body adiposity, or body composition of the offspring to determine the effects of maternal obesity and diabetes. 5) Mechanistic investigations of the role of stress at a cellular or systemic level as a mediator of the long-term consequences of maternal obesity and diabetes. 6) Mechanistic investigations on the effect of maternal obesity and diabetes on factors that influence the development of cardiovascular disease in the offspring. Examples include lipid metabolism, inflammation, vascular reactivity, hypertension, endothelial dysfunction, endocrine systems, and hormones. 7) Mechanistic investigations on the effect of maternal obesity and diabetes on factors that influence the development of cancer in the offspring. 8) Investigation of the role of epigenetics as a mechanism mediating the effects of maternal obesity and diabetes on development of metabolic, cancer, or cardiovascular disease in the fetus.

This funding opportunity will use the R01 and R21 award mechanisms. This funding opportunity uses just-in-time concepts. It also uses the modular as well as the nonmodular budget formats (see http:// grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions, available at http://grants.nih. gov/grants/funding/phs398/phs398.html. Otherwise, follow the instructions for nonmodular research grant applications. For further assistance contact GrantsInfo, 301-435-0714 (telecommunications for the hearing impaired: TTY 301-451-0088) or by e-mail: [e-mail].

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for federal grants or cooperative agreements. The D&B number can be obtained by calling 866-705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The deadline for receipt of letters of intent is February 16, 2006, with March 16, 2006 the deadline for receipt of applications. The complete version of this RFA is available at http://grants.nih.gov/grants/ guide/rfa-files/RFA-DK-05-014.html.

Contact: Karen Teff, Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes, Digestive and Kidney Disease Democracy II, Room 734, 6707 Democracy Boulevard, Bethesda, MD 20892 USA, 301-451-7335, fax: [phone], e-mail: kt216q@.nih.gov; Cristina Rabadan-Diehl, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Rockledge II, Room 10186, 6701 Rockiedge Drive, Bethesda, MD 20892 USA, 301-435-0550, fax: [phone], e-mail: [e-mail]; Cindy Davis, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, EPN Room 3159, Bethesda, MD 20892 USA, Rockville, MD 20852 USA (express/courier service), 301-594-9692, fax: [phone], e-mail: [e-mail]. Reference RFA-DK-05-014.