Currently, 65% of adults in the United States are overweight and one in five is obese, representing a modern health crisis. Obesity and its related diseases are the leading cause of death in western society, with associated risks of hypertension, coronary heart disease, stroke, diabetes, and cancer. The 20% incidence of childhood obesity portends a further increase in the prevalence of adult obesity. There is limited understanding of the mechanisms for this epidemic and even less knowledge of effective approaches for obesity prevention. Epidemiologic studies confirm that gestational programming has contributed importantly to the epidemic of obesity, as preterm or intrauterine growth restricted (IUGR) infants have a paradoxical increased risk of adult metabolic syndrome. Studies in our laboratory model human obesity programming, as IUGR offspring of nutrient- restricted rat dams exhibit increased appetite, weight gain and the development of obesity. Our proposed studies will determine the mechanisms of long-term appetite plasticity associated with maternal food/nutrient restriction (MFR)-induced fetal IUGR. We hypothesize that 1) IUGR resulting in suppression of fetal/neonatal plasma leptin levels impairs the development of anorexigenic mechanisms (e.g., neurocircuitry, gene expression, cellular responsiveness), and 2) leptin administration to IUGR newborns will prevent programmed offspring hyperphagia. The proposed studies will determine mechanisms of impaired satiety-induced hyperphagia, focusing on the leptin and serotonin anorexigenic pathways. We will examine central nuclei responses, receptor expression and signaling pathways, by physiologic and pharmacologic modulation. Intrinsic neuronal properties will be examined by extra- and intracellular electrophysiology. We will confirm the primary role of leptin deficiency in programmed hyperphagia, contrast mechanisms of programmed versus diet-induced obese (DIO), and explore novel preventative strategies. We will initially determine the effect of MFR on the newborn leptin surge, and the correlation of leptin levels with development of neuropeptide-Y (NPY) and POMC projections from the arcuate (ARC) to the paraventricular nucleus (PVN). We will examine the mechanisms, including receptor specificity, of reduced anorexigenic responses to leptin and fenfluramine (d-fen). We will further determine ARC and PVN responsiveness (i.e., cFOS) and expression of anorexigenic/orexigenic signaling factors and neuropeptides following fed/fasting and leptin/d-fen. Extra- and intracellular electrophysiology studies will test our hypothesis that MFR offspring will demonstrate increased POMC membrane potential due to reduced excitatory/ increased inhibitory inputs. Finally, a model of leptin antagonism of controls, as well as leptin supplementation to MFR offspring will confirm our proposed mechanism of programmed hyperphagia. These studies will provide important new information elucidating mechanisms for programming of orexigenic-mediated ingestive behavior, and provide a model to determine strategies for the prevention of child and adult obesity.

Public Health Relevance

Currently, 65% of adults in the United States are overweight and one in five is obese, representing a modern health crisis. Obesity and its related diseases are the leading cause of death in western society, with associated risks of hypertension, coronary heart disease, stroke, diabetes, and breast, prostate and colon cancer. As childhood obesity is a major risk factor for adult obesity, the 20% incidence of childhood obesity portends a further increase in the prevalence of adult obesity. Obesity is central to the development of metabolic syndrome as a result of the unique production of adipose tissue hormones and cellular factors. There is limited understanding of the mechanisms for this epidemic and even less knowledge of effective approaches for obesity prevention. Our studies and others have demonstrated that gestational programming has contributed importantly to the epidemic of obesity. Appetite and satiety mechanisms develop during fetal life in utero to assure acquisition of food and water intake during the neonatal period. At birth, all mammalians offspring have developed functional ingestive mechanisms. Importantly, setpoints for appetite regulation are programmed or predetermined during late fetal life and/or the newborn period, such that low birth weight or intrauterine growth restricted (IUGR) offspring demonstrate markedly increased appetite, weight gain and the development of obesity. The proposed studies will determine mechanisms which account for increased appetite in growth restricted offspring. We hypothesize that 1) suppression of the obesity hormone leptin which occurs in IUGR offspring impairs the development of satiety mechanisms leading to offspring obesity, and 2) leptin administration to IUGR newborns will prevent programmed offspring obesity. These studies will provide important new information elucidating mechanisms for programming of orexigenic-mediated ingestive behavior, and provide a model to determine strategies for the prevention of child and adult obesity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD054751-05
Application #
8250374
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Raiten, Daniel J
Project Start
2008-04-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$286,288
Indirect Cost
$84,328
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Desai, Mina; Li, Tie; Han, Guang et al. (2014) Programmed hyperphagia secondary to increased hypothalamic SIRT1. Brain Res 1589:26-36
Desai, Mina; Jellyman, Juanita K; Han, Guang et al. (2014) Maternal obesity and high-fat diet program offspring metabolic syndrome. Am J Obstet Gynecol 211:237.e1-237.e13
Ross, Michael G; Desai, Mina (2013) Developmental programming of offspring obesity, adipogenesis, and appetite. Clin Obstet Gynecol 56:529-36
Guberman, Cristiane; Jellyman, Juanita K; Han, Guang et al. (2013) Maternal high-fat diet programs rat offspring hypertension and activates the adipose renin-angiotensin system. Am J Obstet Gynecol 209:262.e1-8
Desai, Mina; Beall, Marie; Ross, Michael G (2013) Developmental origins of obesity: programmed adipogenesis. Curr Diab Rep 13:27-33
Fukami, Tatsuya; Sun, Xiaoping; Li, Tie et al. (2012) Mechanism of programmed obesity in intrauterine fetal growth restricted offspring: paradoxically enhanced appetite stimulation in fed and fasting states. Reprod Sci 19:423-30
Desai, Mina; Ross, Michael G (2011) Fetal programming of adipose tissue: effects of intrauterine growth restriction and maternal obesity/high-fat diet. Semin Reprod Med 29:237-45
Desai, Mina; Li, Tie; Ross, Michael G (2011) Fetal hypothalamic neuroprogenitor cell culture: preferential differentiation paths induced by leptin and insulin. Endocrinology 152:3192-201
Abdennebi-Najar, Latifa; Desai, Mina; Han, Guang et al. (2011) Basal, endogenous leptin is metabolically active in newborn rat pups. J Matern Fetal Neonatal Med 24:1486-91
Belkacemi, Louiza; Desai, Mina; Nelson, D Michael et al. (2011) Altered mitochondrial apoptotic pathway in placentas from undernourished rat gestations. Am J Physiol Regul Integr Comp Physiol 301:R1599-615

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