The growing prevalence of obesity and associated type II diabetes is a major health concern, particularly among children. Maternal obesity represents a developmental risk factor that contributes to metabolic perturbations in the offspring. Recent data from our lab indicate that maternal obesity is associated with abnormally high levels of leptin in the embryo, but whether this pathological hyperleptinemia contributes to the metabolic malprogramming of the developing embryos remains largely unknown. Similarly, the neurobiological mechanisms underlying the detrimental effects of maternal diabetes on glucose homeostasis remain poorly understood. The autonomic nervous system plays a critical role in glucose metabolism through both its sympathetic and parasympathetic branches. We recently found an unanticipated role for prenatal leptin in the development of cholinergic projections to pancreatic islets and that this developmental effect has an impact on adult glucose homeostasis. The overall hypothesis of this proposal is that maternal obesity predisposes the offspring to diabetes by disrupting the development of hindbrain cholinergicpancreas circuits. We also hypothesize that leptin signaling in cholinergic neurons plays an important role in the nutritional malprogramming of glucose homeostasis. Our multidisciplinary approach incorporates a complementary set of genetic, optogenetic, axonal labeling, electrophysiological, and physiological tools to address the following aims:
Specific Aim 1. We will use viral axonal labeling and immunohistochemical experiments to study the development of hindbrain cholinergic innervation of pancreatic b cells in a context of maternal obesity. We will also use optogenetic approaches to test if hindbrain cholinergicpancreas circuits are altered in animals exposed to maternal obesity.
Specific Aim 2. We will systematically examine leptin levels in embryos and pups born to obese dams. We will then perform immunohistochemical labeling (pSTAT3 and pERK), slice electrophysiological recordings (measuring neuronal excitability, currents and synaptic inputs), and in vitro explant cultures to test the hypothesis that maternal obesity disrupts the neurophysiological, intracellular, and neurotrophic response of hindbrain cholinergic neurons to leptin in the offspring. Particular attention will be paid to the response of hindbrain cholinergic neurons innervating the pancreas.
Specific Aim 3. Finally, we will expose dams carrying mice with genetic deletion of leptin receptor specifically in cholinergic neurons to a high fat/high sucrose diet to explore the importance of cholinergic leptin receptor signaling in mediating the detrimental effects of maternal obesity on the development of parasympathetic projections to pancreatic islets and glucose regulation. Completion of these aims will advance our understanding of how maternal obesity programs in the offspring essential components of neural systems required to maintain glucose homeostasis and may identify novel biomarkers and therapeutic targets.

Public Health Relevance

The experiments proposed in this study are designed to study the role of the fat-derived hormone leptin in the wiring of the pancreas in a context of maternal obesity. These studies might provide new insights into the hormonal mechanisms that are involved in the development of neuroendocrine systems that control lifelong glucose regulation and may have important implications for our understanding of the early mechanisms that contribute to diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK084142-06A1
Application #
9523890
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Hyde, James F
Project Start
2010-08-10
Project End
2023-03-31
Budget Start
2018-04-03
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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Maillard, Julien; Park, Soyoung; Croizier, Sophie et al. (2016) Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits. Hum Mol Genet 25:3208-3215
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Kayser, Brandon D; Goran, Michael I; Bouret, Sebastien G (2015) Perinatal overnutrition exacerbates adipose tissue inflammation caused by high-fat feeding in C57BL/6J mice. PLoS One 10:e0121954
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Bellefontaine, Nicole; Chachlaki, Konstantina; Parkash, Jyoti et al. (2014) Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction. J Clin Invest 124:2550-9
Langlet, Fanny; Mullier, Amandine; Bouret, Sebastien G et al. (2013) Tanycyte-like cells form a blood-cerebrospinal fluid barrier in the circumventricular organs of the mouse brain. J Comp Neurol 521:3389-405

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