# Leptin and the Nutritional Programming of Obesity and Diabetes

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2021 · $520,924

## Abstract

SUMMARY
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 cholinergicèpancreas 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 cholinergicèpancreas 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 gluc...

## Key facts

- **NIH application ID:** 10171571
- **Project number:** 5R01DK084142-09
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** PAT LEVITT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,924
- **Award type:** 5
- **Project period:** 2010-08-10 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171571

## Citation

> US National Institutes of Health, RePORTER application 10171571, Leptin and the Nutritional Programming of Obesity and Diabetes (5R01DK084142-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171571. Licensed CC0.

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