# Gating of Leptin Transport into the Cerebrospinal Fluid at the Choroid Plexus

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2021 · $37,980

## Abstract

Project Summary
The central goal of this proposal is to elucidate how leptin transport into the cerebrospinal fluid (CSF)
and brain is gated at the choroid plexus (ChP), how such gating influences the action of leptin on reward-
related dopaminergic neurons, and how saturated ChP transport may contribute to leptin resistance in
obesity. Regulation of energy expenditure and feeding are crucial to an animal’s ability to survive and maintain
physiological homeostasis. Leptin is an endocrine factor secreted by adipocytes that participates in the regulation
of food intake and body weight. Acting on receptors in the brain, leptin exerts an overall effect to decrease
feeding, increase energy expenditure, and promote a lean phenotype. Leptin must enter the brain to reach its
receptors. In obesity, circulating leptin levels are elevated, but the ratio of CSF to serum leptin is reduced, and
leptin suppresses food intake when administered centrally but not peripherally. This suggests insufficient
transport of leptin into the CSF as a potential contributor to the development of obesity. Preliminary work has
implicated transcytosis through the blood-cerebrospinal fluid barrier of the ChP epithelium as a critical pathway
of leptin entry into the brain. In fact, local deletion of endocytic receptor low density lipoprotein receptor-related
protein 1 (LRP1) in the ChP epithelium impairs feeding suppression by peripheral leptin while keeping intact the
decrease in food intake in response to centrally delivered leptin. However, the real time dynamics of this
proposed transcytotic transport at the ChP are poorly understood. I propose to apply novel in vivo imaging
techniques to study leptin transcytosis through the ChP epithelium as well as its access to and effects
on leptin-sensitive dopaminergic circuitry in the ventral tegmental area (VTA) in real time in awake,
behaving mice. In Aim 1, I will refine recently developed tools to visualize leptin transcytosis at the ChP in real
time (see preliminary data) and quantitatively assess the effects of LRP1 deletion or overexpression on leptin
transport from the blood into the CSF. Once it reaches the brain, leptin is known to engage a number of neural
circuits. Dopaminergic neurons in the VTA encode the motivational salience of food and are normally inhibited
by leptin, leading to reduced motivation for food consumption. In obesity, however, dysregulated VTA
dopaminergic activity promotes compulsive eating. In Aim 2, I will extend the imaging toolkit to track the access
of leptin to the VTA parenchyma in parallel with recording the activity of individual VTA dopaminergic neurons,
and rigorously assess the interplay between leptin transcytosis at the ChP and the VTA dopaminergic responses
to palatable food in lean and obese mice. Additionally, I will confirm if LRP1 overexpression in the ChP epithelium
could be protective against the development of obesity. These studies will provide novel insights into the
pathways and ...

## Key facts

- **NIH application ID:** 10381319
- **Project number:** 1F30DK131642-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Peter Nikolaevich Kalugin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,980
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381319

## Citation

> US National Institutes of Health, RePORTER application 10381319, Gating of Leptin Transport into the Cerebrospinal Fluid at the Choroid Plexus (1F30DK131642-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10381319. Licensed CC0.

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