# Astrocytic Target Mechanisms in Obesity

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $412,988

## Abstract

Project Summary
 Obesity and its associated complications impose a huge burden to our society. However, the
mechanisms underlying this disorder and its related pathologies remain unclear, and effective treatments are
still lacking. At its core, obesity results from an imbalance between energy intake and energy expenditure.
Most work has focused on neural regulation of energy balance, however, an important but poorly understood
element is the role played by astrocytes in the regulation of energy states although they play crucial functions
in regulating synaptic strength and neural activity. To further our understanding of the processes of obesity and
to seek effective therapeutics, it is necessary to consider astrocytic influence on energy homeostasis and
determine the underlying mechanisms. Our long-term goal is to enable the development of novel targets to
correct diet-induced obesity (DIO). Our overall objective for this application is to determine the ability of
hypothalamic astrocytes to correct DIO and determine the mechanisms of that correction. Our central
hypothesis is that astrocyte can react to and negatively regulate energy surfeit in DIO by reducing the synaptic
strength at orexigenic agouti-related protein (AgRP) neurons in arcuate nucleus (ARC) in mice, which will be
achieved by elevating extracellular adenosine. Our hypothesis has been formulated on the basis of our recent
study and our preliminary data that astrocyte activation reduces feeding and silences AgRP neurons via
adenosine A1 signaling, induces energy expenditure, and elevates extracellular adenosine. The rational for
the proposed research is that, once it is known how astrocytes regulate energy states, it may be feasible to
manipulate them pharmacologically to correct or reverse obesity, and potentially a variety of eating disorders.
 To accomplish our goals, we have assembled a research team that combines a diverse range of
expertise including glial biology, neurobiology, and energy metabolism. To test our central hypothesis and
thereby accomplish our overall objective, we will carry out three Specific Aims: (1) Determine how astrocytes
control synaptic strength at AgRP neurons; (2) Determine how astrocytes contribute to synaptic alterations
during (HFD) feeding; (3) Identify astrocytic target in the treatment of HFD-induced obesity (DIO). Experiments
proposed here will be examined using a multifaceted approach that includes cell type-specific electrophysiology,
chemogenetic- and optogenetic astrocytic manipulation, time-lapse deep-brain measurements of adenosine,
temporal control of pharmacology, and metabolic assays. Adenosine augmentation therapy in obesity will also
be performed with an integrated chemical and genetic approach to target adenosine kinase inhibitor to arcuate
astrocytes. Results using these cutting-edge methods will give us unprecedented access to understanding glial
control of energy states. Together, the proposed research represents a new and subst...

## Key facts

- **NIH application ID:** 9999552
- **Project number:** 5R01DK112759-05
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Yunlei Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,988
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999552

## Citation

> US National Institutes of Health, RePORTER application 9999552, Astrocytic Target Mechanisms in Obesity (5R01DK112759-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999552. Licensed CC0.

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