# Astrocytic regulation of energy balance on high-fat diet

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $702,139

## Abstract

Summary
Brain-derived neurotrophic factor (BDNF) binds to full-length tropomyosin receptor kinase (TrkB.FL), inducing its
dimerization and activation. This activates many signaling cascades that cooperatively promote neuronal survival
and regulate neuronal development and synaptic transmission in many brain regions. This signaling pathway is
also critical for the control of energy balance, as mutations in the TrkB.FL kinase domain or BDNF lead to
hyperphagia and severe obesity in mice and humans. In addition to TrkB.FL, the Ntrk2 gene produces two
truncated receptors, a predominant TrkB.T1 and a minor TrkB.T2 (we use TrkB.T to refer both isoforms). TrkB.T
has a short intracellular sequence and lacks the tyrosine kinase domain. Neurons mainly express TrkB.FL,
whereas astrocytes only express TrkB.T. While binding of BDNF to TrkB.T1 induces Ca2+ signals and activates
Rho GTPase in cultured astrocytes, it remains unclear if astrocytic TrkB.T plays a role in the control of energy
balance. We generated astrocyte specific Ntrk2 conditional knockout (aNtrk2 cKO) mice where Ntrk2 deletion
starts at 5 weeks of age and abolishes TrkB.T expression in astrocytes. We found that the Ntrk2 deletion in
mature astrocytes blocked astrocytic reactivity in the arcuate nucleus of the hypothalamus (ARH) and gave mice
total resistance to diet-induced obesity (DIO) by reducing energy intake and increasing energy expenditure. In
addition to nutritional and trophic support to neurons, astrocytes contact synapses through their processes to
regulate synaptic transmission by taking up neurotransmitters from the synaptic cleft and releasing
gliotransmitters into the synaptic cleft. Thus, we hypothesize that TrkB.T-mediated Ca2+ signals promote
astrocytic reactivity in response to high-fat diet (HFD) feeding, which in turn disrupts astrocytic support to neurons
and astrocytic regulation of synapses and shifts energy homeostasis to energy surplus. Our studies will focus
on astrocytes, AgRP/NPY neurons, and POMC neurons in the ARH. We propose to examine the impact of Ntrk2
gene deletion on astrocytes in the ARH (Aim 1), to determine the impact of astrocytic Ntrk2 deletion on neurons
and synaptic transmission (Aim 2), to identify the site where astrocytic TrkB.T ablation blocks diet-induced
obesity (Aim 3), and to determine if attenuating astrocytic Ca2+ signals can prevent obesity in HFD-fed mice (Aim
4). In conclusion, this research project will test several novel concepts, including a crucial role for TrkB.T-
mediated Ca2+ signals in induction of astrocytic reactivity, an active role for TrkB.T in the regulation of energy
balance, and altered astrocytic regulation of synaptic transmission in HFD-fed mice. Our studies will likely show
that attenuating TrkB.T-mediated Ca2+ signals in astrocytes can be a novel and effective strategy for therapeutic
interventions of DIO, the most common form of obesity in humans.

## Key facts

- **NIH application ID:** 10901948
- **Project number:** 5R01DK134650-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** BAOJI XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $702,139
- **Award type:** 5
- **Project period:** 2023-08-09 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901948

## Citation

> US National Institutes of Health, RePORTER application 10901948, Astrocytic regulation of energy balance on high-fat diet (5R01DK134650-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901948. Licensed CC0.

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