# Alpha2/delta1- thrombospondin-3 signaling in the central control of metabolic function

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2024 · $32,222

## Abstract

Project Summary (Parent grant)
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play essential roles in the central regulation of
energy and glucose homeostasis. BDNF signaling greatly influences many aspects of neuronal function,
including survival, differentiation and synaptic plasticity and transmission. Deficits in BDNF function have been
linked to over feeding and severe obesity in humans and mice. Accordingly, we showed that mice with BDNF
depletion in the brain (BDNF2L/2LCk-cre) exhibit increased food intake, obesity, insulin resistance and dyslipidemia.
Diminished a2d-1 (Cacna2d1) function in ventromedial hypothalamus (VMH) of BDNF2L/2LCk-cre mice contributes
to the metabolic alterations that they exhibit. In support, viral-mediated rescue of deficient a2d-1 expression in
the VMH of BDNF2L/2LCk-cre mice mitigated their hyperphagia and obesity. Importantly, it dramatically improved
hepatic lipid accumulation and normalized deficits in glycemic control even though rescued mutants remained
significantly heavier than wild type controls. Furthermore, a2d-1 knock down in the adult VMH resulted in
susceptibility to diet-induced obesity (DIO). a2d-1 serves as a receptor for astrocyte-derived thrombospondins
(TSP) to mediate excitatory synapse assembly. Electrophysiological analysis indicates that the metabolic effects
of a2d-1 are related changes in the excitatory tone onto VMH neurons, implicating thrombospondin signaling.
This project will test the hypothesis that TSP/a2d-1 signaling in the VMH facilitates synaptic remodeling during
conditions of positive energy balance to increase the excitatory drive onto neurons mediating energy, glucose
and lipid homeostasis. Aim 1 will determine how gain or loss of a2d-1 function in the adult VMH affects metabolic
function and mechanisms activated by a2d-1 that prevent hepatic steatosis and glucose intolerance during
obesogenic conditions. Aim 2 will examine the effects of gain or loss of astrocytic TSP function in the adult VMH
in the regulation of metabolic function and whether these effects are a2d-1-dependent. Aim 3 will determine
whether a2d-1 and TSP mediates the effects of caloric status on the excitatory synaptic physiology and activity
of VMH neurons. Finally, Aim 4 will map the connectivity of VMH a2d-1+ neurons, examine their responses to
caloric signals in vivo and the effects of stimulating or inhibiting these cells on metabolic function. Findings from
this project will inform novel mechanisms facilitating metabolic health in individuals who are persistently
overweight and new targets for the treatment of metabolic dysfunction. Importantly, they have the potential to
inform pathological mechanisms underlying metabolic disturbances in individuals administered the anti-epileptic
and anti-nociceptive drugs gabapentin and pregabalin, which bind and inhibit a2d-1.

## Key facts

- **NIH application ID:** 11099058
- **Project number:** 3R01DK138586-01S1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Maribel Rios
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $32,222
- **Award type:** 3
- **Project period:** 2024-03-20 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099058

## Citation

> US National Institutes of Health, RePORTER application 11099058, Alpha2/delta1- thrombospondin-3 signaling in the central control of metabolic function (3R01DK138586-01S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/11099058. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*