# Neural mechanisms for VGF regulation of energy balance

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $421,632

## Abstract

Body weight is controlled in large part by communication between the brain and peripheral metabolic tissues,
including white and brown adipose tissue, via the sympathetic nervous system to regulate energy expenditure
and lipolysis. Pharmacotherapeutic intervention to reduce adiposity, however, has been relatively
unsuccessful. We have identified the neurotrophin-inducible neuronal protein VGF (non-acronymic), and one
of its processed C-terminal peptides TLQP-21, as central and peripheral regulators of energy expenditure and
lipolysis. TLQP-21 activates the Complement C3a Receptor 1 (C3aR1), an integral component of the innate
immune system, and in adipocytes, enhances lipolysis mediated by the beta-adrenergic agonist isoproterenol.
Mice with VGF ablated in the adult ventromedial hypothalamus (VMH) and arcuate (ARC) have increased
adiposity and decreased energy expenditure, a phenotype that is consistent with a key physiological role for
TLQP-21 in the adult CNS, one that is also congruent with many actions of brain-derived neurotrophic factor
(BDNF) in the hypothalamus. Utilizing floxed (lox-p flanked) VGF and C3aR1 mouse models together with
established transgenic Cre-driver lines and targeted AAV-Cre administration, we will test the hypothesis that in
adults, VGF and its peptides, particularly TLQP-21, regulate energy expenditure, lipolysis, and glucose
homeostasis via central modulation of sympathetic outflow from the VMH and paraventricular hypothalamus
(PVH), which receives extensive VGF-containing projections from ARC/VMH, and provides essential BDNF-
and VGF-containing sympathetic outflow pathways to brown adipose tissue (BAT). Two specific aims are
proposed. Aim 1 will probe the roles of VGF in the CNS pathways that originate in the PVH and VMH, which
can be activated by `designer receptors exclusively activated by designer drugs' (DREADD), and regulate
energy expenditure, glucose metabolism and lipolysis via sympathetic outflow from hypothalamus. Aim 2 will
define the site(s) of action and function(s) of the pivotal VGF-derived peptide TLQP-21, determining whether its
actions in the adult CNS are dependent on C3aR1 that is expressed on neurons, microglia, and/or astrocytes.
The complementary research expertise of the PIs will be essential for successful completion of our aims,
providing fundamental insight into the mechanisms by which VGF, its peptide TLQP-21, and the TLQP-21
receptor C3aR1, contribute to hypothalamic-sympathetic circuits that control energy and glucose homeostasis,
potentially identifying promising new drug targets for the treatment of obesity and diabetes.

## Key facts

- **NIH application ID:** 10197299
- **Project number:** 3R01DK117504-03S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** CHRISTOPH BUETTNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,632
- **Award type:** 3
- **Project period:** 2018-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197299

## Citation

> US National Institutes of Health, RePORTER application 10197299, Neural mechanisms for VGF regulation of energy balance (3R01DK117504-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197299. Licensed CC0.

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