# Modulation of peptidergic neurons by the gluconeogenic enzyme Glucose-6-Phosphatase

> **NIH NIH R21** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2020 · $408,999

## Abstract

Neuropeptides (NPs) play crucial roles in behavior and physiology. NPs are short proteins that are
stored and released from Large Dense Core Vesicles of peptidergic neurons. Peptidergic neurons activate
neural circuits that regulate and modulate a range of physiological processes and impact an array of
behaviors, including feeding, social interactions, circadian behavior and others. Some peptidergic neurons
can express multiple NPs, and most contain also small Synaptic Vesicles that release classic
neurotransmitters. An additional level of complexity is imparted by various degrees of NP processing, which
can occur prior or after their release (i.e. regulated transport, localization, processing etc.). Thus, peptidergic
neurons are multimodal that can convey information within the nervous system. In addition, some NPs act
also as neurohormones and can signal to tissues other than the CNS. Even though the functions of many
NPs have been characterized and their receptors have been identified, little is known about how their activity
is modulated.
 In the fruit fly Drosophila, cell fate of many peptidergic neurons is dependent on the transcriptional
activator Dimmed (DIMM). The recent discovery that many DIMM positive neurons express G6P-GAL4, a
marker for cells expressing the highly conserved enzyme Glucose-6-phosphatase (G6P), implies that G6P
has a non-canonical role in Drosophila. G6P is better known for its role in gluconeogenesis, a process
restricted to the liver and kidney of mammals, for the generation of glucose from non-carbohydrate precursors
to maintain blood glucose homeostasis when animals are food-deprived. Initial characterization of Drosophila
G6P has established that G6P-expressing peptidergic neurons have gluconeogenic capacity and are able to
use alanine as a substrate to generate glucose. Moreover, G6P is necessary for NP accumulation in neural
processes, and preliminary data presented in this application reveal that G6P is required in these neurons to
generate appropriately sized Golgi complexes. Based on these data, G6P (and by inference
gluconeogenesis) are proposed to play a critical role in peptidergic neurons, presumably in the biogenesis of
Golgi and/or LDCV structures, to affect NP release, thereby modulating physiological and behavioral
processes. Importantly, mammals harbor, three G6P genes, only one of which (G6PC1) is involved in hepatic
gluconeogenesis. The other two genes, G6PC2 and G6PC3, are expressed in secretory cells of other tissues,
including the brain and CNS. The function of these non-canonical mammalian G6P genes is not known, but
given their similarities to Drosophila G6P with regard to expression and cellular context, it is intriguing to posit
that the G6PC2 and G6PC3 enzymes have similar roles in mammals as the single G6P enzyme in the fly
CNS.
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## Key facts

- **NIH application ID:** 10040862
- **Project number:** 1R21NS118118-01
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Hubert O Amrein
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,999
- **Award type:** 1
- **Project period:** 2020-09-17 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040862

## Citation

> US National Institutes of Health, RePORTER application 10040862, Modulation of peptidergic neurons by the gluconeogenic enzyme Glucose-6-Phosphatase (1R21NS118118-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10040862. Licensed CC0.

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