# Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $513,189

## Abstract

Leptin, GABAergic Neurons and Feedback / Feedforward Regulation of Energy Balance
Neurons in the arcuate nucleus (ARC), especially AgRP and POMC neurons, play key roles in regulating
energy balance. They receive feedback information on the current status of fat stores (via leptin) and
“feedforward” information on future, anticipated changes in energy balance. The neural mechanisms
responsible for feedback and feedforward regulation, however, are unknown. Previous studies have
suggested an important role for GABAergic neurons; in the ARC in relaying feedback regulation, and in the
dorsomedial hypothalamus (DMH) in relaying feedforward regulation. With regards to feedback regulation,
progress has been hampered by lack of knowledge regarding “unknown” neurons that reside in the ARC. In
short, we have lacked a “parts list”. Recently, using single neuron transcriptomics, we discovered many novel
GABAergic neurons in the ARC, including some which express LEPRs (Campbell JN et al., Nat Neurosci,
2017). Building on these discoveries, Aims 1 and 2 will address mechanisms of feedback regulation. Aim 3
will extend our discovery that vDMH GABAergic neurons mediate feedforward regulation of AgRP neurons.
 Aim 1: To use single neuron transcriptomics to assess leptin’s effects on gene expression in all
subtypes of ARCLepr and vDMHLepr neurons. By capturing nuclei from all LEPR-expressing neurons in the
ARC and vDMH, and looking at genome-wide transcriptional responses to leptin at the single nuclei level, this
Aim will identify cell type-specific transcriptional effects of leptin in all subtypes of LEPR-expressing neurons.
 Aim 2: To investigate the role of novel ARCGABAergic neurons in regulating energy balance. The
following neurons will be studied: LEPR-expressing, GABAergic ARCTrh/Cxcl12 neurons – which express the
highest level of LEPRs in the ARC, LEPR-expressing, GABAergic ARCTbx19 neurons – which are
transcriptionally similar to the leptin-regulated “RIP-Cre” neurons that control energy expenditure, GABAergic
ARCTrh-Lef1 neurons – which are enriched for transcripts corresponding to human body mass index (BMI)
GWAS-linked loci, GABAergic ARCSST neurons – which are transcriptionally similar to AgRP neurons and
thus likely to share functions, and finally GABAergic ARCHtr3b neurons – which are transcriptionally distinct
but express the interesting, unique ionotropic serotonin receptor, 5-HT3AB.
 Aim 3: To determine the means by which food-cue, “feedforward” regulation reaches the vDMHLepr-
GABAergic à AgRP circuit. We and others unexpectedly found that AgRP neurons, in addition to being
regulated by feedback signals such as leptin, are also regulated rapidly by sensory cues that “anticipate” food
consumption. Importantly, this is mediated, at least in part, by vDMHLepr-GABAergic neurons which synapse onto
AgRP neurons. This Aim seeks the source of this regulation. Our studies suggest a key role for a functionally
distinct subset of glutamatergic neurons in ...

## Key facts

- **NIH application ID:** 10380846
- **Project number:** 5R01DK089044-13
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** BRADFORD B LOWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $513,189
- **Award type:** 5
- **Project period:** 2010-08-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380846

## Citation

> US National Institutes of Health, RePORTER application 10380846, Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance (5R01DK089044-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10380846. Licensed CC0.

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