# AgRP neurons: circadian control and interactions with the HPA axis

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $607,303

## Abstract

AgRP neurons: circadian control and interactions with the HPA axis
AgRP neurons play a key role driving feeding. They are activated by feedback signals reporting low energy
stores, and their activation promotes the seeking and eating of food. Remarkably, they are also regulated by
feedforward cues that anticipate future needs and outcomes. The central role of AgRP neurons is further
highlighted by their ability to cause many of the adaptive physiologic responses to fasting. Given the primacy
of AgRP neurons, it is important that we understand how they are regulated, what processes they control, and
how they bring about such control. With this in mind, this grant pursues the following two Aims:
Aim 1: To study SCN / circadian feedforward activation of AgRP neurons and feeding. In this Aim, we
extend the concept of feedforward anticipatory regulation by determining if the SCN engages AgRP neurons to
proactively schedule daily feeding and prevent future energy deficits. While it is known that feeding is under
circadian control, and that this is important because mis-timed feeding causes disease, it is entirely unknown
how the circadian system does this. To investigate SCN control of AgRP neurons, we have developed the
unique ability to continuously monitor AgRP neuron activity in vivo over many days, while simultaneously
monitoring rhythms in feeding, body temperature (Tb), locomotor activity (LMA), and in other neurons. Using
this approach, we have found that: i) AgRP neuron activity oscillates with a 24 hr cycle (peaking later in the
day, falling later in the night) in both light/dark and constant darkness conditions, ii) that peaks and troughs in
AgRP neuron activity are in-phase with SCN neurons, and iii) that with “jet lag” (6 hr advancement of the light
cycle), the AgRP neuron rhythm re-entrains gradually over 8 days in parallel with rhythms in feeding, Tb and
LMA. Based on this and optogenetic stimulation studies, we propose that the SCN, by inhibiting an intervening
GABAergic neuron, activates (disinhibits) AgRP neurons, and that this causes circadian control of feeding.
Aim 2: To investigate reciprocal interactions between AgRP neurons and the HPA axis. In this Aim, we
examine reciprocal interactions between AgRP neurons and the HPA axis. First, we follow up on our discovery
that corticosterone directly activates AgRP neurons by establishing the electrophysiologic, transcriptional and
epigenomic mechanism for this activation. Also, we determine if activation of AgRP neurons by corticosterone
causes the metabolic consequences of Cushing’s syndrome and chronic stress. Second, we extend the role of
AgRP neurons in causing brain-based adaptations to fasting by establishing their role in driving the HPA axis.
We have discovered that AgRP neurons potently activate PVHCrh neurons and the HPA axis, and we propose
that they do this by inhibiting GABAergic “gateway” neurons that connect AgRP neurons to PVH-Crh neurons.
Finally, linking Aims 1 and 2, ...

## Key facts

- **NIH application ID:** 10116601
- **Project number:** 2R01DK096010-09A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** BRADFORD B LOWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $607,303
- **Award type:** 2
- **Project period:** 2012-07-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116601

## Citation

> US National Institutes of Health, RePORTER application 10116601, AgRP neurons: circadian control and interactions with the HPA axis (2R01DK096010-09A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116601. Licensed CC0.

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