Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis

Amelia M. Douglass; Jon M. Resch; Joseph C. Madara; Hakan Kucukdereli; Ofer Yizhar; Abhinav Grama; Masahito Yamagata; Zongfang Yang; Bradford B. Lowell

doi:10.1038/s41586-023-06358-0

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Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis

Journal article

Peer reviewed

Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis

Amelia M. Douglass, Jon M. Resch, Joseph C. Madara, Hakan Kucukdereli, Ofer Yizhar, Abhinav Grama, Masahito Yamagata, Zongfang Yang and Bradford B. Lowell

Nature (London), Vol.620(7972), pp.154-162

08/03/2023

DOI: 10.1038/s41586-023-06358-0

PMCID: PMC11168300

PMID: 37495689

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https://pmc.ncbi.nlm.nih.gov/articles/PMC11168300/pdf/nihms-1995667.pdfView

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Abstract

Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands1,2,3,4,5. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVHCrh neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical ‘hunger neurons’ drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVHCrh neurons.

Details

Title: Subtitle: Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis
Creators: Amelia M. Douglass
Jon M. Resch
Joseph C. Madara
Hakan Kucukdereli
Ofer Yizhar
Abhinav Grama
Masahito Yamagata
Zongfang Yang
Bradford B. Lowell
Resource Type: Journal article
Publication Details: Nature (London), Vol.620(7972), pp.154-162
DOI: 10.1038/s41586-023-06358-0
PMID: 37495689
PMCID: PMC11168300
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Language: English
Date published: 08/03/2023
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984449859902771

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