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

Research output: Contribution to journalArticlepeer-review


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 demands 1–5. 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 PVH Crh 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 PVH Crh neurons.

Original languageEnglish
Pages (from-to)154-162
Number of pages9
Issue number7972
Early online date26 Jul 2023
StatePublished - 3 Aug 2023

All Science Journal Classification (ASJC) codes

  • General


Dive into the research topics of 'Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis'. Together they form a unique fingerprint.

Cite this