Amygdala–liver signalling orchestrates glycaemic responses to stress

J. R. E. Carty, K. Devarakonda, R. M. O’Connor, A. Krek, D. Espinoza, M. Jimenez-Gonzalez, A. Alvarsson, R. F. Hampton, R. Li, Y. Qiu, S. Petri, A. Shtekler, A. Rajbhandari, K. Conner, M. Bayne, D. Garibay, J. Martin, V. Lehmann, L. Wang, K. Beaumont, I. Kurland, G. C. Yuan, P. J. Kenny and S. A. Stanley ()
Additional contact information
J. R. E. Carty: Icahn School of Medicine at Mount Sinai
K. Devarakonda: Icahn School of Medicine at Mount Sinai
R. M. O’Connor: Icahn School of Medicine at Mount Sinai
A. Krek: Icahn School of Medicine at Mount Sinai
D. Espinoza: Icahn School of Medicine at Mount Sinai
M. Jimenez-Gonzalez: Icahn School of Medicine at Mount Sinai
A. Alvarsson: Icahn School of Medicine at Mount Sinai
R. F. Hampton: Icahn School of Medicine at Mount Sinai
R. Li: Icahn School of Medicine at Mount Sinai
Y. Qiu: The Albert Einstein College of Medicine
S. Petri: Icahn School of Medicine at Mount Sinai
A. Shtekler: Icahn School of Medicine at Mount Sinai
A. Rajbhandari: Icahn School of Medicine at Mount Sinai
K. Conner: Icahn School of Medicine at Mount Sinai
M. Bayne: Icahn School of Medicine at Mount Sinai
D. Garibay: Icahn School of Medicine at Mount Sinai
J. Martin: Icahn School of Medicine at Mount Sinai
V. Lehmann: Icahn School of Medicine at Mount Sinai
L. Wang: Icahn School of Medicine at Mount Sinai
K. Beaumont: Icahn School of Medicine at Mount Sinai
I. Kurland: The Albert Einstein College of Medicine
G. C. Yuan: Icahn School of Medicine at Mount Sinai
P. J. Kenny: Icahn School of Medicine at Mount Sinai
S. A. Stanley: Icahn School of Medicine at Mount Sinai

Nature, 2025, vol. 646, issue 8085, 697-706

Abstract: Abstract Behavioural adaptations to environmental threats are crucial for survival1,2 and necessitate rapid deployment of energy reserves3–5. The amygdala coordinates behavioural adaptations to threats6, but little is known about its involvement in underpinning metabolic adaptations. Here we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeAVMH neurons), which precipitates hyperglycaemia and hypophagia. The glycaemic actions of MeAVMH neurons occur independently of adrenal or pancreatic glucoregulatory hormones. Using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver that promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose, resulting in diabetes-like dysregulation of glucose homeostasis. Our findings reveal an amygdala–liver axis that regulates rapid glycaemic adaptations to stress and links recurrent stress to metabolic dysfunction.

Date: 2025
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DOI: 10.1038/s41586-025-09420-1

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