
==== Front
bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

10.1101/2024.05.20.594873
preprint
1
Article
Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability
Hashsham Abdullah http://orcid.org/0000-0002-8584-0142

Kodur Nandan http://orcid.org/0009-0007-9261-7356

Su Jiaao
Tomlinson Abigail J.
Yacawych Warren T.
Flak Jon N. http://orcid.org/0000-0002-3433-4602

Lewis Kenneth T.
Oles Lily R. http://orcid.org/0000-0002-2178-1390

Mori Hiroyuki
Bozadjieva-Kramer Nadejda http://orcid.org/0000-0001-9796-2916

Turcu Adina F.
MacDougald Ormond A. http://orcid.org/0000-0001-6907-7960

Myers Martin G. http://orcid.org/0000-0001-9468-2046

Affinati Alison H. http://orcid.org/0000-0002-4967-9240

21 5 2024
2024.05.20.594873http://biorxiv.org/lookup/doi/10.1101/2024.05.20.594873
nihpp-2024.05.20.594873.pdf
Abstract

The brain augments glucose production during fasting, but the mechanisms are poorly understood. Here, we show that Cckbr -expressing neurons in the ventromedial hypothalamic nucleus (VMN Cckbr cells) prevent low blood glucose during fasting through sympathetic nervous system (SNS)-mediated augmentation of adipose tissue lipolysis and substrate release. Activating VMN Cckbr neurons mobilized gluconeogenic substrates without altering glycogenolysis or gluconeogenic enzyme expression. Silencing these cells (Cckbr TetTox animals) reduced fasting blood glucose, impaired lipolysis, and decreased circulating glycerol (but not other gluconeogenic substrates) despite normal insulin, counterregulatory hormones, liver glycogen, and liver gluconeogenic gene expression. Furthermore, β3-adrenergic adipose tissue stimulation in Cckbr TetTox animals restored lipolysis and blood glucose. Hence, VMN Cckbr neurons impact blood glucose not by controlling islet or liver physiology, but rather by mobilizing gluconeogenic substrates. These findings establish a central role for hypothalamic and SNS signaling during normal glucose homeostasis and highlight the importance of gluconeogenic substrate mobilization during physiologic fasting.
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