A brain-liver circuit regulates glucose homeostasis
Open accessAbstract
Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.
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Local administration of insulin and inhibition of fat oxidation in the arcuate nucleus increase hepatic insulin sensitivity via a mechanism requiring intact hepatic vagal innervation, and also activate hindbrain neurons within the NTS and DMX.
“Consistent with this hypothesis, both local administration of insulin and inhibition of fat oxidation in the ARC increase hepatic insulin sensitivity via a mechanism that requires intact hepatic vagal innervation, and also activates hindbrain neurons within both the NTS and DMX (147).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [147]
Accumulating evidence suggests that leptin, insulin, and nutrient-related signals in the CNS improve hepatic insulin sensitivity.
“Although accumulating evidence suggests that leptin (10 -13), insulin (14,15), and nutrient-related signals (16 -18) in the CNS improve hepatic insulin sensitivity”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [18]
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- Authors
- Pocai, A., Obici, S., Schwartz, G. J., & Rossetti, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Rossetti, Luciano
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 1
- Issue
- 1
- Pages
- 53-61
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2054716401
- Cited by
- 392
- References
- 43
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 20 · 2023: 9 · 2022: 15 · 2021: 14 · 2020: 19 · 2019: 16 · 2018: 10 · 2017: 22 · 2016: 19 · 2015: 17 · 2014: 15 · 2013: 21 · 2012: 26
- FWCI
- 27.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-48321, DK-47208, R01DK047208, DK20541, DK-45024)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glucose homeostasis, fasting hyperglycemia, liver gluconeogenesis, glucose production, nucleus tractus solitarius, dorsal motor nucleus of the vagus, brainstem neurons, ATP-sensitive potassium channels, fat oxidation, diabetes mellitus
- MeSH terms
- Adenosine Triphosphate, Animals, Brain, Central Nervous System, Glucose, Homeostasis, Hyperglycemia, Kinetics, Liver, Male, Models, Biological, Neurons, Oxygen, Pancreas, Phosphoric Monoester Hydrolases, Potassium, Vagus Nerve, Potassium Channels, Glucose Clamp Technique, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Lipid Metabolism, Rats
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