Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis

Lam, Tony K T; Pocai, Alessandro; Gutierrez-Juarez, Roger; Obici, Silvana; Bryan, Joseph; Aguilar-Bryan, Lydia; Schwartz, Gary J; Rossetti, Luciano

doi:10.1038/nm1201

Cited by 432Regulation of Appetite and ObesityPancreatic function and diabetesDiabetes Treatment and Management

Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis

Lam, Tony K T, Pocai, Alessandro, Gutierrez-Juarez, Roger, Obici, Silvana, Bryan, Joseph, Aguilar-Bryan, Lydia, Schwartz, Gary J, Rossetti, Luciano·2005·Nature Medicine

DOI 10.1038/nm1201

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Abstract

Increased glucose production is a hallmark of type 2 diabetes and alterations in lipid metabolism have a causative role in its pathophysiology. Here we postulate that physiological increments in plasma fatty acids can be sensed within the hypothalamus and that this sensing is required to balance their direct stimulatory action on hepatic gluconeogenesis. In the presence of physiologically-relevant increases in the levels of plasma fatty acids, negating their central action on hepatic glucose fluxes through (i) inhibition of the hypothalamic esterification of fatty acids, (ii) genetic deletion (Sur1-deficient mice) of hypothalamic K(ATP) channels or pharmacological blockade (K(ATP) blocker) of their activation by fatty acids, or (iii) surgical resection of the hepatic branch of the vagus nerve led to a marked increase in liver glucose production. These findings indicate that a physiological elevation in circulating lipids can be sensed within the hypothalamus and that a defect in hypothalamic lipid sensing disrupts glucose homeostasis.

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Authors: Lam, T. K. T., Pocai, A., Gutierrez-Juarez, R., Obici, S., Bryan, J., Aguilar-Bryan, L., Schwartz, G. J., & Rossetti, L.
Affiliations: Albert Einstein College of Medicine (US)
Baylor College of Medicine (US)
Corresponding author: Rossetti, Luciano
ORCID: Lam, Tony K T
Pocai, Alessandro
Bryan, Joseph
Schwartz, Gary J
Rossetti, Luciano
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2005-02-27
Volume: 11
Issue: 3
Pages: 320-327
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm1201
OpenAlex: W2067378751
Cited by: 432
References: 50
Citations by year: 2026: 7 · 2025: 5 · 2024: 11 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 14 · 2019: 20 · 2018: 12 · 2017: 19 · 2016: 20 · 2015: 23 · 2014: 23 · 2013: 31 · 2012: 25
FWCI: 12.10
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: American Diabetes Association
National Institutes of Health (5r01dk057671-03)
National Institute on Aging (P01AG021654, AG 21654, T32AG023475)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-48321, DK 57671, DK52771, DK-47208, R01DK047208, DK20541, R01DK052771, DK-45024)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: circulating fatty acids, glucose homeostasis, hepatic gluconeogenesis, type 2 diabetes, ATP-sensitive potassium channels, SUR1, fatty acid esterification, vagus nerve, hepatic glucose production, lipid metabolism
MeSH terms: Animals, Coenzyme A Ligases, Diabetes Mellitus, Type 2, Dietary Fats, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Glyburide, Glucose, Glucose-6-Phosphatase, Homeostasis, Hypothalamus, Injections, Intraventricular, Liver, Male, Triazenes, Vagotomy, Rats, Sprague-Dawley, Potassium Channels, Inwardly Rectifying, Potassium Channel Blockers, Rats

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Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis

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