Insulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production
Open accessAbstract
Insulin action in the central nervous system regulates energy homeostasis and glucose metabolism. To define the insulin-responsive neurons that mediate these effects, we generated mice with selective inactivation of the insulin receptor (IR) in either pro-opiomelanocortin (POMC)- or agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus. While neither POMC- nor AgRP-restricted IR knockout mice exhibited altered energy homeostasis, insulin failed to normally suppress hepatic glucose production during euglycemic-hyperinsulinemic clamps in AgRP-IR knockout (IR(DeltaAgRP)) mice. These mice also exhibited reduced insulin-stimulated hepatic interleukin-6 expression and increased hepatic expression of glucose-6-phosphatase. These results directly demonstrate that insulin action in POMC and AgRP cells is not required for steady-state regulation of food intake and body weight. However, insulin action specifically in AgRP-expressing neurons does play a critical role in controlling hepatic glucose production and may provide a target for the treatment of insulin resistance in type 2 diabetes.
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Insulin hyperpolarizes and silences both AgRP and POMC neurons and activates PI3K signaling in both.
“insulin hyperpolarizes and silences both AgRP and POMC neurons (96) and activates PI3K signaling in both these neuronal populations (204).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [96]
Insulin action in AgRP-expressing cells is required for the maintenance of normal liver insulin sensitivity.
“implying a role for insulin action in AgRP expressing cells in the maintenance of normal liver insulin sensitivity (96).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [96]
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- Authors
- Könner, A. C., Janoschek, R., Plum, L., Jordan, S. D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G. S., Kahn, C. R., Cowley, M. A., Ashcroft, F. M., & Brüning, J. C.
- Affiliations
- University of Cologne (DE)
- University of Oxford (GB)
- Oregon National Primate Research Center (US)
- Stanford Medicine (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Brüning, Jens C.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 5
- Issue
- 6
- Pages
- 438-449
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2072556905
- Cited by
- 695
- References
- 34
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 38 · 2023: 31 · 2022: 21 · 2021: 58 · 2020: 42 · 2019: 37 · 2018: 44 · 2017: 52 · 2016: 45 · 2015: 38 · 2014: 46 · 2013: 36 · 2012: 33
- FWCI
- 13.34
- 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-6-2202)
- National Center for Research Resources (RR-0163)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- insulin action, insulin receptor, agouti-related protein, proopiomelanocortin, arcuate nucleus, hypothalamic neurons, hepatic glucose production, energy homeostasis, dietary intake, body weight, interleukin-6, glucose-6-phosphatase, insulin resistance, type 2 diabetes, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Animals, Body Weight, Electrophysiology, Female, Glucose, Glucose Tolerance Test, Glucose-6-Phosphatase, Homeostasis, Hyperinsulinism, Hypothalamus, Immunoenzyme Techniques, Insulin, Liver, Male, Mice, Inbred C57BL, Neurons, Pro-Opiomelanocortin, Receptor, Insulin, Blotting, Western, Interleukin-6, Phosphatidylinositol Phosphates, Mice, Knockout, Integrases, Phosphatidylinositol 3-Kinases, Mice, Agouti-Related Protein
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