The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Hypothalamic Leptin Signaling Regulates Hepatic Insulin Sensitivity via a Neurocircuit Involving the Vagus Nerve
Open accessAbstract
Recent evidence suggests that hormones such as insulin and leptin act in the hypothalamus to regulate energy balance and glucose metabolism. Here we show that in leptin receptor-deficient Koletsky (fak/fak) rats, adenovirally induced expression of leptin receptors in the area of the hypothalamic arcuate nucleus improved peripheral insulin sensitivity via enhanced suppression of hepatic glucose production, with no change of insulin-stimulated glucose uptake or disposal. This effect was associated with increased insulin signal transduction via phosphatidylinositol-3-OH kinase (as measured by pY-insulin receptor substrate-1 and pS-PKB/Akt) in liver, but not skeletal muscle, and with reduced hepatic expression of the gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate kinase. Moreover, the beneficial effects of hypothalamic leptin signaling on hepatic insulin sensitivity were blocked by selective hepatic vagotomy. We conclude that hypothalamic leptin action increases peripheral insulin sensitivity primarily via effects on the liver and that the mechanism underlying this effect is dependent on the hepatic branch of the vagus nerve.
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“This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver (66, 146), and offers compelling evidence of a novel mechanism through which the brain normalizes diabetic hyperglycemia without the need for insulin (67).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [66]
In the citing paper
“restoring leptin receptor signaling to the ARC of leptin receptor-deficient Koletsky rats, improved insulin sensitivity was shown to involve enhanced insulin-induced suppression of glucose production, rather than changes of glucose uptake (66).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [66]
In the citing paper
“Thus, leptin action in the ARC increases peripheral insulin sensitivity primarily via effects on the liver, and like insulin, this effect is PI3K-dependent and involves inhibition of hepatic gluconeogenic gene expression.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [66]
In the citing paper
“Moreover, the beneficial effects of restoring hypothalamic leptin signaling to Koletsky rats on hepatic insulin sensitivity were blocked by selective hepatic vagotomy (66).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [66]
In the citing paper
“This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [13]
In the citing paper
“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 [13]
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Metadata
- Authors
- German, J., Kim, F., Schwartz, G. J., Havel, P. J., Rhodes, C. J., Schwartz, M. W., & Morton, G. J.
- Affiliations
- University of Washington (US)
- Albert Einstein College of Medicine (US)
- University of California, Davis (US)
- University of Chicago (US)
- Corresponding author
- Morton, Gregory J.
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-07-02
- Volume
- 150
- Issue
- 10
- Pages
- 4502-4511
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2754686
- OpenAlex
- W2067242542
- Cited by
- 164
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 22 · 2014: 8 · 2013: 17 · 2012: 18
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1u24dk076126-01, 5r01dk073878-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-083042, U24-DK076126, DK068384, DK 035816, DK052989, DK 047208, R01DK052989, DK-020541, R01DK047208, P01DK068384, R01DK055267, R01-DK-073878, DK-073878, P60DK020541, P30DK035816, P30DK017047, P30DK020541, R01DK083042)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin signaling, hypothalamus, hepatic insulin sensitivity, vagus nerve, hepatic vagotomy, arcuate nucleus, leptin receptor, hepatic glucose production, gluconeogenesis, glucose-6-phosphatase, PI3K/Akt signaling, IRS-1, energy balance, glucose metabolism
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Gluconeogenesis, Glucose, Insulin, Insulin Resistance, Liver, Male, Obesity, Vagotomy, Vagus Nerve, Glucose Clamp Technique, Genetic Therapy, Signal Transduction, Gene Expression, Genes, Reporter, Phosphatidylinositol 3-Kinases, Rats, Receptors, Leptin
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