Hypothalamic AMP-Activated Protein Kinase Regulates Glucose Production
Open accessAbstract
OBJECTIVE: The fuel sensor AMP-activated protein kinase (AMPK) in the hypothalamus regulates energy homeostasis by sensing nutritional and hormonal signals. However, the role of hypothalamic AMPK in glucose production regulation remains to be elucidated. We hypothesize that bidirectional changes in hypothalamic AMPK activity alter glucose production. RESEARCH DESIGN AND METHODS: To introduce bidirectional changes in hypothalamic AMPK activity in vivo, we first knocked down hypothalamic AMPK activity in male Sprague-Dawley rats by either injecting an adenovirus expressing the dominant-negative form of AMPK (Ad-DN AMPKα2 [D157A]) or infusing AMPK inhibitor compound C directly into the mediobasal hypothalamus. Next, we independently activated hypothalamic AMPK by delivering either an adenovirus expressing the constitutive active form of AMPK (Ad-CA AMPKα1312 [T172D]) or the AMPK activator AICAR. The pancreatic (basal insulin)-euglycemic clamp technique in combination with the tracer-dilution methodology was used to assess the impact of alternations in hypothalamic AMPK activity on changes in glucose kinetics in vivo. RESULTS: Injection of Ad-DN AMPK into the hypothalamus knocked down hypothalamic AMPK activity and led to a significant suppression of glucose production with no changes in peripheral glucose uptake during the clamps. In parallel, hypothalamic infusion of AMPK inhibitor compound C lowered glucose production as well. Conversely, molecular and pharmacological activation of hypothalamic AMPK negated the ability of hypothalamic nutrients to lower glucose production. CONCLUSIONS: These data indicate that changes in hypothalamic AMPK activity are sufficient and necessary for hypothalamic nutrient-sensing mechanisms to alter glucose production in vivo.
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Inhibition of hypothalamic AMPK lowers food intake and hepatic glucose production, while increasing hypothalamic AMPK has the opposite effect.
“inhibition of hypothalamic AMPK (using an adenovirus expressing the dominant negative form of AMPK) lowers food intake and HGP, while increasing hypothalamic AMPK has the opposite effect (113, 209)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [209]
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Central AMP-activated protein kinase affects sympathetic nerve activity in rats
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Glucagon and lipid signaling in the hypothalamus
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Self-citationNutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats
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Self-citationReversal of diet-induced obesity by central insulin sensitizer FSTL1
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Manganese availability determines insulin sensitivity by enhancing Akt activityPreprint
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- Authors
- Yang, C. S., Lam, C. K. L., Chari, M., Cheung, G. W. C., Kokorovic, A., Gao, S., Leclerc, I., Rutter, G. A., & Lam, T. K. T.
- Affiliations
- University Health Network (CA)
- Section of Cell Biology, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College, South Kensington, London, U.K.;
- Imperial College London (GB)
- Corresponding author
- Lam, Tony K.T.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-08-03
- Volume
- 59
- Issue
- 10
- Pages
- 2435-2443
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3279556
- OpenAlex
- W2110058008
- Cited by
- 86
- References
- 125
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 6 · 2015: 6 · 2014: 6 · 2013: 11 · 2012: 10
- FWCI
- 4.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Library and Archives Canada (Government of Canada) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust (WT082366MA, 081958/Z/07/Z)
- U.S. Public Health Service (R0I DKO71962-01)
- Canadian Institutes of Health Research (MOP-86554)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- AMPK, hypothalamus, glucose production, glucose kinetics, nutrient sensing, energy homeostasis, compound C, AICAR, insulin, glucose uptake
- MeSH terms
- Aminoimidazole Carboxamide, Animals, Blood Glucose, Body Weight, Enzyme Inhibitors, Glucagon, Glucose, Glycolysis, Homeostasis, Hypoglycemic Agents, Hypothalamus, Insulin, Male, Ribonucleotides, Rats, Sprague-Dawley, Rats, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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