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Diabetologia
Published in: Diabetologia 11/2004

01-11-2004 | Article

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

Authors: X. Yu, S. McCorkle, M. Wang, Y. Lee, J. Li, A. K. Saha, R. H. Unger, N. B. Ruderman

Published in: Diabetologia | Issue 11/2004

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Abstract

Aims/hypothesis

Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator.

Methods

AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat.

Results

AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetes-prone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle.

Conclusions/interpretation

The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.
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Metadata
Title
Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition
Authors
X. Yu
S. McCorkle
M. Wang
Y. Lee
J. Li
A. K. Saha
R. H. Unger
N. B. Ruderman
Publication date
01-11-2004
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1570-9

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