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Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor
Ana Andres-Hernando, … , Richard J. Johnson, Miguel A. Lanaspa
Ana Andres-Hernando, … , Richard J. Johnson, Miguel A. Lanaspa
Published December 15, 2020
Citation Information: JCI Insight. 2021;6(1):e140848. https://doi.org/10.1172/jci.insight.140848.
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Research Article Endocrinology Metabolism

Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor

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Abstract

Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via urinary concentration. However, fat is also a source of metabolic water, raising the possibility that vasopressin might have a role in fat accumulation. Fructose has also been reported to stimulate vasopressin. Here, we tested the hypothesis that fructose-induced metabolic syndrome is mediated by vasopressin. Orally administered fructose, glucose, or high-fructose corn syrup increased vasopressin (copeptin) concentrations and was mediated by fructokinase, an enzyme specific for fructose metabolism. Suppressing vasopressin with hydration both prevented and ameliorated fructose-induced metabolic syndrome. The vasopressin effects were mediated by the vasopressin 1b receptor (V1bR), as V1bR-KO mice were completely protected, whereas V1a-KO mice paradoxically showed worse metabolic syndrome. The mechanism is likely mediated in part by de novo expression of V1bR in the liver that amplifies fructokinase expression in response to fructose. Thus, our studies document a role for vasopressin in water conservation via the accumulation of fat as a source of metabolic water. Clinically, they also suggest that increased water intake may be a beneficial way to both prevent or treat metabolic syndrome.

Authors

Ana Andres-Hernando, Thomas J. Jensen, Masanari Kuwabara, David J. Orlicky, Christina Cicerchi, Nanxing Li, Carlos A. Roncal-Jimenez, Gabriela E. Garcia, Takuji Ishimoto, Paul S. Maclean, Petter Bjornstad, Laura Gabriela Sanchez-Lozada, Mehmet Kanbay, Takahiko Nakagawa, Richard J. Johnson, Miguel A. Lanaspa

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Figure 7

Proposed mechanism for the interplay between fructose and vasopressin in metabolic syndrome.

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Proposed mechanism for the interplay between fructose and vasopressin in...
(Left side, orange lines) Fructose stimulates both the expression of fructokinase (KHK) and the induction of the V1bR in the liver. Fructose metabolism in both liver and hypothalamus stimulates the production and secretion of AVP. The actions of AVP on hepatic V1bR potentiate the metabolic effects of fructose on the expression of KHK and lipogenic enzymes FAS and ACC. As a result, AVP and fructose promote fatty liver, adiposity, and body weight gain during the development and progression of metabolic syndrome. (Right side, blue lines) Hydration and other strategies directed to lower circulating AVP levels would decrease the hepatic expression of both V1bR and KHK in response to fructose. As a consequence, less fructose would be metabolized into fat, thus limiting the progression of metabolic syndrome. V1bR, vasopressin 1b receptor; AVP, vasopressin; KHK, ketohexokinase; FAS, fatty acid synthase; ACC, acetyl-CoA carboxylase.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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