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

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 5

Opposing effects of vasopressin receptors in fructose-induced metabolic syndrome.

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Opposing effects of vasopressin receptors in fructose-induced metabolic ...
(A) 30-week cumulative total and fructose-derived caloric intake in WT (black), V1aR-KO (ochre), and V1bR-KO (green) mice on 10% fructose. (B) Serum copeptin levels in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution for 30 weeks. (C) Weekly body weight gain in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution for 30 weeks. (D) Representative H&E images from livers of mice (n > 10 images per animal) of the same groups as in A at 30 weeks. Size bars: 50 μM. (E) Liver triglycerides (normalized to protein levels) at 30 weeks in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution. (F) Serum ALT levels at 30 weeks in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution. (G) Serum insulin levels at 30 weeks in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution. (H) Serum leptin levels at 30 weeks in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution. (I) Representative H&E images from epididymal adipose tissue of mice (n > 10 images per animal) of the same groups as in A at 30 weeks. Size bars: 50 μM. (J) Total fat mass (g) at 30 weeks in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution. (K) Fat mass to total body weight percentage at 30 weeks in WT, V1aR-KO, and V1bR-KO mice receiving a 10% fructose solution. The data in A–C, E–H, and J and K are presented as the mean ± SD and analyzed by 1-way ANOVA with Tukey’s post hoc analysis. *P < 0.05, **P < 0.01. n = 6 mice per group. See also Supplemental Table 5. V1aR, vasopressin 1a receptor; V1bR, vasopressin 1b receptor; PT, portal triad; CV, central vein; ALT, alanine aminotransferase.