Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome

Miguel A. Lanaspa; Takuji Ishimoto; Nanxing Li; Christina Cicerchi; David J. Orlicky; Philip Ruzycki; Christopher Rivard; Shinichiro Inaba; Carlos A. Roncal-Jimenez; Elise S. Bales; Christine P. Diggle; Aruna Asipu; J. Mark Petrash; Tomoki Kosugi; Shoichi Maruyama; Laura G. Sanchez-Lozada; James L. McManaman; David T. Bonthron; Yuri Y. Sautin; Richard J. Johnson

doi:10.1038/ncomms3434

Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome

Miguel A. Lanaspa, Takuji Ishimoto, Nanxing Li, Christina Cicerchi, David J. Orlicky, Philip Ruzycki, Christopher Rivard, Shinichiro Inaba, Carlos A. Roncal-Jimenez, Elise S. Bales, Christine P. Diggle, Aruna Asipu, J. Mark Petrash, Tomoki Kosugi, Shoichi Maruyama, Laura G. Sanchez-Lozada, James L. McManaman, David T. Bonthron, Yuri Y. Sautin, Richard J. Johnson

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Abstract

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductasedeficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

Original language	English
Article number	2434
Pages (from-to)	1-8
Number of pages	8
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3434
State	Published - Sep 10 2013

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Lanaspa, M. A., Ishimoto, T., Li, N., Cicerchi, C., Orlicky, D. J., Ruzycki, P., Rivard, C., Inaba, S., Roncal-Jimenez, C. A., Bales, E. S., Diggle, C. P., Asipu, A., Petrash, J. M., Kosugi, T., Maruyama, S., Sanchez-Lozada, L. G., McManaman, J. L., Bonthron, D. T., Sautin, Y. Y., & Johnson, R. J. (2013). Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome. Nature communications, 4, 1-8. Article 2434. https://doi.org/10.1038/ncomms3434

@article{e2ae8c2d75b848c189daf391f05d0c87,

title = "Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome",

abstract = "Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductasedeficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.",

author = "Lanaspa, {Miguel A.} and Takuji Ishimoto and Nanxing Li and Christina Cicerchi and Orlicky, {David J.} and Philip Ruzycki and Christopher Rivard and Shinichiro Inaba and Roncal-Jimenez, {Carlos A.} and Bales, {Elise S.} and Diggle, {Christine P.} and Aruna Asipu and Petrash, {J. Mark} and Tomoki Kosugi and Shoichi Maruyama and Sanchez-Lozada, {Laura G.} and McManaman, {James L.} and Bonthron, {David T.} and Sautin, {Yuri Y.} and Johnson, {Richard J.}",

note = "Funding Information: We thank Erin Genova and Ashley Bassett from the Department of Pathology at the University of Colorado for their work with the histology. This work was supported by Grants HL-68607 and RC4 DK090859-01 (to R.J.J.), and Grant 1K01DK095930-01 (to M.A.L.) from the National Institutes of Health, Diabetes UK (UK), Grant RD04/0002833 and startup funds from the University of Colorado.",

year = "2013",

month = sep,

day = "10",

doi = "10.1038/ncomms3434",

language = "English",

volume = "4",

pages = "1--8",

journal = "Nature communications",

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Lanaspa, MA, Ishimoto, T, Li, N, Cicerchi, C, Orlicky, DJ, Ruzycki, P, Rivard, C, Inaba, S, Roncal-Jimenez, CA, Bales, ES, Diggle, CP, Asipu, A, Petrash, JM, Kosugi, T, Maruyama, S, Sanchez-Lozada, LG, McManaman, JL, Bonthron, DT, Sautin, YY & Johnson, RJ 2013, 'Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome', Nature communications, vol. 4, 2434, pp. 1-8. https://doi.org/10.1038/ncomms3434

TY - JOUR

T1 - Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome

AU - Lanaspa, Miguel A.

AU - Ishimoto, Takuji

AU - Li, Nanxing

AU - Cicerchi, Christina

AU - Orlicky, David J.

AU - Ruzycki, Philip

AU - Rivard, Christopher

AU - Inaba, Shinichiro

AU - Roncal-Jimenez, Carlos A.

AU - Bales, Elise S.

AU - Diggle, Christine P.

AU - Asipu, Aruna

AU - Petrash, J. Mark

AU - Kosugi, Tomoki

AU - Maruyama, Shoichi

AU - Sanchez-Lozada, Laura G.

AU - McManaman, James L.

AU - Bonthron, David T.

AU - Sautin, Yuri Y.

AU - Johnson, Richard J.

N1 - Funding Information: We thank Erin Genova and Ashley Bassett from the Department of Pathology at the University of Colorado for their work with the histology. This work was supported by Grants HL-68607 and RC4 DK090859-01 (to R.J.J.), and Grant 1K01DK095930-01 (to M.A.L.) from the National Institutes of Health, Diabetes UK (UK), Grant RD04/0002833 and startup funds from the University of Colorado.

PY - 2013/9/10

Y1 - 2013/9/10

N2 - Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductasedeficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

AB - Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductasedeficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

UR - http://www.scopus.com/inward/record.url?scp=84984930218&partnerID=8YFLogxK

U2 - 10.1038/ncomms3434

DO - 10.1038/ncomms3434

M3 - Article

C2 - 24022321

AN - SCOPUS:84984930218

SN - 2041-1723

VL - 4

SP - 1

EP - 8

JO - Nature communications

JF - Nature communications

M1 - 2434

ER -

Endogenous Fructose Production and Metabolism in the Liver Contributes to the Development of Metabolic Syndrome

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