Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue

Devi Thiagarajan; Nosirudeen Quadri; Shabnam Jawahar; Hylde Zirpoli; Carmen Hurtado del Pozo; Raquel López-Díez; Syed Nurul Hasan; Gautham Yepuri; Paul F. Gugger; Brian S. Finlin; Philip A. Kern; Kenneth Gabbay; Ann Marie Schmidt; Ravichandran Ramasamy

doi:10.1002/oby.23496

Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue

Devi Thiagarajan, Nosirudeen Quadri, Shabnam Jawahar, Hylde Zirpoli, Carmen Hurtado del Pozo, Raquel López-Díez, Syed Nurul Hasan, Gautham Yepuri, Paul F. Gugger, Brian S. Finlin, Philip A. Kern, Kenneth Gabbay, Ann Marie Schmidt, Ravichandran Ramasamy

Research output: Contribution to journal › Article › peer-review

Abstract

Objective: Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. Methods: The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. Results: Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. Conclusions: AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.

Original language	English
Pages (from-to)	1647-1658
Number of pages	12
Journal	Obesity
Volume	30
Issue number	8
DOIs	https://doi.org/10.1002/oby.23496
State	Published - Aug 2022

Bibliographical note

Funding Information:
This work was supported in part by grants from the National Institutes of Health: AG026467, HL143697, HL131481, HL132516, and DK109675 (to Ravichandran Ramasamy and Ann Marie Schmidt). cDNA from human samples was from Philip A. Kern's earlier study (NCT02596776) funded by DK107646.

Publisher Copyright:
© 2022 The Obesity Society.

ASJC Scopus subject areas

Medicine (miscellaneous)
Endocrinology, Diabetes and Metabolism
Endocrinology
Nutrition and Dietetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/oby.23496

Cite this

Thiagarajan, D., Quadri, N., Jawahar, S., Zirpoli, H., del Pozo, C. H., López-Díez, R., Hasan, S. N., Yepuri, G., Gugger, P. F., Finlin, B. S., Kern, P. A., Gabbay, K., Schmidt, A. M., & Ramasamy, R. (2022). Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue. Obesity, 30(8), 1647-1658. https://doi.org/10.1002/oby.23496

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title = "Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue",

abstract = "Objective: Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. Methods: The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. Results: Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. Conclusions: AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.",

author = "Devi Thiagarajan and Nosirudeen Quadri and Shabnam Jawahar and Hylde Zirpoli and {del Pozo}, {Carmen Hurtado} and Raquel L{\'o}pez-D{\'i}ez and Hasan, {Syed Nurul} and Gautham Yepuri and Gugger, {Paul F.} and Finlin, {Brian S.} and Kern, {Philip A.} and Kenneth Gabbay and Schmidt, {Ann Marie} and Ravichandran Ramasamy",

note = "Funding Information: This work was supported in part by grants from the National Institutes of Health: AG026467, HL143697, HL131481, HL132516, and DK109675 (to Ravichandran Ramasamy and Ann Marie Schmidt). cDNA from human samples was from Philip A. Kern's earlier study (NCT02596776) funded by DK107646. Publisher Copyright: {\textcopyright} 2022 The Obesity Society.",

year = "2022",

month = aug,

doi = "10.1002/oby.23496",

language = "English",

volume = "30",

pages = "1647--1658",

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T1 - Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue

AU - Thiagarajan, Devi

AU - Quadri, Nosirudeen

AU - Jawahar, Shabnam

AU - Zirpoli, Hylde

AU - del Pozo, Carmen Hurtado

AU - López-Díez, Raquel

AU - Hasan, Syed Nurul

AU - Yepuri, Gautham

AU - Gugger, Paul F.

AU - Finlin, Brian S.

AU - Kern, Philip A.

AU - Gabbay, Kenneth

AU - Schmidt, Ann Marie

AU - Ramasamy, Ravichandran

N1 - Funding Information: This work was supported in part by grants from the National Institutes of Health: AG026467, HL143697, HL131481, HL132516, and DK109675 (to Ravichandran Ramasamy and Ann Marie Schmidt). cDNA from human samples was from Philip A. Kern's earlier study (NCT02596776) funded by DK107646. Publisher Copyright: © 2022 The Obesity Society.

PY - 2022/8

Y1 - 2022/8

N2 - Objective: Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. Methods: The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. Results: Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. Conclusions: AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.

AB - Objective: Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. Methods: The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. Results: Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. Conclusions: AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.

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ER -

Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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