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 journalArticlepeer-review

5 Scopus citations


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 languageEnglish
Pages (from-to)1647-1658
Number of pages12
Issue number8
StatePublished - Aug 2022

Bibliographical note

Publisher Copyright:
© 2022 The Obesity Society.

ASJC Scopus subject areas

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


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