Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity through Augmentation of Mitochondrial Function and Biogenesis

Authors

Ashley Mulcahy Toney, University of Nebraska-LincolnFollow
Rong Fan, University of Nebraska-Lincoln
Yibo Xian, University of Nebraska-Lincoln
Virginia Chaidez, University of Nebraska-LincolnFollow
Amanda E. Ramer-Tait, University of Nebraska-LincolnFollow
Soonkyu Chung, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2019

Citation

Obesity Biology and Integrated Physiology 27 (2019), pp. 612–620.

doi: 10.1002/oby.22404

Comments

Copyright © 2019 The Obesity Society. Used by permission.

Abstract

Objective: Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various cells. However, UroA’s physiological functions related to obesity and insulin resistance remain unclear. Methods: Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high-fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow–derived macrophages. Results: Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow–derived macrophages. Conclusions: UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA’s role in the metabolic benefits of ellagic acid–rich foods and highlights the significance of its microbial transformation in the gut.