Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice

Bo Xia; Xiao Chen Shi; Bao Cai Xie; Meng Qing Zhu; Yan Chen; Xin Yi Chu; Guo He Cai; Min Liu; Shi Zhen Yang; Grant A Mitchell; Wei Jun Pang; Jiang Wei Wu

doi:10.1371/journal.pbio.3000688

Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice

PLoS Biol. 2020 Mar 27;18(3):e3000688. doi: 10.1371/journal.pbio.3000688. eCollection 2020 Mar.

Authors

Affiliations

¹ Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
² Division of Medical Genetics, Department of Paediatrics, Université de Montréal and Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada.

Abstract

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, Brown / drug effects
Adipocytes, Brown / metabolism
Adipocytes, White / drug effects
Adipocytes, White / metabolism
Adipose Tissue, Brown / metabolism*
Adipose Tissue, White / metabolism
Animals
Anti-Obesity Agents / therapeutic use*
Coumarins / therapeutic use*
Diet, High-Fat / adverse effects
Energy Metabolism / drug effects
Fatty Liver / prevention & control
Glucose Intolerance / prevention & control
Insulin Resistance
Maillard Reaction
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Obesity / metabolism
Obesity / prevention & control*
Propylthiouracil / toxicity
Thermogenesis
Triiodothyronine / antagonists & inhibitors
Triiodothyronine / metabolism
Weight Gain / drug effects

Substances

Anti-Obesity Agents
Coumarins
Triiodothyronine
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
Propylthiouracil

Grants and funding

National Key R&D Program of China (grant number No. 2018YFD0500402) received by JWW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The special talent recruitment fund of China received by JWW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.