URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

Dec 5, 2021Molecular metabolism

Blocking URAT1 improves insulin resistance by reducing liver fat buildup and loss of brown fat function in mice fed a high-fat diet

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

Dotinurad, a URAT1-selective inhibitor, significantly improved insulin resistance and reduced hepatic steatosis in mice fed a high-fat diet.

URAT1 is expressed in the liver and brown adipose tissue, in addition to the kidneys.
High-fat diet induced obesity and insulin resistance in mice, characterized by severe hepatic steatosis and elevated serum ALT activity.
Administration of dotinurad reduced HFD-induced hepatic steatosis and inflammation marked by decreased levels of inflammatory cytokine genes.
High-fat diet increased URAT1 expression in brown adipose tissue, leading to lipid accumulation and increased production of reactive oxygen species.
Dotinurad treatment promoted rebrowning of lipid-rich brown adipose tissue, suggesting a role in metabolic regulation.

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OBJECTIVE: Accumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice.

METHODS: Mice fed a high-fat diet (HFD) for 16-18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks.

RESULTS: We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by dotinurad via UCP1 activation.

CONCLUSIONS: In conclusion, a novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

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URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

Abstract

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