Up-regulation of thioesterase superfamily member 2 in skeletal muscle promotes hepatic steatosis and insulin resistance in mice.

Autor: Imai N; Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Nicholls HT; Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Alves-Bezerra M; Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Li Y; Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Ivanova AA; Department of Biochemistry, Emory University, Atlanta, Georgia, USA., Ortlund EA; Department of Biochemistry, Emory University, Atlanta, Georgia, USA., Cohen DE; Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2022 Jan; Vol. 75 (1), pp. 154-169. Date of Electronic Publication: 2021 Dec 08.
DOI: 10.1002/hep.32122
Abstrakt: Background and Aims: Thioesterase superfamily member 2 (Them2) is highly expressed in liver and oxidative tissues, where it hydrolyzes long-chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2 -/- ) are protected against diet-induced obesity, hepatic steatosis (HS), and insulin resistance (IR), liver-specific Them2 -/- mice remain susceptible. The aim of this study was to test whether Them2 activity in extrahepatic oxidative tissues is a primary determinant of HS and IR.
Approach and Results: Upon observing IR and up-regulation of Them2 in skeletal, but not cardiac, muscle of high-fat-diet (HFD)-fed wild-type compared to Them2 -/- mice, we created mice with Them2 specifically deleted in skeletal (S-Them2 -/- ) and cardiac muscle (C-Them2 -/- ), as well as in adipose tissue (A-Them2 -/- ). When fed an HFD, S-Them2 -/- , but not C-Them2 -/- or A-Them2 -/- , mice exhibited reduced weight gain and improved glucose homeostasis and insulin sensitivity. Reconstitution of Them2 expression in skeletal muscle of global Them2 -/- mice, using adeno-associated virus, was sufficient to restore excess weight gain. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2 -/- mice contributed to protection from HFD-induced HS by increasing VLDL triglyceride secretion rates in response to greater demand. Increases in insulin sensitivity were further attributable to alterations in production of skeletal muscle metabolites, including short-chain fatty acids, branched-chain amino acids, and pentose phosphate pathway intermediates, as well as in expression of myokines that modulate insulin responsiveness.
Conclusions: These results reveal a key role for skeletal muscle Them2 in the pathogenesis of HS and IR and implicate it as a target in the management of NAFLD.
(© 2021 American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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