ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure

Timothy D. Heden; Mallory P. Franklin; Christina Dailey; Mara T. Mashek; Chen Chen; Douglas G. Mashek

doi:10.1172/jci.insight.160987

ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure

Timothy D. Heden,¹ Mallory P. Franklin,² Christina Dailey,² Mara T. Mashek,² Chen Chen,² and Douglas G. Mashek²

Published August 10, 2023 - More info

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Abstract

Acyl-CoA thioesterase 1 (ACOT1) catalyzes the hydrolysis of long-chain acyl-CoAs to free fatty acids and coenzyme A and is typically upregulated in obesity. Whether targeting ACOT1 in the setting of high-fat diet induced obesity would be metabolically beneficial is not known. Here we report that male and female ACOT1KO mice are partially protected from high-fat diet induced obesity, an effect associated with increased energy expenditure without alterations in physical activity or food intake. In males, ACOT1 deficiency increased mitochondrial uncoupling protein-2 (UCP2) protein abundance, while reducing 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in white adipose tissue and liver of high-fat fed mice. Moreover, concurrent knockdown of UCP2 with ACOT1 in hepatocytes prevented increases in oxygen consumption observed with ACOT1 knockdown during high lipid loading, suggesting that UCP2-induced uncoupling may increase energy expenditure to attenuate weight gain. Together, these data indicate that targeting ACOT1 may be effective for obesity prevention during caloric excess by increasing energy expenditure.

ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure

Timothy D. Heden,¹ Mallory P. Franklin,² Christina Dailey,² Mara T. Mashek,² Chen Chen,² and Douglas G. Mashek²

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ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure

Timothy D. Heden,1 Mallory P. Franklin,2 Christina Dailey,2 Mara T. Mashek,2 Chen Chen,2 and Douglas G. Mashek2

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Timothy D. Heden,¹ Mallory P. Franklin,² Christina Dailey,² Mara T. Mashek,² Chen Chen,² and Douglas G. Mashek²