mTORC1 inhibition uncouples lipolysis and thermogenesis in white adipose tissue to contribute to alcoholic liver disease.

Autor:	Song Q; Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA., Chen Y; Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA., Ding Q; College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China., Griffiths A; Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA., Liu L; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA., Park J; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA., Liew CW; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA., Nieto N; Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA., Li S; College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China., Dou X; College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China., Jiang Y; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA., Song Z; Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA.
Jazyk:	angličtina
Zdroj:	Hepatology communications [Hepatol Commun] 2023 Feb 09; Vol. 7 (3), pp. e0059. Date of Electronic Publication: 2023 Feb 09 (Print Publication: 2023).
DOI:	10.1097/HC9.0000000000000059
Abstrakt:	Background: Adipose tissue thermogenic activities use fatty acids from lipolysis for heat generation. Therefore, a tight coupling between lipolysis and thermogenesis is physiologically imperative in maintaining not only body temperature but also lipids homeostasis. Adipose tissue dysfunction contributes to alcoholic liver disease (ALD). Here, studies were conducted to examine how alcohol intake affects adipose tissue thermogenic activities and whether altered adipose tissue thermogenesis contributes to ALD. Methods: Both the Lieber-DeCarli and the NIAAA mouse models of ALD were used. Denervation surgery in epididymal fat pads was performed. CL316,243, a selective β3-adrenoceptor agonist, SR59230A, a selective β3 adrenoceptor (ADRB3) antagonist, and rapamycin, a selective mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, were administrated through i.p. injection. Adipocyte-specific Prdm16 knockout mice were subjected to alcohol-containing diet chronically. Results: Chronic alcohol consumption, which enhances adipose tissue lipolysis, inhibits thermogenic activities of beige adipocytes in inguinal white adipose tissue (WAT), leading to an uncoupling status between lipolysis and thermogenesis in WAT at both basal and ADRB3 stimulation states. CL316,243 administration exacerbates liver pathologies of ALD. Alcohol intake inhibits mTORC1 activities in WAT. In mice, mTORC1 inhibition by rapamycin inhibits the thermogenesis of iWAT, whereas enhancing WAT lipolysis. Further investigations using adipocyte-specific Prdm16 knockout mice revealed that functional deficiency of beige adipocytes aggravates liver pathologies of ALD, suggesting that the inhibitory effect of alcohol on WAT browning/thermogenesis contributes to ALD pathogenesis. Conclusion: Chronic alcohol consumption induces an "uncoupling status" between lipolysis and browning/thermogenesis in WAT by inhibiting mTORC1 activation. Diminished WAT browning/thermogenesis, concomitant with enhanced lipolysis, contributes to ALD pathogenesis. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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