Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA.
College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
Hepatol Commun. 2023 Feb 9;7(3):e0059. doi: 10.1097/HC9.0000000000000059. eCollection 2023 Mar 1.
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.
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.
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.
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.
脂肪组织的产热活动利用脂肪分解产生的脂肪酸来产生热量。因此，脂肪分解和产热之间的紧密偶联对于维持体温和脂质稳态是生理上必需的。脂肪组织功能障碍导致酒精性肝病（ALD）。在这里，研究了酒精摄入如何影响脂肪组织的产热活动，以及脂肪组织产热的改变是否导致 ALD。
使用 Lieber-DeCarli 和 NIAAA 两种 ALD 小鼠模型。进行附睾脂肪垫去神经手术。通过腹腔注射给予选择性β3-肾上腺素能受体激动剂 CL316,243、选择性β3 肾上腺素能受体（ADRB3）拮抗剂 SR59230A 和雷帕霉素，一种选择性的雷帕霉素复合物 1（mTORC1）抑制剂。用酒精喂养慢性处理脂肪细胞特异性 Prdm16 敲除小鼠。
慢性酒精摄入增强脂肪组织脂肪分解，抑制腹股沟白色脂肪组织（WAT）中米色脂肪细胞的产热活性，导致 WAT 在基础和 ADRB3 刺激状态下脂肪分解和产热之间出现解偶联状态。CL316,243 给药加剧 ALD 的肝病理学。酒精摄入抑制 WAT 中的 mTORC1 活性。在小鼠中，雷帕霉素抑制 mTORC1 抑制 iWAT 的产热，而增强 WAT 的脂肪分解。进一步使用脂肪细胞特异性 Prdm16 敲除小鼠的研究表明，米色脂肪细胞功能缺陷加剧了 ALD 的肝病理学，表明酒精对 WAT 褐色/产热的抑制作用有助于 ALD 的发病机制。
慢性酒精摄入通过抑制 mTORC1 激活，在 WAT 中诱导脂肪分解和褐色/产热之间的“解偶联状态”。WAT 褐色/产热减少，同时脂肪分解增强，导致 ALD 的发病机制。
