Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice
Hong Shen, … , M. Bishr Omary, Liangyou Rui
Hong Shen, … , M. Bishr Omary, Liangyou Rui
Published March 19, 2019
Citation Information: J Clin Invest. 2019;129(6):2305-2317. https://doi.org/10.1172/JCI124376.
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Research Article Hepatology Article has an altmetric score of 35

Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice

Abstract

Chronic alcohol consumption causes liver injury, inflammation, and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT-sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin, which suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation, and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.

Authors

Hong Shen, Lin Jiang, Jiandie D. Lin, M. Bishr Omary, Liangyou Rui

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Figure 6

Brain alcohol-sensing activates BAT.

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Brain alcohol-sensing activates BAT. (A–B) Differentiated (A) and primar...
(A–B) Differentiated (A) and primary (B) brown adipocytes were treated with ethanol for 5–18 hours. Ucp1 mRNA levels were measured by qPCR and normalized to 18S levels (n = 3 per group). (C–G) C57BL/6 male mice were housed at 30°C and centrally administrated with alcohol for 3 weeks. (C) BAT TAG levels (normalized to BAT weight; n = 5 per group). (D) Representative BAT sections. TH areas were normalized to the total areas (n = 3 mice per group). (E) BAT extracts were immunoblotted with the indicated antibodies. (F) BAT gene expression (normalized to 18S levels; n = 4–5 per group). (G) BAT OCR (normalized to BAT weight, n = 5 mice per group). (H, I) C57BL/6 males were centrally injected with alcohol, and brains were harvested 2 hours later. Brain sections were stained with anti–c-Fos antibody, and c-Fos+ cells were quantified in different hypothalamic areas. PBS, n = 3; EtOH, n = 3. Scale bars: 200 μm. Data are presented as mean ± SEM. *P < 0.05, 2-tailed unpaired Student’s t test.