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Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain
Julie A. Horwath, … , Robin L. Davisson, Colin N. Young
Julie A. Horwath, … , Robin L. Davisson, Colin N. Young
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e90170. https://doi.org/10.1172/jci.insight.90170.
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Research Article Metabolism Neuroscience

Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain

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Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress — which is emerging as a key contributor to a number of chronic diseases including obesity — in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular subfornical organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose–regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.

Authors

Julie A. Horwath, Chansol Hurr, Scott D. Butler, Mallikarjun Guruju, Martin D. Cassell, Allyn L. Mark, Robin L. Davisson, Colin N. Young

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Figure 4

Selective reductions in SFO-ER stress rescue obesity-induced hepatic steatosis, independent of body weight, food intake, or adiposity.

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Selective reductions in SFO-ER stress rescue obesity-induced hepatic ste...
Body weight (A), food intake (B), and cumulative food intake (C) in normal chow–fed and HFD-fed mice following chronic SFO-targeted viral overexpression of the ER chaperone GRP78 (AdGRP78) or control vector (AdLacZ). Regional adipose tissue (D) mass 5 weeks after SFO-targeted AdGRP78 or AdLacZ. Representative liver images in HFD-fed mice (E), as well as liver mass (F) and hepatic triglyceride levels (G) in HFD-fed and normal chow–fed mice following SFO-targeted AdGRP78 or AdLacZ. n = 6–8. H&E staining (H) of the liver in mice 5 weeks after SFO-targeted AdGRP78 or AdLacZ. Representative of n = 4. Scale bar: 100 μm. Radiotelemetric measurements of mean arterial blood pressure (I) and heart rate (J) following adenoviral overexpression of GRP78, or control vector, in the SFO. #P < 0.05 vs. normal chow groups; *P < 0.05 vs. high fat AdLacZ. One-way or two-way repeated measures ANOVA. Box-and-whisker plots represent the median (line within box), upper and lower quartile (bounds of box), and maximum and minimum values (bars).

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