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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 1

Short-term induction of brain ER stress promotes hepatic steatosis independent of changes in body weight, food intake, or adiposity.

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Short-term induction of brain ER stress promotes hepatic steatosis indep...
Liver mass (A) and hepatic triglyceride levels (B) following 3 days of daily intracerebroventricular (ICV) vehicle or thapsigargin (to induce brain ER stress) administration. n = 6–10. (C) H&E staining of the liver in mice that underwent ICV vehicle or thapsigargin dosing. Representative of n = 4. Scale bar: 100 μm. Body weight (D), food intake (E), and cumulative food intake (F) at baseline and during 3 days of daily ICV vehicle or thapsigargin administration. Regional adipose tissue mass (G) following 3 days of ICV vehicle or thapsigargin. n = 6–10. *P < 0.05 vs. ICV vehicle with two-tailed unpaired t-test or 2-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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