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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 3

Obesity elicits robust UPR activation and ER ultrastructural alterations in the SFO.

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Obesity elicits robust UPR activation and ER ultrastructural alterations...
(A) Schematic highlighting the location of the SFO at the base of the lateral ventricle (LV). (B) Real-time PCR measurements of ER stress biomarkers p58IPK, CHOP, and XBP1s from micropunches of the SFO in normal chow–fed or HFD-fed mice. n = 5. Two brains pooled per sample. (C) Western blot and quantitative summary of the ER chaperones GRP78 and PDI in SFO homogenates from normal chow–fed and HFD-fed mice. n = 4. Two brains pooled per sample. *P < 0.05 vs. normal chow with a two-tailed unpaired t-test. Box-and-whisker plots represent the median (line within box), upper and lower quartile (bounds of box), and maximum and minimum values (bars). (D) Representative electron micrographs of rough ER (arrows) in SFO neurons of a normal chow–fed (left) and HFD-fed mouse (right). The electron micrographs are representative of 20–28 neuronal and dendritic fragments evaluated from 3 mice in each group. Scale bar = 2 μm

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