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Relief of endoplasmic reticulum (ER) stress in the brain subfornical organ (SFO) selectively prevents high fat diet (HFD)‐induced hepatic dysfunction but not the development of adiposity or hypertension
Author(s) -
Young Colin N.,
Horwath Julie A.,
Butler Scott D.,
Mark Allyn L.,
Davisson Robin L.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.929.4
Subject(s) - endocrinology , medicine , subfornical organ , unfolded protein response , endoplasmic reticulum , obesity , downregulation and upregulation , angiotensin ii , blood pressure , biology , gene , biochemistry
Fatty liver, in concert with obesity and hypertension, are hallmarks of metabolic syndrome. ER stress in the brain has been suggested to contribute, although the precise neural regions involved remain unclear. We tested the hypothesis that ER stress in the SFO mediates HFD‐induced obesity, hypertension, and hepatic dysfunction. C57Bl/6 mice were instrumented with radiotelemeters for measurement of mean arterial pressure (MAP) and underwent SFO‐targeted microinjections of an adenovirus encoding the ER chaperone GRP78 (AdGRP78), an approach we have shown to reduce ER stress. Mice were fed normal chow (NC) or HFD for 10 weeks. Relative to NC, HFD control (AdLacZ, n=7) and SFO‐targeted AdGRP78 (n=7) mice demonstrated similar significant increases in body weight (Δ19±1 vs 18±1 g, AdLacZ vs AdGRP78, p>;0.05), adiposity and MAP (Δ7±2 vs 8±2 mmHg, AdLacZ vs AdGRP78, p>;0.05). However, HFD induced profound hepatomegaly (0.98±0.02 vs 1.88±0.11 g, NC vs AdLacZ, p<0.05), that was prevented with SFO‐targeted AdGRP78 (1.31±0.08 g). SFO‐targeted AdGRP78 also prevented obesity‐induced lipid accumulation in the liver and upregulation of hepatic gluconeogenic markers (e.g. Pepck mRNA 1.6±0.1 vs 0.7±0.2 fold NC, AdLacZ vs AdGRP78, p<0.05). These findings suggest that ER stress in the SFO selectively mediates obesity‐induced hepatic dysfunction, but not the development of adiposity or hypertension. HL63887, HL96571, HL84207