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

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

doi:10.1172/jci.insight.90170

Cited by 22 publications

(35 citation statements)

References 55 publications

(116 reference statements)

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“…The HFD murine model (at least with 10 weeks of feeding) represents a scenario of steatosis without significant liver injury. In line with this, our recent findings using 3 day pharmacological manipulations of the CNS also demonstrated a rapid resolution of hepatic steatosis in HFD fed mice (Horwath et al 2017). Although comparisons in time course between rodents and humans is difficult, clinical literature also suggests that hepatic steatosis can be rapidly resolved within 1 month in humans (Choudhary et al 2015).…”

Section: Discussionsupporting

confidence: 69%

Liver sympathetic denervation reverses obesity‐induced hepatic steatosis

Hurr

Simonyan

Morgan

et al. 2019

The Journal of Physiology

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Non-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. r In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. r Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. r Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity.

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Section: Discussionsupporting

confidence: 69%

Liver sympathetic denervation reverses obesity‐induced hepatic steatosis

Hurr

Simonyan

Morgan

et al. 2019

The Journal of Physiology

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“…It is worth noting that ER stress in the CNS may be primarily responsible for defective liver metabolism irrespective of energy imbalance. Horwath and colleagues [ 98 ] have identified the subfornical organ (SFO), a brain area located at the base of the lateral ventricle, with significantly higher ER stress markers such as p58, CHOP, and XBP1 in mice fed a HFD for 15 weeks which was associated with hepatic steatosis. Interestingly, overexpression of GRP78 (ER chaperone) specifically in the SFO was able to rescue ER stress and hepatic steatosis independent of energy balance.…”

Section: Endoplasmic Reticulum (Er) Stress In the Cnsmentioning

confidence: 99%

Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

et al. 2020

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Obesity prevalence is increasing at an unprecedented rate throughout the world, and is a strong risk factor for metabolic, cardiovascular, and neurological/neurodegenerative disorders. While low-grade systemic inflammation triggered primarily by adipose tissue dysfunction is closely linked to obesity, inflammation is also observed in the brain or the central nervous system (CNS). Considering that the hypothalamus, a classical homeostatic center, and other higher cortical areas (e.g. prefrontal cortex, dorsal striatum, hippocampus, etc.) also actively participate in regulating energy homeostasis by engaging in inhibitory control, reward calculation, and memory retrieval, understanding the role of CNS oxidative stress and inflammation in obesity and their underlying mechanisms would greatly help develop novel therapeutic interventions to correct obesity and related comorbidities. Here we review accumulating evidence for the association between ER stress and mitochondrial dysfunction, the main culprits responsible for oxidative stress and inflammation in various brain regions, and energy imbalance that leads to the development of obesity. Potential beneficial effects of natural antioxidant and anti-inflammatory compounds on CNS health and obesity are also discussed.

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“…) and recently extended to the SFO (Horwath et al . ). Global reduction of brain ER stress, via CNS selective administration of the ER stress inhibitor taurosodeoxycholic acid (TUDCA), rapidly rescues obesity‐induced hypertension (Purkayastha et al .…”

Section: Introductionmentioning

confidence: 97%

“…; Horwath et al . ). Although these findings indicate that CNS ER stress contributes to the maintenance of hypertension in obesity, interestingly, we found that selective reduction of ER stress in the SFO does not influence hypertension in high‐fat diet‐fed mice (Horwath et al .…”

Section: Introductionmentioning

confidence: 97%

Endoplasmic reticulum stress in the pathogenesis of hypertension

Young

2017

Experimental Physiology

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What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an integrative view of ER stress in cardiovascular control systems, including systems within the brain, kidney and peripheral vasculature, as related to development of hypertension. The endoplasmic reticulum (ER) is a cellular organelle specialized in the synthesis, folding, assembly and modification of proteins. In situations of increased protein demand, complex signalling pathways, termed the unfolded protein response, influence a series of cellular feedback loops to control ER function strictly. Although this is initially a compensatory attempt to maintain cellular homeostasis, chronic activation of the unfolded protein response, known as ER stress, leads to sustained changes in cellular function. A growing body of literature points to ER stress in diverse cardioregulatory systems, including the brain, kidney and vasculature, as central to the development of hypertension. Here, these recent findings from essential and obesity-related forms of hypertension are highlighted in an integrative manner, with discussion of the potential upstream causes and downstream consequences of ER stress. Given that hypertension is a leading medical and socio-economic global challenge, emerging findings suggest that targeting ER stress might represent a viable strategy for the treatment of hypertensive disease.

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

Cited by 22 publications

References 55 publications

Liver sympathetic denervation reverses obesity‐induced hepatic steatosis

Liver sympathetic denervation reverses obesity‐induced hepatic steatosis

Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

Endoplasmic reticulum stress in the pathogenesis of hypertension

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