Circumventricular organs: Targets for integration of circulating fluid and energy balance signals?

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

“…In light of our findings of ER stress-mediated cardiovascular and metabolic effects (Figure 2, A-C, H, and I), we focused our attention on the sensory circumventricular SFO. This tiny forebrain CNS nucleus located at the base of the lateral ventricle is highly vascularized and lacks a blood-brain-barrier ( Figure 3A), unlike the vast majority of brain regions, including the hypothalamus (29)(30)(31). This unique feature makes the SFO highly susceptible to ER stress during obesity due to its constant exposure to circulating metabolites, hormones, and inflammatory mediators.…”

“…This unique feature makes the SFO highly susceptible to ER stress during obesity due to its constant exposure to circulating metabolites, hormones, and inflammatory mediators. Well known for its role in fluid and cardiovascular homeostasis, an emerging body of evidence suggests that the SFO may also be intricately involved in metabolic control and serve as a central integrator to couple metabolic and cardiovascular responses (30,32,33).…”

“…In this regard, circumventricular regions such as the SFO, anatomically situated outside of the blood-brain-barrier, may be particularly susceptible to ER stress due to constant exposure to circulating ER stress-inducing factors. The SFO has recently emerged as a unique CNS area that is involved in integrative metabolic control (30,32), so we reasoned that ER stress in the SFO may be a particularly relevant contributor to NAFLD. Indeed, selectively reducing UPR activation in the SFO resulted in a restoration of obesity-induced hepatomegaly and heaptic steatosis.…”

“…Indeed, selectively reducing UPR activation in the SFO resulted in a restoration of obesity-induced hepatomegaly and heaptic steatosis. While the underlying molecular mechanisms in the SFO that modulate hepatic lipid regulation remain to be determined, the SFO contains extensive efferent connections to brainstem and hypothalamic metabolic control regions (29)(30)(31). Thus, it is possible that ER stress in the SFO alters downstream CNS networks that influence liver metabolism through hormonal (i.e., insulin/glucagon) as well as autonomic nervous system control (17)(18)(19)(20).…”

The 17th international symposium in obesity; targeting the gut to treat obesity and its metabolic comorbidities

“…The hypothalamus and the brainstem along with other structures such as the circumventricular organs 8 are implicated in interfacing important peripheral homeostatic signals (for example, signals informing the brain about the energy balance and nutritional status). 3,5 The variations in the adipose-derived hormone leptin or in the gastrointestinal hormones ghrelin, glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) constitute significant homeostatic signals.…”