Vertical sleeve gastrectomy reduces blood pressure and hypothalamic endoplasmic reticulum stress in mice

Abstract

Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes remarkable improvements in cardiometabolic health, including hypertension remission. However, the mechanisms responsible remain undefined and poorly studied. Therefore, we developed and validated the first murine model of VSG that recapitulates the blood pressure-lowering effect of VSG using gold-standard radiotelemetry technology. We used this model to investigate several potential mechanisms, including body mass, brain endoplasmic reticulum (ER) stress signaling and brain inflammatory signaling, which are all critical contributors to the pathogenesis of obesity-associated hypertension. Mice fed on a high-fat diet underwent sham or VSG surgery and radiotelemeter implantation. Sham mice were fed ad libitum or were food restricted to match their body mass to VSG-operated mice to determine the role of body mass in the ability of VSG to lower blood pressure. Blood pressure was then measured in freely moving unstressed mice by radiotelemetry. VSG decreased energy intake, body mass and fat mass. Mean arterial blood pressure (MAP) was reduced in VSG-operated mice compared with both sham-operated groups. VSG-induced reductions in MAP were accompanied by a body mass-independent decrease in hypothalamic ER stress, hypothalamic inflammation and sympathetic nervous system tone. Assessment of gut microbial populations revealed VSG-induced increases in the relative abundance of Gammaproteobacteria and Enterococcus, and decreases in Adlercreutzia. These results suggest that VSG reduces blood pressure, but this is only partly due to the reduction in body weight. VSG-induced reductions in blood pressure may be driven by a decrease in hypothalamic ER stress and inflammatory signaling, and shifts in gut microbial populations.

Brown Adipose Tissue is Associated with Improved Cardiometabolic Health and Regulates Blood Pressure

“…In healthy adults, cold stimulation of brown fat increases energy expenditure and 176 improves systemic glucose utilization, fatty acid oxidation, and insulin sensitivity 28,29,30,31 . This 177 observation is consistent with animal models, where transplantation of thermogenic adipose 178 tissue mass improved glucose and triglyceride metabolism, while genetic ablation of 179 thermogenic fat had the opposite effect 3,32,33 . The effects of thermogenic adipose tissue on 180 cardiometabolic health and obesity-associated diseases in humans, however, have been largely 181 unexplored until now.…”

Bile acids at the cross-roads of gut microbiome–host cardiometabolic interactions

“…The risk of CVD events in patients with concomitant hypertension is estimated to be raised by two to threefold [ 95 ]; therefore, elevated blood pressure represents a central modifiable risk factor in prevention of the disease. Hypertension remission is a relatively common phenomenon associated with bariatric surgery and McGavigan and colleagues hypothesized that the alterations observed in microbiome composition and bile metabolism following the procedure may have a role in this effect [ 96 ]. In this respect, it is interesting to note that FXR is expressed widely in vascular smooth muscle cells as well as in the heart, particularly the atrial myocardium [ 97 ].…”

Endoplasmic reticulum stress in the pathogenesis of hypertension

“…A recent study by McGavigan et al . () suggests that brain ER stress might also be involved (Fig. ).…”

“…; McGavigan et al . , b). Alternatively, bariatric surgery might influence afferent inputs through surgical disruption of the nerves after stomach transection or, indirectly, via alterations in metabolic and humoral factors; however, whether afferent signalling modulates the UPR in the brain remains unknown.…”