Abstract MP55: Bardet-biedl Syndrome 3 Gene In Pomc Neurons Regulates Glucose Homeostasis And Baroreflex Sensitivity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Deng-Fu Guo ◽  
Donald A Morgan ◽  
Paul Williams ◽  
Yuying Zhao ◽  
Mohamed Shaban ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Glucose Homeostasis ◽  
Baroreflex Sensitivity ◽  
Energy Homeostasis ◽  
Gene Deletion ◽  
Gene Knockout ◽  
Conscious State ◽  
Bardet Biedl Syndrome ◽  
Reporter Mice ◽  
Ciliary Localization

Bardet-Biedl syndrome (BBS) proteins have emerged as critical regulators of various physiological functions including energy and glucose homeostasis, autonomic function and blood pressure. BBS3 protein is a cilia related protein that mediates the ciliary localization of the BBSome, a protein complex composed of eight BBS protein. Consistent with this, we found that BBS3 gene knockout in human RPE1 cells disrupt the ciliary localization of BBS2 and BBS9 proteins, indicating a loss of BBSome-mediated cargo trafficking to cilia. We previously demonstrated that disruption of the BBSome through Bbs1 gene deletion in the anorexigenic pro-opiomelanocortin (POMC) neurons altered energy homeostasis and sympathetic nerve traffic. However, the significance of BBS3-mediated ciliary localization of the BBSome in POMC neurons is not clear. To address this, we investigated the consequence of Bbs3 gene deletion in POMC neurons . We generated mice lacking the Bbs3 gene in POMC neurons by crossing Bbs3 fl/fl mice with mice expressing inducible Cre in POMC neurons (POMC ERCre ). To visualize Cre recombinase we further crossed POMC ERCre /Bbs3 fl/fl mice with tdTomato reporter mice. To induce Cre expression tamoxifen (75 mg/kg for 5 days) was injected at 6 weeks of age. Interestingly, both male and female POMC ERCre /Bbs3 fl/fl mice did not develop obesity as indicated by the lack of difference in body weight (male 28.1 + 0.5 vs 28.3 + 1.2g, female 21.9 + 0.7 vs 21.4 + 0.5g), fat mass (male 2.9 + .0.4 vs 3.4 + 0.5g, female 2.7 + .3 vs 2.3 + 0.2g) and weight of white and brown fat pads. Insulin and glucose tolerance tests revealed that POMC ERCre /Bbs3 fl/fl mice have glucose intolerance, whereas insulin sensitivity was normal. Blood pressure and renal SNA were comparable between POMC ERCre /Bbs3 fl/fl and control mice measured in the conscious state. In contrast, measurement of renal SNA response to changes in arterial pressure evoked by infusion of sodium nitroprusside and phenylephrine showed reduced baroreflex sensitivity in POMC ERCre /Bbs3 fl/fl mice. These findings demonstrate that POMC neuron BBS3, that mediate cargo transport to cilia, is not necessary for the regulation of energy homeostasis, but is involved in the regulation of glucose homeostasis and baroreflex sensitivity.

Abstract 035: Differential Effects of Bardet-biedl Syndrome 1 Gene Deletion From Agouti-related Peptide Neurons

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Deng F Guo ◽  
John J Reho ◽  
Donald A Morgan ◽  
Kamal Rahmouni
Keyword(s):  
Body Weight ◽  
Vascular Function ◽  
Energy Homeostasis ◽  
Gene Deletion ◽  
Vascular Endothelial ◽  
Bardet Biedl Syndrome ◽  
Related Peptide ◽  
Reporter Mice ◽  
The Central Nervous System ◽  
Human Disorder

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive human disorder associated with several clinical features including obesity and hypertension. We previously demonstrated that Bbs1 gene deletion from the central nervous system caused obesity and hypertension in mice highlighting the importance of neuronal BBS proteins for energy homeostasis and cardiovascular regulation. Here, we investigated the role of Bbs1 gene in the orexigenic agouti-related peptide (AgRP) neurons. We crossed Bbs1 fl/fl mice with AgRP Cre mice and confirmed Cre recombinase activity in AgRP neurons using td-Tomato reporter mice. Interestingly, female AgRP Cre /Bbs1 fl/fl mice developed profound obesity as indicated by the increased body weight (46.8±2.0 g vs control littermates, 35.5±1.9 g at 25 weeks of age). In contrast, body weight of male AgRP Cre /Bbs1 fl/fl mice (48.5±1.2 g) was similar to the controls (46.7±1.2 g). There was no change in the expression of hypothalamic genes regulating food intake (AgRP, proopiomelanocortin and neuropeptide Y) in AgRP Cre /Bbs1 fl/fl mice relative to controls. Next, we assessed the consequence on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from AgRP neurons. Interestingly, deletion of the Bbs1 gene in AgRP neurons did not recapitulate the hypertension phenotype of BBS as indicated by the lack of difference in mean AP (107±5.0 vs 106±5.2 mmHg in controls) and heart rate (597±23.5 vs 589±16.4 in control). However, conscious renal SNA was significantly higher in AgRP Cre /Bbs1 fl/fl mice relative to controls (114±10 vs 78±6 spikes/sec, p<0.05). In addition, the depressor effect of ganglionic blockade (hexamethonium) was higher in AgRP Cre /Bbs1 fl/fl mice (-64.4±10 vs -55.8±8.3 mmHg in control). Finally, we used wire myography to measure mesenteric artery vascular function and found impairment in acetylcholine induced relaxation in AgRP Cre /Bbs1 fl/fl mice (Max. relaxation: 78 ± 6% vs 26 ± 9% in controls; p<0.05), but no changes in the relaxation evoked by sodium nitroprusside, suggesting endothelial, but not smooth muscle, dysfunction. These findings demonstrate that Bbs1 gene in AgRP neurons is critical for energy homeostasis, renal sympathetic outflow and vascular endothelial function.

Abstract T6: Adipocyte Bardet-Biedl Syndrome 1 Gene Is Critical For Blood Pressure Regulation

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yuying Zhao ◽  
Deng-Fu Guo ◽  
Kamal Rahmouni
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Adipose Tissue ◽  
Gene Deletion ◽  
Blood Pressure Regulation ◽  
Conditional Knockout ◽  
Pressure Regulation ◽  
Bardet Biedl Syndrome ◽  
Male And Female ◽  
Fat Pads

Bardet-Biedl syndrome (BBS) proteins have emerged as critical regulators of various physiological functions including blood pressure. The presence of hypertension in BBS patients is consistent with the finding that BBS knockout mice exhibit increased renal sympathetic nerve activity and arterial pressure. However, the role and contribution of Bbs genes in various tissues such as adipose tissue to blood pressure regulation remains unclear. To address this, we generated a novel conditional knockout mouse that lacks the Bbs1 gene in adipocytes by breeding mice bearing floxed alleles of the Bbs1 gene (Bbs1 flox/flox ) with mice expressing Cre specifically in adipocytes (Adiponectin Cre mice). Cre-mediated recombination was verified by loss of Bbs1 expression in fat pads, but not in other tissues such as the kidneys, liver and skeletal muscle. Next, we assessed whether adipocyte Bbs1 gene deletion affects body weight and glucose homeostasis. Interestingly, no body weight phenotype was observed in both male and female Adipo Cre /Bbs1 flox/flox mice compared to their control littermates (males: 40.5±2.9 g vs 37.4±5.1 g; female: 27.7±4.0 g vs 27.5±3.6 g; 16 weeks old). However, insulin tolerance test uncovered impaired insulin-induced glucose clearance in both male and female Adipo Cre /Bbs1 flox/flox mice. Subsequently, we measured blood pressure and found that Adipo Cre /Bbs1 flox/flox mice have a remarkable increase in systolic blood pressure (130.4±11.2 mmHg) compared to the control littermates (119.1±4.5 mmHg, p <0.05). Finally, measurement of the expression of the renin-angiotensin system components revealed significantly elevated angiotensinogen mRNA (2.43±1.31 AU vs 1±0.72 AU, p <0.01) and angiotensin-converting enzyme mRNA (2.96±2.51 AU vs 1±0.95 AU, p <0.05) in peri-renal adipose tissue, but not in other fat pads such as brown and inguinal adipose tissues. Interestingly, gene expression of angiotensin receptor 1a was not significantly altered by Bbs1 gene deletion. Taken together, our findings demonstrate that Bbs1 gene in adipose tissue play an important role in the control of insulin sensitivity and blood pressure.

Exercise and pyridostigmine prevents gastric emptying delay and increase blood pressure and cisplatin-induced baroreflex sensitivity in rats

Life Sciences ◽  
2021 ◽  
Vol 267 ◽  
pp. 118972
Author(s):  
Mariana Sousa Silva ◽  
Yasmim de Andrade Gomes ◽  
Mickael Laudrup de Sousa Cavalcante ◽  
Pedro Victor Nogueira Telles ◽  
Alda Cássia Alves da Silva ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Gastric Emptying ◽  
Baroreflex Sensitivity ◽  
Increase Blood Pressure

Heart rate and blood pressure variability and baroreflex sensitivity in patients with acute brain injury

2005 ◽  
Vol 20 (4) ◽  
pp. 394 ◽  
Author(s):  
V. Papaioannou ◽  
M. Giannakou ◽  
N. Maglaveras ◽  
E. Sofianos ◽  
M. Giala
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Brain Injury ◽  
Blood Pressure Variability ◽  
Baroreflex Sensitivity ◽  
Acute Brain Injury

scholarly journals Blood pressure reduction after gastric bypass surgery is explained by a decrease in cardiac output

2017 ◽  
Vol 122 (2) ◽  
pp. 223-229 ◽  
Author(s):  
Peter M. van Brussel ◽  
Bas van den Bogaard ◽  
Barbara A. de Weijer ◽  
Jasper Truijen ◽  
C.T. Paul Krediet ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Gastric Bypass ◽  
Body Weight ◽  
Cardiac Output ◽  
Baroreflex Sensitivity ◽  
Bypass Surgery ◽  
Gastric Bypass Surgery ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Left Ventricular Contractility

Blood pressure (BP) decreases in the first weeks after Roux-and-Y gastric bypass surgery. Yet the pathophysiology of the BP-lowering effects observed after gastric bypass surgery is incompletely understood. We evaluated BP, systemic hemodynamics, and baroreflex sensitivity in 15 obese women[mean age 42 ± 7 standard deviation (SD) yr, body mass index 45 ± 6 kg/m2] 2 wk before and 6 wk following Roux-and-Y gastric bypass surgery. Six weeks after gastric bypass surgery, mean body weight decreased by 13 ± 5 kg (10%, P < 0.001). Office BP decreased from 137 ± 10/86 ± 6 to 128 ± 12/81 ± 9 mmHg ( P < 0.001, P < 0.01), while daytime ambulatory BP decreased from 128 ± 14/80 ± 9 to 114 ± 10/73 ± 6 mmHg ( P = 0.01, P = 0.05), whereas nighttime BP decreased from 111 ± 13/66 ± 7 to 102 ± 9/62 ± 7 mmHg ( P = 0.04, P < 0.01). The decrease in BP was associated with a 1.6 ± 1.2 l/min (20%, P < 0.01) decrease in cardiac output (CO), while systemic vascular resistance increased (153 ± 189 dyn·s·cm−5, 15%, P < 0.01). The maximal ascending slope in systolic blood pressure decreased (192 mmHg/s, 19%, P = 0.01), suggesting a reduction in left ventricular contractility. Baroreflex sensitivity increased from 9.0 [6.4–14.3] to 13.8 [8.5–19.0] ms/mmHg (median [interquartile range]; P < 0.01) and was inversely correlated with the reductions in heart rate ( R = −0.64, P = 0.02) and CO ( R = −0.61, P = 0.03). In contrast, changes in body weight were not correlated with changes in either BP or CO. The BP reduction following Roux-and-Y gastric bypass surgery is correlated with a decrease in CO independent of changes in body weight. The contribution of heart rate to the reduction in CO together with enhanced baroreflex sensitivity suggests a shift toward increased parasympathetic cardiovascular control. NEW & NOTEWORTHY The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patients.

scholarly journals Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet

2016 ◽  
Vol 4 (12) ◽  
pp. e12837 ◽  
Author(s):  
Laurence Britton ◽  
Lesley Jaskowski ◽  
Kim Bridle ◽  
Nishreen Santrampurwala ◽  
Janske Reiling ◽  
...  
Keyword(s):  
Liver Injury ◽  
Glucose Homeostasis ◽  
Gene Deletion ◽  
Hfe Gene ◽  
Calorie Diet ◽  
High Calorie Diet ◽  
High Calorie

Arterial baroreflex sensitivity and blood pressure variabilities before and after carotid surgery

1991 ◽  
Vol 69 (16) ◽  
pp. 763-768 ◽  
Author(s):  
M. Hirschl ◽  
M. M. Hirschl ◽  
D. Magometschnigg ◽  
B. Liebisch ◽  
O. Wagner ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Baroreflex Sensitivity ◽  
Carotid Surgery ◽  
Arterial Baroreflex ◽  
Before And After ◽  
Arterial Baroreflex Sensitivity

A noninvasive measure of baroreflex sensitivity without blood pressure measurement

2002 ◽  
Vol 143 (3) ◽  
pp. 441-447 ◽  
Author(s):  
L.Ceri Davies ◽  
Helen Colhoun ◽  
Andrew J.S. Coats ◽  
Massimo Piepoli ◽  
Darrel P. Francis
Keyword(s):  
Blood Pressure ◽  
Pressure Measurement ◽  
Baroreflex Sensitivity ◽  
Blood Pressure Measurement

scholarly journals Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure

2016 ◽  
Vol 310 (7) ◽  
pp. H861-H872 ◽  
Author(s):  
Yujia Wang ◽  
Zenghui Wu ◽  
Eric Thorin ◽  
Johanne Tremblay ◽  
Julie L. Lavoie ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Gene Knockout ◽  
Target Cells ◽  
Wild Type ◽  
Cell Contractility ◽  
Risk Gene ◽  
Kinase Phosphorylation

EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca2+ flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.

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