Abstract 173: Modulation of the Metabolic Effects of Leptin by the Brain Renin-Angiotensin System

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Kristin E Claflin ◽  
Aline M Hilzendeger ◽  
Curt D Sigmund ◽  
Justin L Grobe
Keyword(s):  
Physical Activity ◽  
Food Intake ◽  
Metabolic Rate ◽  
Cross Talk ◽  
Renin Angiotensin System ◽  
Suppressive Effect ◽  
Metabolic Effects ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

Genetic deletion or delivery of antagonists of the renin-angiotensin system (RAS) directly to the brain abolishes both renal and adipose sympathetic nervous activity (SNA) responses to leptin, suggesting a cross-talk between these central cardiovascular / metabolic control systems. To further explore this mechanism of cross-talk, we examined the sensitivity of metabolic responses in mice with transgenic hyperactivity of the brain RAS (“sRA” mice) to acute leptin treatment. sRA mice, previously shown to exhibit hypertension, polydipsia, and elevated SNA and resting metabolic rate, exhibit brain-specific RAS hyperactivity through neuronal expression of human renin via the synapsin promoter and expression of human angiotensinogen via its own promoter. When housed at standard room temperature (23°C), twice-daily leptin injections (1 mg/kg, i.p., 3 hrs into light phase and 2 hrs preceding dark phase of a 12:12-hr cycle) caused significant and similar reductions in body mass (control -0.76±0.13, n=5 male; sRA -0.65±0.09 g/d, n=5 male, P=0.46) and food intake (-1.43±0.69 vs -1.99±0.27 kcal/d, P=0.63) in littermate control and sRA mice. When housed at thermoneutrality (30°C) in an OxyMax (Columbus Instruments) CLAMS apparatus, leptin injections had minimal effects on total daily food intake in control mice (from 7.4±0.6 at baseline to 8.1±0.5 kcal/d with leptin, n=4 male + 4 female, P=0.29), but reduced food intake in sRA mice (from 8.3±0.7 to 6.0±0.4 kcal/d, n=4 male + 4 female, P=0.003). sRA mice were more sensitive to leptin’s suppressive effect on physical activity (control from 998±148 to 655±90, P=0.10; sRA from 1232±304 to 588±41 counts/d, P=0.005). Unexpectedly, leptin had a suppressive effect upon metabolic rate in sRA mice (control from 16.4±1.3 to 16.8±0.9, P=0.44; sRA from 20.2±1.1 to 17.5±0.9 kcal/kg lean/hr, P<0.001). Together, these data support a cross-talk between the brain RAS and leptin signaling in the control of metabolic function. These data suggest a complex and context-dependent mechanism of interaction between leptin and brain angiotensin, with gross alterations in leptin-induced food, physical activity, and metabolic rate responses when tested in a thermoneutral environment.

scholarly journals Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system

2012 ◽  
Vol 302 (3) ◽  
pp. R313-R320 ◽  
Author(s):  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Fluid Intake ◽  
Renin Angiotensin System ◽  
Metabolic Effects ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intracellular Form ◽  
Efferent Pathways ◽  
The Brain ◽  
Pituitary Adrenal Axis

The purpose of this review is two-fold. First, I will highlight recent advances in our understanding of the mechanisms regulating angiotensin II (ANG II) synthesis in the brain, focusing on evidence that renin is expressed in the brain and is expressed in two forms: a secreted form, which may catalyze extracellular ANG I generation from glial or neuronal angiotensinogen (AGT), and an intracellular form, which may generate intracellular ANG in neurons that may act as a neurotransmitter. Second, I will discuss recent studies that advance the concept that the renin-angiotensin system (RAS) in the brain not only is a potent regulator of blood pressure and fluid intake but may also regulate metabolism. The efferent pathways regulating the blood pressure/dipsogenic effects and the metabolic effects of elevated central RAS activity appear different, with the former being dependent upon the hypothalamic-pituitary-adrenal axis, and the latter being dependent upon an interaction between the brain and the systemic (or adipose) RAS.

Abstract 1375: Brain Renin Angiotensin Blockade Attenuates Cytokines and Oxidative Stress in the Paraventricular Nucleus of Hypothalamus and Decreases Sympathoexcitation in Heart Failure Rats

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ying Ma ◽  
Yu-Ming Kang* ◽  
Zhi-Ming Yang ◽  
Joseph Francis*
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Paraventricular Nucleus ◽  
Cross Talk ◽  
Renin Angiotensin System ◽  
Heart Weight ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain ◽  
And Oxidative Stress

Introduction: Neurohumoral mechanisms play an important role in the pathophysiology of congestive heart failure (HF). Recent studies suggest that the brain renin angiotensin system (RAS) plays an important role in regulating body fluids and sympathetic drive in HF. In addition, it has been shown that there is cross talk between cytokines and RAS in cardiovascular disease. In this study we determined whether blockade of brain RAS attenuate inflammatory cytokines and oxidative stress in HF rats. Methods and Results: Adult male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannulae and subjected to coronary artery ligation to induce HF and confirmed by echocardiography. Rats were treated with an angiotensin type 1 receptors (AT1-R) antagonist losartan (LOS, 20 μg/hr, ICV) or vehicle (VEH) for 4 weeks. At the end of the study, left ventricular (LV) function was measured by echocardiography and rats were sacrificed, and brain and plasma samples were collected for measurements of cytokines and superoxide using immunohistochemistry, Western blot and real time RT-PCR. HF rats induced significant increases in Nuclear Factor-kappaB (NF-κB) p50-positive neurons and activated microglia in the paraventricular nucleus (PVN) of hypothalamus, and TNF-α, IL-1β, IL-6 and NF-κB p50 in hypothalamus when compared with sham rats. These animals also had increased staining for dihydroethidium (DHE) and plasma levels of norepinephrine (NE), an indirect indicator of sympathetic activity. In contrast, ICV treatment with LOS attenuated cytokine expression and oxidative stress in the PVN and hypothalamus when compared with VEH treated HF rats. ICV treatment with LOS also reduced plasma NE levels, and proinflammatory cytokine, heart weight to body weight ratio with decreased LV end-diastolic pressure. Conclusions : These findings suggest the cross talk between the cytokines and renin angiotensin system within the brain contribute to sympatho-excitation in HF.

Abstract P061: Selective Deletion of Intracellular Renin in the Brain Causes Hypertension and Elevated Sympathetic Nervous System Activity

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keisuke Shinohara ◽  
Benjamin J Weidemann ◽  
Matthew D Folchert ◽  
Xuebo Liu ◽  
Donald A Morgan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Rate ◽  
Systolic Blood Pressure ◽  
Neural Circuit ◽  
Resting Metabolic Rate ◽  
Renin Angiotensin System ◽  
Power Spectral Analysis ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

Renin expression is regulated by two distinct promoter-1st exon combinations that target renin either for secretion (exon 1a for secreted renin) or cytoplasmic retention (exon 1b for intracellular renin, icREN). We developed icREN knockout (KO) mice by selectively deleting exon 1b. icREN KO mice are essentially brain-specific knockouts of icREN because icREN is predominantly expressed in the brain. Notably, systolic blood pressure measured by telemetry was increased in icREN KO mice (130±2 mmHg, n=8 vs 122±2 mmHg in controls, n=7, P<0.01). The low- to high-frequency ratio (LF/HF) derived from power spectral analysis of heart rate variability, a parameter of sympathetic nerve activity (SNA), was increased in icREN KO mice (KO: 1.24±0.21, n=7 vs control: 0.70±0.11, n=7, P<0.05). Body weight (BW) was normal in icREN KO mice compared to controls, but the BW gain and fat accumulation induced by high fat diet (HFD) were attenuated in male icREN KO mice (BW at 16 wks of HFD- KO: 36.8±1.2 g, n=8 vs control: 41.9±1.4 g, n=9; relative fat mass at 14 wks of HFD- KO: 27.7±1.7%, n=8 vs control: 34.4±2.3%, n=9, both P<0.05). The resting metabolic rate measured by respirometry was increased in icREN KO mice (0.156±0.005 kcal/h, n=46, P<0.05) vs controls (0.145±0.003 kcal/h, n=53), whereas food consumption and absorbed calories were not different. We previously reported that the brain renin-angiotensin system facilitates renal SNA (RSNA) response to acute intracerebroventricular (ICV) injection of leptin. Interestingly, the RSNA response to ICV leptin was greater in icREN KO mice (KO: 214±40 % baseline, n=5 vs control: 114±18 % baseline, n=10, P<0.01). AT1a receptor mRNA was upregulated in the paraventricular nucleus of icREN KO mice (P<0.05). Chronic ICV injection of losartan not only abolished the elevated blood pressure in icREN KO mice, but reduced it to below baseline in controls (systolic blood pressure, 111±3 mmHg in KO, n=5; 124±4 mmHg in controls, n=6). These data suggest that icREN deletion increases the activity of brain renin-angiotensin system and elevates blood pressure and metabolic rate through sympathetic activation. We conclude that this novel icREN isoform contributes to cardiovascular and metabolic control possibly as part of an inhibitory neural circuit.

scholarly journals A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

2012 ◽  
Vol 303 (2) ◽  
pp. H197-H206 ◽  
Author(s):  
Aline M. Hilzendeger ◽  
Donald A. Morgan ◽  
Leonard Brooks ◽  
David Dellsperger ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Food Intake ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Renin Angiotensin System ◽  
Melanocortin Receptor ◽  
Nerve Activity ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT1aR−/−), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT1aR−/− vs. AT1aR+/+ mice. ICV leptin in rats increased AT1aR and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT1aR mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

The Brain-Renin-Angiotensin System: Update

1986 ◽  
pp. 123-133 ◽  
Author(s):  
Thomas Unger ◽  
Detlev Ganten ◽  
Gerald Ludwig ◽  
Rudolf E. Lang
Keyword(s):  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

The renin angiotensin system and the brain: New developments

2017 ◽  
Vol 46 ◽  
pp. 1-8 ◽  
Author(s):  
Ehab Farag ◽  
Daniel I. Sessler ◽  
Zeyd Ebrahim ◽  
Andrea Kurz ◽  
Joseph Morgan ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Angiotensin System ◽  
New Developments ◽  
Renin Angiotensin ◽  
The Brain

Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction

1999 ◽  
Vol 276 (5) ◽  
pp. H1608-H1615 ◽  
Author(s):  
Weiguo Zhang ◽  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Renin Angiotensin System ◽  
Coronary Artery Ligation ◽  
Arterial Baroreflex ◽  
Baroreflex Control ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Air Jet ◽  
Baroreflex Function ◽  
The Brain

Blockade of brain “ouabain” prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain “ouabain” may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg ⋅ kg−1 ⋅ day−1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the α2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.

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