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Article ; Online: Alleviating Hypertension by Selectively Targeting Angiotensin Receptor-Expressing Vagal Sensory Neurons.

Baumer-Harrison, Caitlin / Elsaafien, Khalid / Johnson, Dominique N / Peñaloza Aponte, Jesus D / de Araujo, Alan / Patel, Sagar / Bruce, Erin B / Harden, Scott W / Frazier, Charles J / Scott, Karen A / de Lartigue, Guillaume / Krause, Eric G / de Kloet, Annette D

The Journal of neuroscience : the official journal of the Society for Neuroscience

2024 Volume 44, Issue 9

Abstract: Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a ... ...

Abstract	Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NG
MeSH term(s)	Mice ; Male ; Female ; Animals ; Desoxycorticosterone Acetate/pharmacology ; Hypertension ; Solitary Nucleus/physiology ; Sensory Receptor Cells ; Blood Pressure/physiology ; Phenylephrine/pharmacology ; Ion Channels ; Red Fluorescent Protein
Chemical Substances	tdTomato ; Desoxycorticosterone Acetate (6E0A168OB8) ; Phenylephrine (1WS297W6MV) ; Piezo1 protein, mouse ; Ion Channels ; Red Fluorescent Protein
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1154-23.2023
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Article ; Online: The intricacies of the renin-angiotensin-system in metabolic regulation.

Bruce, Erin B / de Kloet, Annette D

Physiology & behavior

2017 Volume 178, Page(s) 157–165

Abstract: Over recent years, the renin-angiotensin-system (RAS), which is best-known as an endocrine system with established roles in hydromineral balance and blood pressure control, has emerged as a fundamental regulator of many additional physiological and ... ...

Abstract	Over recent years, the renin-angiotensin-system (RAS), which is best-known as an endocrine system with established roles in hydromineral balance and blood pressure control, has emerged as a fundamental regulator of many additional physiological and pathophysiological processes. In this manuscript, we celebrate and honor Randall Sakai's commitment to his trainees, as well as his contribution to science. Scientifically, Randall made many notable contributions to the recognition of the RAS's roles in brain and behavior. His interests, in this regard, ranged from its traditionally-accepted roles in hydromineral balance, to its less-appreciated functions in stress responses and energy metabolism. Here we review the current understanding of the role of the RAS in the regulation of metabolism. In particular, the opposing actions of the RAS within adipose tissue vs. its actions within the brain are discussed.
Language	English
Publishing date	2017-09-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2016.11.020
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Article: The intricacies of the renin-angiotensin-system in metabolic regulation

Bruce, Erin B / de Kloet, Annette D

Physiology & behavior. 2017 Sept. 01, v. 178

2017

Abstract	Over recent years, the renin-angiotensin-system (RAS), which is best-known as an endocrine system with established roles in hydromineral balance and blood pressure control, has emerged as a fundamental regulator of many additional physiological and pathophysiological processes. In this manuscript, we celebrate and honor Randall Sakai's commitment to his trainees, as well as his contribution to science. Scientifically, Randall made many notable contributions to the recognition of the RAS's roles in brain and behavior. His interests, in this regard, ranged from its traditionally-accepted roles in hydromineral balance, to its less-appreciated functions in stress responses and energy metabolism. Here we review the current understanding of the role of the RAS in the regulation of metabolism. In particular, the opposing actions of the RAS within adipose tissue vs. its actions within the brain are discussed.
Keywords	adipose tissue ; blood pressure ; brain ; endocrine system ; energy metabolism ; renin-angiotensin system ; stress response
Language	English
Dates of publication	2017-0901
Size	p. 157-165.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2016.11.020
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Article ; Online: ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats.

Bruce, Erin B / Sakarya, Yasemin / Kirichenko, Nataliya / Toklu, Hale Z / Sumners, Colin / Morgan, Drake / Tümer, Nihal / Scarpace, Philip J / Carter, Christy S

Experimental gerontology

2018 Volume 111, Page(s) 133–140

Abstract: The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2] ...

Abstract	The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.
MeSH term(s)	Adiposity/drug effects ; Age Factors ; Angiotensin I/genetics ; Angiotensin I/metabolism ; Animals ; Diminazene/analogs & derivatives ; Diminazene/pharmacology ; Disease Models, Animal ; Gene Expression ; Male ; Obesity/metabolism ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Peptidyl-Dipeptidase A/blood ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Rats ; Rats, Inbred F344 ; Renin-Angiotensin System/drug effects
Chemical Substances	Peptide Fragments ; Angiotensin I (9041-90-1) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; angiotensin converting enzyme 2 (EC 3.4.17.-) ; angiotensin I (1-7) (IJ3FUK8MOF) ; diminazene aceturate (JI8SAD85NO) ; Diminazene (Y5G36EEA5Z)
Language	English
Publishing date	2018-07-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	390992-x
ISSN	1873-6815 ; 0531-5565
ISSN (online)	1873-6815
ISSN	0531-5565
DOI	10.1016/j.exger.2018.07.008
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Article: Drugs, exercise, and the melanocortin-4 receptor-- different means, same ends: treating obesity.

Schaub, Jay W / Bruce, Erin B / Haskell-Luevano, Carrie

Advances in experimental medicine and biology

2010 Volume 681, Page(s) 49–60

Abstract: As the percentage of obese humans expands, new options for weight loss are being explored. Body weight homeostasis is the result of a balance between energy intake (food) and expenditure (activity). A shift in homeostasis into a negative balance results ... ...

Abstract	As the percentage of obese humans expands, new options for weight loss are being explored. Body weight homeostasis is the result of a balance between energy intake (food) and expenditure (activity). A shift in homeostasis into a negative balance results in weight loss. Two potential options available for the management of body weight, as related to the melanocortin system, are exercise (increase energy expenditure) and drugs targeting the melanocortin-4 receptors for satiety.
MeSH term(s)	Animals ; Exercise/physiology ; Humans ; Melanocortins/metabolism ; Obesity/drug therapy ; Obesity/metabolism ; Obesity/physiopathology ; Receptor, Melanocortin, Type 4/metabolism
Chemical Substances	Melanocortins ; Receptor, Melanocortin, Type 4
Language	English
Publishing date	2010
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4419-6354-3_4
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Article ; Online: Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway.

Toklu, Hale Z / Scarpace, Philip J / Sakarya, Yasemin / Kirichenko, Nataliya / Matheny, Michael / Bruce, Erin B / Carter, Christy S / Morgan, Drake / Tümer, Nihal

Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme

2017 Volume 42, Issue 1, Page(s) 59–67

Abstract: Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative ... ...

Abstract	Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Aging ; Animals ; Cognitive Dysfunction/etiology ; Cognitive Dysfunction/prevention & control ; Crosses, Genetic ; Cyclic N-Oxides/administration & dosage ; Cyclic N-Oxides/adverse effects ; Cyclic N-Oxides/therapeutic use ; Energy Intake/drug effects ; Free Radical Scavengers/administration & dosage ; Free Radical Scavengers/adverse effects ; Free Radical Scavengers/therapeutic use ; Hypothalamus/drug effects ; Hypothalamus/metabolism ; Infusion Pumps, Implantable ; Infusions, Intraventricular ; Male ; Nerve Tissue Proteins/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Nootropic Agents/administration & dosage ; Nootropic Agents/adverse effects ; Nootropic Agents/therapeutic use ; Obesity/drug therapy ; Obesity/physiopathology ; Oxidative Stress/drug effects ; Rats, Inbred BN ; Rats, Inbred F344 ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Sirtuin 1/metabolism ; Spin Labels
Chemical Substances	Cyclic N-Oxides ; Free Radical Scavengers ; Nerve Tissue Proteins ; Nootropic Agents ; STAT3 Transcription Factor ; Spin Labels ; Stat3 protein, rat ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Sirt1 protein, rat (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; tempol (U78ZX2F65X)
Language	English
Publishing date	2017-01
Publishing country	Canada
Document type	Journal Article
ZDB-ID	2236708-1
ISSN	1715-5320 ; 1715-5312
ISSN (online)	1715-5320
ISSN	1715-5312
DOI	10.1139/apnm-2016-0067
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Article: Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway

Toklu, Hale Z / Scarpace, Philip J / Sakarya, Yasemin / Kirichenko, Nataliya / Matheny, Michael / Bruce, Erin B / Carter, Christy S / Morgan, Drake / Tümer, Nihal

Applied Physiology, Nutrition, and Metabolism. 2016 Oct. 6, v. 42, no. 1

2016

Abstract	Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5′AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.
Keywords	NADP (coenzyme) ; Rattus norvegicus ; body composition ; enzyme activity ; feeding behavior ; food intake ; free radical scavengers ; hypothalamus ; inflammation ; leptin ; males ; metabolism ; obesity ; oxidative stress ; phosphorylation ; protein kinases ; rats ; signal transduction ; transactivators ; weight gain
Language	English
Dates of publication	2016-1006
Size	p. 59-67.
Publishing place	NRC Research Press
Document type	Article
ZDB-ID	2236708-1
ISSN	1715-5320 ; 1715-5312
ISSN (online)	1715-5320
ISSN	1715-5312
DOI	10.1139/apnm-2016-0067
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Article ; Online: Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice.

Wang, Lei A / de Kloet, Annette D / Smeltzer, Michael D / Cahill, Karlena M / Hiller, Helmut / Bruce, Erin B / Pioquinto, David J / Ludin, Jacob A / Katovich, Michael J / Raizada, Mohan K / Krause, Eric G

Neuropharmacology

2018 Volume 133, Page(s) 85–93

Abstract: This study used mice to evaluate whether coupling expression of corticotropin-releasing hormone (CRH) and angiotensin converting enzyme 2 (ACE2) creates central interactions that blunt endocrine and behavioral responses to psychogenic stress. Central ... ...

Abstract	This study used mice to evaluate whether coupling expression of corticotropin-releasing hormone (CRH) and angiotensin converting enzyme 2 (ACE2) creates central interactions that blunt endocrine and behavioral responses to psychogenic stress. Central administration of diminazene aceturate, an ACE2 activator, had no effect on restraint-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis; however, mice that ubiquitously overexpress ACE2 had reduced plasma corticosterone (CORT) and pituitary expression of POMC mRNA. The Cre-LoxP system was used to restrict ACE2 overexpression to CRH synthesizing cells and probe whether HPA axis suppression was the result of central ACE2 and CRH interactions. Within the paraventricular nucleus of the hypothalamus (PVN), mice with ACE2 overexpression directed to CRH had a ≈2.5 fold increase in ACE2 mRNA, which co-localized with CRH mRNA. Relative to controls, mice overexpressing ACE2 in CRH cells had a decreased CORT response to restraint as well as decreased CRH mRNA in the PVN and CEA and POMC mRNA in the pituitary. Administration of ACTH similarly increased plasma CORT, indicating that the blunted HPA axis activation that accompanies ACE2 overexpression in CRH cells is centrally mediated. Anxiety-like behavior was assessed to determine whether the decreased HPA axis activation was predictive of anxiolysis. Mice with ACE2 overexpression directed to CRH cells displayed decreased anxiety-like behavior in the elevated plus maze and open field when compared to that of controls. Collectively, these results suggest that exogenous ACE2 suppresses CRH synthesis, which alters the central processing of psychogenic stress, thereby blunting HPA axis activation and attenuating anxiety-like behavior.
MeSH term(s)	Adrenocorticotropic Hormone/pharmacology ; Animals ; Anxiety/drug therapy ; Anxiety/etiology ; Corticotropin-Releasing Hormone/blood ; Corticotropin-Releasing Hormone/genetics ; Corticotropin-Releasing Hormone/metabolism ; Corticotropin-Releasing Hormone/therapeutic use ; Diminazene/analogs & derivatives ; Diminazene/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Activators/therapeutic use ; Hormones/pharmacology ; Hypothalamo-Hypophyseal System/drug effects ; Hypothalamo-Hypophyseal System/metabolism ; Injections, Intraventricular ; Male ; Maze Learning/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Pituitary Gland/metabolism ; Pituitary-Adrenal System/diagnostic imaging ; Pituitary-Adrenal System/metabolism ; Pro-Opiomelanocortin/genetics ; Pro-Opiomelanocortin/metabolism ; RNA, Messenger/metabolism ; Stress, Psychological/drug therapy ; Stress, Psychological/genetics ; Stress, Psychological/metabolism
Chemical Substances	Enzyme Activators ; Hormones ; RNA, Messenger ; Pro-Opiomelanocortin (66796-54-1) ; Adrenocorticotropic Hormone (9002-60-2) ; Corticotropin-Releasing Hormone (9015-71-8) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; angiotensin converting enzyme 2 (EC 3.4.17.-) ; diminazene aceturate (JI8SAD85NO) ; Diminazene (Y5G36EEA5Z)
Language	English
Publishing date	2018-01-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2018.01.025
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Article ; Online: Anorexic response to rapamycin does not appear to involve a central mechanism.

Toklu, Hale Z / Bruce, Erin B / Sakarya, Yasemin / Carter, Christy S / Morgan, Drake / Matheny, Michael K / Kirichenko, Nataliya / Scarpace, Philip J / Tümer, Nihal

Clinical and experimental pharmacology & physiology

2016 Volume 43, Issue 9, Page(s) 802–807

Abstract: The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of ... ...

Abstract	The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 μg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain.
MeSH term(s)	Animals ; Anorexia/drug therapy ; Anorexia/metabolism ; Anorexia/physiopathology ; Body Weight/drug effects ; Eating/drug effects ; Energy Intake/drug effects ; Rats ; Sirolimus/pharmacology ; Sirolimus/therapeutic use ; Treatment Outcome
Chemical Substances	Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2016-09-27
Publishing country	Australia
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	189277-0
ISSN	1440-1681 ; 0305-1870 ; 0143-9294
ISSN (online)	1440-1681
ISSN	0305-1870 ; 0143-9294
DOI	10.1111/1440-1681.12601
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