Angiotensin-(1-7) for Obesity

Overseen By Aimee C Cauffman, BSN

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Amy Arnold

Must not be taking: Anticoagulants, Glucocorticoids, Psychostimulants, others

Disqualifiers: Diabetes, Cardiovascular disease, Renal impairment, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The objective of this study is to better define the role of the hormone angiotensin-(1-7) in energy balance. We will test the overall hypothesis that angiotensin-(1-7) increases resting energy expenditure and promotes markers of heat production (thermogenesis) in white adipose tissue in human obesity.

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications that influence energy expenditure, like psychostimulants, or treatments like anticoagulants and chronic systemic glucocorticoid therapy. If you are on these medications, you may need to stop them to participate.

Is Angiotensin-(1-7) safe for humans?

Research suggests that Angiotensin-(1-7) is generally safe in humans, as it has been studied for its beneficial effects on cardiovascular and metabolic health, including obesity and diabetes. It has shown protective roles in various conditions, indicating a favorable safety profile. ^{1 2 3 4 5}

How is the drug Angiotensin-(1-7) unique in treating obesity?

Angiotensin-(1-7) is unique because it works by activating the ACE2/Ang-(1-7)/Mas pathway, which helps regulate metabolism and counteracts the effects of Angiotensin II, a hormone that can increase during obesity and contribute to metabolic issues. This drug also promotes the conversion of white fat to beige fat, which can increase energy expenditure and aid in weight management. ^{1 2 3 6 7}

What evidence supports the effectiveness of the drug Angiotensin-(1-7) for treating obesity?

Research suggests that Angiotensin-(1-7) may help treat obesity by improving metabolism and reducing insulin resistance, as it has shown positive effects in animal studies on glucose and lipid metabolism, which are important for managing obesity. ^{1 4 6 8 9}

Who Is on the Research Team?

Amy C Arnold, PhD

Principal Investigator

Pennsylvania State University College of Medicine

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with obesity (BMI of 30-40) who can consent to participate. It's not for those with immune or blood disorders, diabetes, serious heart conditions, liver or kidney issues, pregnant/nursing women, drug/alcohol abusers, current smokers/athletes, or anyone on certain medications.

Inclusion Criteria

Satisfactory history and physical exam

I am a person of any gender or race.

I understand the study and can agree to participate.

Exclusion Criteria

Prisoners

My liver tests are more than twice the normal range.

I am currently pregnant, nursing, or I am postmenopausal.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous infusion of angiotensin-(1-7) or saline for 120 minutes to assess changes in energy expenditure and metabolic markers

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin-(1-7)
• Saline

Trial Overview The study tests if the hormone angiotensin-(1-7) increases energy expenditure and promotes heat production in fat tissue among obese individuals. Participants will receive either angiotensin-(1-7) or saline as a control to compare effects.

How Is the Trial Designed?

Group I: Angiotensin-(1-7) Experimental Treatment 1 Intervention

Subjects will receive intravenous infusion of three ascending doses of angiotensin-(1-7). The doses are: 2, 4, and 8 ng/kg/min. Each dose will be maintained for 10 minutes, with the highest dose maintained for an additional 90 minutes. The total infusion period is 120 minutes.

Group II: Placebo Placebo Group 1 Intervention

Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7). The total infusion period is 120 minutes.

Angiotensin-(1-7) is already approved in United States, European Union for the following indications:

Approved in United States as TXA127 for:

• Duchenne muscular dystrophy (DMD)
• Limb-girdle muscular dystrophy (LGMD)
• Congenital muscular dystrophy MDC1A
• Marfan syndrome
• Dystrophic Epidermolysis Bullosa (DEB)
• Pulmonary arterial hypertension
• Myelodysplastic Syndrome (MDS)

Approved in European Union as TXA127 for:

• Duchenne muscular dystrophy (DMD)

Who Is Running the Clinical Trial?

Amy Arnold

Lead Sponsor

Trials

2

Recruited

40+

Published Research Related to This Trial

Angiotensin-(1-7) has shown potential as a therapeutic agent for treating and preventing metabolic disorders, particularly in the context of rising obesity and metabolic syndrome rates worldwide.

The activation of the ACE2/Ang-(1-7)/Mas pathway may counteract the negative effects of Angiotensin II, which is linked to appetite regulation and fat metabolism, suggesting a promising approach for managing metabolic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. Santos, SH., Andrade, JM.[2020]

The renin-angiotensin system is linked to obesity and metabolic diseases, influencing appetite, metabolism, and fat tissue growth, as shown by various animal and human studies.

New pharmaceuticals that inhibit the renin-angiotensin system, originally designed for treating hypertension and heart failure, may also be effective in addressing obesity and metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of angiotensin in obesity and metabolic disease. Mathai, ML., Chen, N., Cornall, L., et al.[2019]

In a study involving 12 non-obese and 11 obese men, the application of Angiotensin II (Ang II) resulted in subtle changes in tissue metabolism and blood flow, but did not show a significant increase in responsiveness to Ang II in obese individuals.

Obese subjects exhibited higher baseline levels of certain metabolites in adipose tissue and muscle, indicating altered metabolic responses, yet the overall effects of Ang II on tissue perfusion and metabolism were minimal across both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic and metabolic responses to interstitial angiotensin II in normal weight and obese men. Boschmann, M., Adams, F., Schaller, K., et al.[2006]

Angiotensin II (Ang II) plays a significant role in metabolism and may contribute to obesity-related conditions like hypertension and type 2 diabetes by acting through its receptors in adipose tissue.

The review discusses how Ang II is produced and its signaling pathways, as well as the potential of pharmaceutical agents targeting the renin-angiotensin system (RAS) to treat obesity-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Goossens, GH., Blaak, EE., van Baak, MA.[2019]

Chronic infusion of angiotensin-(1-7) in obese female mice improved glucose tolerance, highlighting a significant sex difference in response to this treatment compared to male mice, who showed similar insulin sensitivity but did not experience the same level of improvement in glucose tolerance.

Both male and female obese mice experienced reduced body mass and adiposity with angiotensin-(1-7) treatment, suggesting its potential as a therapeutic target for obesity-related insulin resistance, particularly in females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex differences in metabolic effects of angiotensin-(1-7) treatment in obese mice. White, MC., Miller, AJ., Loloi, J., et al.[2020]

In a study of 175 adolescents born prematurely, those with overweight or obesity showed significantly higher levels of angiotensin II (Ang II) and lower levels of angiotensin-(1-7), indicating an imbalance in the renin-angiotensin system that could contribute to health issues.

This imbalance was associated with higher blood pressure, suggesting that obesity may increase the risk of hypertension and cardiovascular disease in preterm-born individuals by exacerbating existing cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm. South, AM., Nixon, PA., Chappell, MC., et al.[2020]

Angiotensin-(1-7) (Ang-[1-7]) protects heart cells from high glucose-induced damage by inhibiting the reactive oxygen species-leptin-p38 MAPK/ERK1/2 pathways, which are activated during diabetic conditions.

In laboratory tests on H9c2 heart cells, Ang-(1-7) treatment led to increased cell viability, reduced apoptosis, and lower reactive oxygen species production, demonstrating its potential as a therapeutic agent in diabetic cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. Lei, Y., Xu, Q., Zeng, B., et al.[2022]

Chronic administration of Angiotensin 1-7 (Ang 1-7) for 4 weeks significantly improves endothelial function in mice with diet-induced obesity, as shown by enhanced relaxation responses to acetylcholine.

Ang 1-7 treatment also reduces oxidative stress markers in the aorta, indicating its protective role against endothelial dysfunction caused by obesity, although it does not fully normalize altered contractile responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged treatment with angiotensin 1-7 improves endothelial function in diet-induced obesity. Beyer, AM., Guo, DF., Rahmouni, K.[2021]

Angiotensin-(1-7) (Ang-(1-7)) promotes the expression of thermogenic genes in white adipose tissue and enhances mitochondrial respiration in adipocytes, indicating its role in increasing energy expenditure.

The effects of Ang-(1-7) on thermogenesis are mediated through the Mas receptor, as shown by experiments with Mas+/+ and Mas-/- mice, suggesting that targeting this pathway could be a potential therapeutic strategy for obesity, especially in individuals with lower levels of Ang-(1-7).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) induces beige fat thermogenesis through the Mas receptor. Vargas-Castillo, A., Tobon-Cornejo, S., Del Valle-Mondragon, L., et al.[2023]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. [2020]

2. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The role of angiotensin in obesity and metabolic disease. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Hemodynamic and metabolic responses to interstitial angiotensin II in normal weight and obese men. [2006]

4. England pubmed.ncbi.nlm.nih.gov

Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Sex differences in metabolic effects of angiotensin-(1-7) treatment in obese mice. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm. [2020]

7. Japan pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Prolonged treatment with angiotensin 1-7 improves endothelial function in diet-induced obesity. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) induces beige fat thermogenesis through the Mas receptor. [2023]