Angiotensin-(1–7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice

Justin Loloi, Amanda J. Miller, Sarah S. Bingaman, Yuval Silberman, Amy Arnold

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1–7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1–7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1–7) mas receptor antagonist A779 (400 or 800 ng·kg-1· min-1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 (n  6 –13/group). Captopril reduced body weight (28  2 vs. 41  2 g saline; P  0.001), lowered systolic BP (109  6 vs. 144  7 mmHg saline; P  0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31  4 vs. 16  2 mg·kg-1·min-1 saline; P  0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23  2 mg·kg-1·min-1; P  0.042), with no effect on body weight (32  2 g; P  0.441) or BP (111  7 mmHg; P  0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1–7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.

Original languageEnglish (US)
Pages (from-to)E1204-E1211
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume315
Issue number6
DOIs
StatePublished - Dec 1 2018

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7-Ala-angiotensin (1-7)
Obese Mice
Captopril
Angiotensins
Peptidyl-Dipeptidase A
Insulin
Blood Pressure
Insulin Resistance
Body Weight
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II
Glucose Clamp Technique
Water
High Fat Diet
Inbred C57BL Mouse
Arterial Pressure
Therapeutics
Animal Models
Hormones
Diet

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

@article{d3717ce2f21f4c93a78badd5734f3dde,
title = "Angiotensin-(1–7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice",
abstract = "Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1–7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1–7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60{\%} high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1–7) mas receptor antagonist A779 (400 or 800 ng·kg-1· min-1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 (n  6 –13/group). Captopril reduced body weight (28  2 vs. 41  2 g saline; P  0.001), lowered systolic BP (109  6 vs. 144  7 mmHg saline; P  0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31  4 vs. 16  2 mg·kg-1·min-1 saline; P  0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23  2 mg·kg-1·min-1; P  0.042), with no effect on body weight (32  2 g; P  0.441) or BP (111  7 mmHg; P  0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1–7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.",
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Angiotensin-(1–7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice. / Loloi, Justin; Miller, Amanda J.; Bingaman, Sarah S.; Silberman, Yuval; Arnold, Amy.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 315, No. 6, 01.12.2018, p. E1204-E1211.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Angiotensin-(1–7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice

AU - Loloi, Justin

AU - Miller, Amanda J.

AU - Bingaman, Sarah S.

AU - Silberman, Yuval

AU - Arnold, Amy

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N2 - Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1–7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1–7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1–7) mas receptor antagonist A779 (400 or 800 ng·kg-1· min-1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 (n  6 –13/group). Captopril reduced body weight (28  2 vs. 41  2 g saline; P  0.001), lowered systolic BP (109  6 vs. 144  7 mmHg saline; P  0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31  4 vs. 16  2 mg·kg-1·min-1 saline; P  0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23  2 mg·kg-1·min-1; P  0.042), with no effect on body weight (32  2 g; P  0.441) or BP (111  7 mmHg; P  0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1–7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.

AB - Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1–7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1–7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1–7) mas receptor antagonist A779 (400 or 800 ng·kg-1· min-1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 (n  6 –13/group). Captopril reduced body weight (28  2 vs. 41  2 g saline; P  0.001), lowered systolic BP (109  6 vs. 144  7 mmHg saline; P  0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31  4 vs. 16  2 mg·kg-1·min-1 saline; P  0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23  2 mg·kg-1·min-1; P  0.042), with no effect on body weight (32  2 g; P  0.441) or BP (111  7 mmHg; P  0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1–7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.

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