Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice

Eric Jacques Belin de Chantemele, James D. Mintz, William E. Rainey, David W Stepp

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin-angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.

Original languageEnglish (US)
Pages (from-to)271-279
Number of pages9
JournalHypertension
Volume58
Issue number2
DOIs
StatePublished - Aug 1 2011

Fingerprint

Obese Mice
Leptin
High Fat Diet
Obesity
Aldosterone
Adrenergic Agents
Cardiovascular System
Blood Pressure
Blood Vessels
Heart Rate
Tachyphylaxis
Phenylephrine
Renin-Angiotensin System
Cardiac Output
Stroke Volume
Weight Loss

Keywords

  • Blood pressure
  • adrenergic reactivity
  • aldosterone
  • cardiac output
  • high fat diet

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice. / Belin de Chantemele, Eric Jacques; Mintz, James D.; Rainey, William E.; Stepp, David W.

In: Hypertension, Vol. 58, No. 2, 01.08.2011, p. 271-279.

Research output: Contribution to journalArticle

@article{7a968256dd524645a36b7d57ae252507,
title = "Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice",
abstract = "Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin-angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.",
keywords = "Blood pressure, adrenergic reactivity, aldosterone, cardiac output, high fat diet",
author = "{Belin de Chantemele}, {Eric Jacques} and Mintz, {James D.} and Rainey, {William E.} and Stepp, {David W}",
year = "2011",
month = "8",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.110.168427",
language = "English (US)",
volume = "58",
pages = "271--279",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice

AU - Belin de Chantemele, Eric Jacques

AU - Mintz, James D.

AU - Rainey, William E.

AU - Stepp, David W

PY - 2011/8/1

Y1 - 2011/8/1

N2 - Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin-angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.

AB - Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin-angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.

KW - Blood pressure

KW - adrenergic reactivity

KW - aldosterone

KW - cardiac output

KW - high fat diet

UR - http://www.scopus.com/inward/record.url?scp=80051474126&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051474126&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.110.168427

DO - 10.1161/HYPERTENSIONAHA.110.168427

M3 - Article

VL - 58

SP - 271

EP - 279

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 2

ER -