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Cited by 110Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesCardiovascular, Neuropeptides, and Oxidative Stress Research

Leptin and the Cardiovascular System

Open access
Rahmouni, K.·2004·Recent Progress in Hormone Research
DOI 10.1210/rp.59.1.225
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Abstract

Obesity is associated with increased cardiovascular morbidity and mortality, in part through development of hypertension. Recent observations suggest that the cardiovascular actions of leptin may help explain the link between excess fat mass and cardiovascular diseases. Leptin is an adipocyte-derived hormone that acts in the central nervous system to promote weight loss by decreasing food intake and increasing metabolic rate. Leptin causes a significant increase in overall sympathetic nervous activity, which appears to be due to direct hypothalamic effects and is mediated by neuropeptide systems such as the melanocortin system and corticotropin-releasing hormone. Renal sympathoactivation to leptin is preserved in the presence of obesity, despite resistance to the metabolic effects of leptin. Such selective leptin resistance, in the context of circulating hyperleptinemia, could predispose to obesity-related hypertension. Some in vitro studies have suggested that leptin may have peripheral actions such as endothelium-mediated vasodilation that might oppose sympathetically induced vasoconstriction. However, we and others have shown that leptin does not have direct vasodilator effects in vivo. The fact that chronic leptin administration or overexpression of leptin produces hypertension supports the concept that the hemodynamic actions of leptin are due predominantly to sympathetic activation. Exploration of the sites and mechanisms of leptin resistance should provide novel therapeutic strategies for obesity, insulin resistance, and hypertension.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that leptin’s cardiovascular actions are mediated predominantly by sympathetic activation, with selective leptin resistance preserving renal sympathoactivation despite resistance to leptin’s metabolic effects. It proposes this mechanism may help explain obesity-related hypertension, while in vivo evidence does not support a meaningful direct vasodilator role for leptin.

Key findings

  • Leptin is a 167-amino acid adipocyte-derived hormone that circulates in lean subjects at 5–15 ng/ml and acts in the CNS to reduce food intake and increase energy expenditure; it also increases sympathetic nerve activity (SNA) to brown adipose tissue, kidney, hindlimb, and adrenal beds.
  • In animal models, leptin resistance can be selective: agouti obese mice showed reduced anorexic/weight-reducing responses to leptin but identical renal SNA responses versus lean littermates; MC4-R heterozygotes had 50% of the normal renal SNA response and homozygote knockouts had none.
  • Pressor evidence includes chronic leptin infusion increasing plasma leptin from 1 to 94 ng/ml for 12 days and raising arterial pressure and heart rate; leptin-overexpressing transgenic mice had 10-fold higher plasma leptin and higher arterial pressure; leptin reconstitution in ob/ob mice increased systolic blood pressure by as much as 25 mmHg.
  • In humans, evidence is indirect: muscle SNA correlates positively with plasma leptin in healthy nondiabetic men, and leptin correlates with resting metabolic rate, but direct leptin infusion studies in humans are lacking; one child with congenital leptin deficiency lost 16 kg on leptin replacement without a change in arterial pressure.

Methods

  • Design: narrative review synthesizing experimental animal and human literature, including the authors’ own studies; no systematic review or meta-analysis is described.
  • Data/sample: cited animal models include Sprague-Dawley rats, ob/ob and db/db mice, Zucker rats, agouti obese mice, diet-induced obese mice, transgenic leptin-overexpressing mice, and nonhuman primates, alongside human observational and clinical reports.
  • Main analysis: qualitative synthesis of mechanisms and findings; no formal statistical pooling or primary data analysis is reported.

Limitations

  • Stated in the paper: direct evidence for leptin regulation of the sympathetic nervous system in humans is lacking because leptin infusion studies in humans are absent; mechanisms responsible for increased SNA in obesity remain unknown; the role of nitric oxide in blood pressure responses to leptin remains controversial; mechanisms by which leptin contributes to cardiovascular complications remain unknown; further animal experimentation is needed.
  • Evident from the text: many mechanistic conclusions rely on animal models, and much human evidence is correlational or indirect, so causal inference in humans is limited.
  • Evident from the text: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or formal quality assessment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/rp.59.1.225

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 118 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Leptin does not have direct vasodilator effects in vivo.

    “However, we and others have shown that leptin does not have direct vasodilator effects in vivo.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Leptin-induced increases in renal sympathetic nerve activity can be suppressed by baroreflex activation.

    “Leptin-induced increases in renal SNA can be suppressed by baroreflex activation, suggesting that the increase in renal SNA subserves circulatory functions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hausberg et al., 2002a

      Not checked in the free run.

  • Findingcitation

    Leptin, at a low dose that does not alter baseline sympathetic nerve activity, acutely enhances sympathetic outflow to brown adipose tissue in response to hypothermia in lean rats.

    “Leptin, at a low dose that does not alter baseline SNA, acutely enhances sympathetic outflow to BAT in response to hypothermia in lean rats.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hausberg et al., 2002b

      Not checked in the free run.

  • Findingcitation

    Renal sympathoactivation to leptin is preserved in the presence of obesity, despite resistance to the metabolic effects of leptin.

    “Renal sympathoactivation to leptin is preserved in the presence of obesity, despite resistance to the metabolic effects of leptin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Correia et al., 2002

      Not checked in the free run.

    • cites Rahmouni et al., 2002

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  • Findingcitation

    Sympathoactivation to intravenous leptin can be abolished completely by selective lesioning of the hypothalamic arcuate nucleus.

    “Third, sympathoactivation to intravenous leptin can be abolished completely by selective lesioning of the hypothalamic arcuate nucleus (Haynes, 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Haynes, 2000

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  • May combine two claims. 24
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Findingcitation

    Leptin-induced sympathoexcitation remains apparent after transection of the sympathetic nerves distal to the recording site and disappears after ganglion blockade with intravenous chlorisondamide.

    “First, leptin-induced sympathoexcitation remains apparent after transection of the sympathetic nerves distal to the recording site and disappears after ganglion blockade with intravenous chlorisondamide (Haynes et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Haynes et al., 1997

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  • May combine two claims.

    Findingcitation

    Direct administration of leptin to the third cerebral ventricle, at subsystemic doses, increases sympathetic nerve activity and dose-dependently increases plasma catecholamines.

    “Second, direct administration of leptin to the third cerebral ventricle, at subsystemic doses, increases SNA (Haynes, 2000) and dose-dependently increases plasma catecholamines (Satoh et al., 1999).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Haynes, 2000

      Not checked in the free run.

    • cites Satoh et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Chronic leptin administration or overexpression of leptin produces hypertension.

    “The fact that chronic leptin administration or overexpression of leptin produces hypertension supports the concept that the hemodynamic actions of leptin are due predominantly to sympathetic activation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Shek et al., 1998

      Not checked in the free run.

    • cites Aizawa-Abe et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    There is a gene dose effect, with MC4-R heterozygotes having 50% of the normal response to leptin and homozygote knockouts having no renal sympathetic nerve activity response to leptin.

    “Indeed, we have shown a gene dose effect, with MC4-R heterozygotes having 50% of the normal response to leptin and homozygote knockouts having no renal SNA response to leptin (Rahmouni et al., 2003b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rahmouni et al., 2003b

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Both LY294002 and wortmannin markedly attenuate the increase in renal sympathetic nerve activity induced by leptin, without affecting sympathoactivation to stimulation of the melanocortin system.

    “Both LY294002 and wortmannin markedly attenuated the increase in renal SNA induced by leptin, without affecting sympathoactivation to stimulation of the melanocortin system (Rahmouni et al., 2003a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rahmouni et al., 2003a

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A CRH receptor antagonist blocks leptin-induced sympathoactivation to brown adipose tissue but not to the kidney.

    “Our results show that a CRH receptor antagonist blocked leptin-induced sympathoactivation to BAT but not to the kidney (Correia et al., 2001a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Correia et al., 2001a

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In diet-induced obese mice, lumbar sympathetic nerve activity responses to leptin are attenuated, as compared to lean mice, whereas leptin-induced increases in renal sympathetic nerve activity occur with the same time course and magnitude in both diet-induced obese and lean mice.

    “Second, in diet-induced obese mice, lumbar SNA responses to leptin are attenuated, as compared to lean mice, whereas leptin-induced increases in renal SNA occur with the same time course and magnitude in both diet-induced obese and lean mice (K.Rahmouni, D.A. Morgan, A.L. Mark, W.G. Haynes, unpublished data).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites K.Rahmouni, D.A. Morgan, A.L. Mark, W.G. Haynes, unpublished data

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Blockade of the adrenergic system or nitric oxide synthase did not reveal any pressor effect of leptin.

    “Blockade of the adrenergic system or NO synthase did not reveal any pressor effect of leptin (Mitchell et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mitchell et al., 2001

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Leptin caused significant increases in both renal and brown adipose tissue sympathetic nerve activity.

    “Leptin caused significant increases in both renal and BAT SNA.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some genetic models of obesity (e.g., the Zucker fatty rat, agouti obese mouse) are used as models of obesity hypertension.

    “Some genetic models of obesity (e.g., the Zucker fatty rat, agouti obese mouse) are also used as models of obesity hypertension (Kurtz et al., 1989;Mark et al., 1999).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kurtz et al., 1989

      Not checked in the free run.

    • cites Mark et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin is a 167-amino acid protein expressed mainly by adipocytes and released in the blood in proportion to the size of adipose tissue.

    “This hormone is a 167-amino acid protein expressed mainly by adipocytes and released in the blood in proportion to the size of adipose tissue, which is consistent with leptin's role as a signal of the energy stores (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al., 1994

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Enhanced sympathetic nerve activity is a common feature of obesity, which would play a major role in obesity-induced hypertension and cardiovascular disease.

    “These findings demonstrate that enhanced SNA is a common feature of obesity, which would play a major role in obesity-induced hypertension and cardiovascular disease (Hall et al., 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hall et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin action in the central nervous system promotes weight loss by decreasing food intake and increasing energy expenditure.

    “Leptin action in the CNS promotes weight loss by decreasing food intake and increasing energy expenditure (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Friedman and Halaas, 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight loss induced by low-calorie diet or gastric bypass reduces arterial pressure and corrects diabetes and other comorbidities associated with obesity.

    “Subsequently, clinical studies have demonstrated that weight loss induced by low-calorie diet or gastric bypass reduces arterial pressure and corrects diabetes and other comorbidities associated with obesity (Carson et al., 1994;Richards et al., 1996).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carson et al., 1994

      Not checked in the free run.

    • cites Richards et al., 1996

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity is associated with circulating hyperleptinemia, reflecting resistance to leptin because, despite high circulating levels of leptin, such subjects remain obese.

    “Obesity is known to be associated with circulating hyperleptinemia, reflecting resistance to leptin because, despite high circulating levels of leptin, such subjects remain obese (Considine et al., 1996).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Considine et al., 1996

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Epidemiological studies have documented a close relationship between body mass index (BMI) and cardiovascular events.

    “Epidemiological studies have documented a close relationship between body mass index (BMI) and cardiovascular events (Hubert et al., 1983;Kushner, 1993;Kopelman, 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hubert et al., 1983

      Not checked in the free run.

    • cites Kushner, 1993

      Not checked in the free run.

    • cites Kopelman, 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin is an adipocyte-derived hormone that acts in the central nervous system to promote weight loss by decreasing food intake and increasing metabolic rate.

    “Leptin is an adipocyte-derived hormone that acts in the central nervous system to promote weight loss by decreasing food intake and increasing metabolic rate.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhang et al., 1994

      Not checked in the free run.

    • cites Friedman and Halaas, 1998

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Long-term renal sympathetic stimulation by leptin would be expected to raise arterial pressure by causing vasoconstriction and by increasing renal tubular sodium reabsorption.

    “Long-term renal sympathetic stimulation by leptin would be expected to raise arterial pressure by causing vasoconstriction and by increasing renal tubular sodium reabsorption.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Leptin causes regional sympathoactivation via different neuropeptide pathways, with melanocortins mediating renal sympathoactivation and CRF mediating brown adipose tissue sympathetic nerve activity to leptin.

    “In summary, leptin appears to causes regional sympathoactivation via different neuropeptide pathways, with melanocortins mediating renal sympathoactivation and CRF mediating BAT SNA to leptin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intravenous infusion of leptin at a dose that increased plasma leptin from 1 to 94 ng/ml for 12 days increased arterial pressure and heart rate, despite a decrease in food intake that would be expected to decrease arterial pressure.

    “Shek et al. (1998) demonstrated that intravenous infusion of leptin at a dose that increased plasma leptin from 1 to 94 ng/ml for 12 days increased arterial pressure and heart rate, despite a decrease in food intake that would be expected to decrease arterial pressure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shek et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta 1 synthesis, and type IV collagen production.

    “In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta 1 (TGF-␤ 1 ) synthesis, and type IV collagen production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wolf et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Leptin may produce a modest antinatriuretic effect, probably due to activation of renal sympathetic nerve activity, that opposes pressure natriuresis.

    “This study (Shek et al., 1998) provided no support for a significant natriuretic action of leptin and instead suggested that leptin actually may produce a modest antinatriuretic effect (probably due to the activation of the renal SNA) that opposes pressure natriuresis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shek et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mesangial cells, leptin stimulates glucose transport and type I collagen production.

    “Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-␤ type II receptor, but not TGF-␤ 1 , and stimulates glucose transport and type I collagen production (Wolf et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wolf et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mesangial cells, leptin upregulates synthesis of the TGF-beta type II receptor but not TGF-beta 1.

    “Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-␤ type II receptor, but not TGF-␤ 1 , and stimulates glucose transport and type I collagen production (Wolf et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wolf et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The role of nitric oxide in blood pressure responses to leptin remains controversial, and consistent negative results in conscious animals argue against a meaningful stimulation of nitric oxide generation.

    “Thus, the role of NO in blood pressure responses to leptin remains controversial but consistent negative results of studies in conscious animals argue against a meaningful stimulation of NO generation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nitric oxide is a potent vasodilator and one of the most important vasoactive factors released by endothelial cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The PI3-K pathway appears to be involved in modulation of neuronal firing rate via activation of KATP channels.

    “The PI3-K pathway also appears to be involved in the modulation of neuronal firing rate via the activation of the potassium-adenosine triphosphate channels (K ATP ).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Leptin has diverse cardiovascular actions, although sympathoactivation is probably the most important.

    “Leptin has diverse cardiovascular actions, although sympathoactivation is probably the most important.”
    Quote in the paperNot a substantial claim
27 of 27

  • The paper relies on this without support.

    Proinflammatory cytokines promote hypertension.

    “that are known to promote hypertension”

  • The paper relies on this without support.

    Weight loss would be expected to lower arterial pressure substantially.

    “This weight loss would be expected to lower arterial pressure substantially”

  • The paper relies on this without support.

    Nitric oxide is a potent vasodilator and one of the most important vasoactive factors released by endothelial cells.

    “Endothelial cells release several vasoactive factors, of which nitric oxide (NO) is perhaps the most important with potent vasodilator action.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Leptin may impact myocardial function via direct peripheral effects or via secondary central nervous system-mediated responses, and there is an extensive literature documenting that leptin can influence many parameters associated with obesity and heart failure.

    “Importantly, leptin may impact on myocardial function via direct peripheral effects or via secondary central nervous system-mediated responses, and there is an extensive literature documenting that leptin can influence many parameters associated with obesity and heart failure (216, 289).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [289]

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Authors
Rahmouni, K.
Affiliations
University of Iowa (US)
Corresponding author
Rahmouni, K.
ORCID
Rahmouni, K.
Venue
Recent Progress in Hormone Research
Publisher
The Endocrine Society
Published
2004-01-01
Volume
59
Issue
1
Pages
225-244
ISSN
0079-9963 (ISSN-L)
DOI
10.1210/rp.59.1.225
OpenAlex
W2017356413
Semantic Scholar
ff945797b84cf3af7c5b73569fed53b073d6e072
Cited by
110
References
110
Citations by year
2025: 1 · 2024: 2 · 2023: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 13 · 2012: 7
FWCI
0.97
Type
journal article
Language
en
Open access
Locations
  • Recent Progress in Hormone Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5p50hl044546-05)
  • National Heart, Lung, and Blood Institute (HL-14388, HL-44546, P01HL014388)
  • National Center for Research Resources (RR 00059, M01RR000059)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
Keywords
leptin, cardiovascular system, obesity, hypertension, leptin resistance, sympathetic activity, hypothalamic regulation, melanocortin system, corticotropin-releasing factor, hyperleptinemia, vasodilation, insulin resistance
MeSH terms
Animals, Blood Pressure, Cardiovascular Diseases, Cardiovascular System, Humans, Kidney, Obesity, Receptors, Cell Surface, Sympathetic Nervous System, Signal Transduction, Leptin, Receptors, Leptin

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