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Cited by 89Receptor Mechanisms and SignalingCardiovascular Function and Risk FactorsAdipose Tissue and Metabolism

Adrenergic receptors and metabolism: role in development of cardiovascular disease

Open access
Ciccarelli, Michele, Santulli, Gaetano, Pascale, Valeria, Trimarco, Bruno, Iaccarino, Guido·2013·Frontiers in Physiology
DOI 10.3389/fphys.2013.00265PMC PMC3789271
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Abstract

Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: (1) increased lipolysis and elevated levels of fatty acids in plasma, (2) increased gluconeogenesis by the liver to provide substrate for the brain, and (3) moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies, however, they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that chronic over-activation of the adrenergic system drives metabolic alterations—insulin resistance, altered glucose and lipid metabolism, and mitochondrial dysfunction—that contribute to the development and progression of heart failure. It focuses on the divergent roles of β1- and β2-adrenergic receptors and proposes GRK2 as a molecular link between chronic adrenergic stimulation and impaired myocardial glucose uptake.

Key findings

  • Cardiac muscle generates ATP almost exclusively (about 90%) through oxidative phosphorylation, with fatty acid oxidation as the major pathway in the adult heart and increased glucose contribution during stress or injury.
  • Chronic adrenergic stimulation produces metabolic responses including increased lipolysis and elevated plasma fatty acids, increased hepatic gluconeogenesis, and moderate inhibition of pancreatic insulin release; when sustained, these become detrimental, contributing to insulin resistance, altered glucose and lipid metabolism, and mitochondrial dysfunction.
  • β1- and β2-adrenergic receptors regulate different signaling pathways: β1 primarily signals via Gαs/AC/cAMP/PKA to regulate contractility, relaxation and rate, whereas β2 signals via Gαi/Gβγ and PI3K, and is implicated in overall glucose homeostasis and in modulating fatty acid and glucose metabolism.
  • Acute β2-AR activation increases glucose uptake in myocytes and skeletal muscle (comparable to insulin stimulation) via PI3K/Akt-mediated phosphorylation of TBC1D4/AS160 and AMPK; however, chronic β2-AR stimulation is detrimental, and GRK2 upregulation in the failing heart impairs myocardial glucose uptake at early disease stages, before cardiac dilation and reduced function are evident.

Methods

  • Narrative review article; no primary data, systematic search strategy, or meta-analysis is described.
  • Synthesizes published animal-model, in vitro, ex vivo, and human imaging/physiological studies on adrenergic signaling, cardiac substrate metabolism, insulin resistance, and heart failure, including PET studies of myocardial glucose and fatty acid uptake and studies of GRK2.
  • No formal data extraction, quality appraisal, or quantitative synthesis is reported.

Limitations

  • The paper does not state explicit limitations; it is a narrative review without a described systematic search or inclusion criteria.
  • Evident from the text: the review itself notes conflicting results in the literature (e.g., β2-AR stimulation increasing glucose uptake acutely versus impaired glucose extraction with stable β2-AR overexpression, and opposing findings on mitochondrial GRK2 as protective versus pro-death), which the author attributes to differences in models and acute versus chronic stimulation; these discrepancies remain unresolved.
  • Evident from the text: the central GRK2 hypothesis linking chronic adrenergic stimulation to altered myocardial metabolism is presented as a proposed synthesis requiring further study ("Further studies will be needed to evaluate this hypothesis").

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

Integrity signals

Registry

Crossref · 10.3389/fphys.2013.00265

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 60 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Cardiac insulin resistance contributes to the development of left ventricular dysfunction by reducing cardiac efficiency through metabolic shift toward fatty acids utilization.

    “cardiac insulin resistance contributes to the development of left ventricular (LV) dysfunction by reducing cardiac efficiency through metabolic shift toward fatty acids utilization (Peterson et al., 2004b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Peterson et al., 2004b

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  • Premisecitation

    Cardiac muscle generates ATP almost exclusively (about 90%) through oxidative phosphorylation.

    “cardiac muscle generates ATP almost exclusively (about 90%) through oxidative phosphorylation (Stanley et al., 2005)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stanley et al., 2005

      Not checked in the free run.

  • Premisecitation

    Impairment of cardiac muscle energy metabolism represents an important risk factor for the development of cardiac diseases.

    “an impairment of cardiac muscle energy metabolism represents an important risk factor for the development of cardiac diseases (Stanley et al., 2005; Neubauer, 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Stanley et al., 2005

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    • cites Neubauer, 2007

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  • Premisecitation

    Heart function relies to a great extent on cardiac muscle oxidative metabolism.

    “Heart function relies to a great extent on cardiac muscle oxidative metabolism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stanley et al., 2005

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  • Premisecitation

    Insulin receptor signaling is critically involved in increasing glucose uptake in the myocardium.

    “Insulin receptor signaling is critically involved in increasing glucose uptake in the myocardium”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Peterson et al., 2004b

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  • May combine two claims. 20
  • Classified as probably not a substantial claim. 3
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Neurohormonal activation increases plasma FFA levels, inhibits insulin receptor signaling and causes the loss of myocyte glucose uptake.

    “neurohormonal activation (Kostis and Sanders, 2005; Zucker, 2006), which increases plasma FFA levels, inhibits insulin receptor signaling and causes the loss of myocyte glucose uptake (Opie and Sack, 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Opie and Sack, 2002

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    Interpretationcitation

    Cardiac insulin resistance reduces the metabolic efficiency of the heart, which leads to a contractile dysfunction.

    “these studies indicate that cardiac insulin resistance reduces the metabolic efficiency of the heart, which leads to a contractile dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Insulin resistance is a known and recognized phenomenon leading to heart failure, as seen in PET studies showing that the failing human myocardium has reduced glucose uptake in favor of FFA uptake.

    “insulin resistance is a known and recognized phenomenon leading to HF (Boudina et al., 2009) as seen in positron emission tomographic (PET) studies showing that the failing human myocardium has reduced glucose uptake in favor of FFA uptake (Witteles et al., 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Boudina et al., 2009

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    • cites Witteles et al., 2004

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    Premisecitation

    This metabolic remodeling is characterized by a lower oxidative capacity, contractile dysfunction and cardiac muscle insulin resistance.

    “This metabolic remodeling is characterized by a lower oxidative capacity, contractile dysfunction and cardiac muscle insulin resistance (Stanley et al., 2005; Neubauer, 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Stanley et al., 2005

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    • cites Neubauer, 2007

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    Premisecitation

    In both animal models of heart failure and human disease these metabolic alterations reduce myocardial oxygen efficiency and lead to a depletion of intracellular ATP.

    “in both animal models of HF and in human disease these metabolic alterations reduce myocardial oxygen efficiency and lead to a depletion of intracellular ATP (Neubauer et al., 1992; Taylor et al., 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Neubauer et al., 1992

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    • cites Taylor et al., 2001

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    Premisecitation

    In the adult heart the major pathway for ATP production is fatty acid oxidation, while the relative contribution of glucose increases during stress or injury such as exercise or ischemia.

    “In the adult heart the major pathway for ATP production is fatty acid oxidation while the relative contribution of glucose increases during stress or injury, such as exercise or ischemia (Bing et al., 1954; Wisneski et al., 1987).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bing et al., 1954

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    • cites Wisneski et al., 1987

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  • May combine two claims.

    Premisecitation

    The Sympathetic Nervous System is maladaptively activated in response to a chronic reduction in cardiac output and is characterized by an increased secretion and reduced cardiac catecholamine reuptake.

    “The Sympathetic Nervous System (SNS) is maladaptively activated in response to a chronic reduction in cardiac output and it is characterized by an increased secretion and reduced cardiac catecholamine reuptake (Eisenhofer et al., 1996).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eisenhofer et al., 1996

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    Premisecitation

    A profound state of insulin resistance has been found in the hearts of ob/ob mice and the ability of these hearts to modulate substrate utilization in response to insulin and changes is altered.

    “a profound state of insulin resistance has been found in the hearts of ob/ob mice and the ability of these hearts to modulate substrate utilization in response to insulin and changes is altered (Mazumder et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mazumder et al., 2004

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    Premisecitation

    FFA-mediated activation of protein kinase C phosphorylates insulin receptors and results in reduced capillary opening and reduced myocyte glucose import.

    “FFA-mediated activation of protein kinase C, which phosphorylates insulin receptors and results in reduced capillary opening and reduced myocyte glucose import (Itani et al., 2002; Wagenmakers et al., 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Itani et al., 2002

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    • cites Wagenmakers et al., 2006

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    Premisecitation

    Norepinephrine promotes both coronary vasoconstriction and increased plasma FFA levels.

    “norepinephrine promotes both coronary vasoconstriction and increased plasma FFA levels (Paolisso et al., 1991)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Paolisso et al., 1991

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    Premisecitation

    Increased catecholamines have directly detrimental effects on the heart, which cause marked enzyme loss as an index of diffuse myocardial damage, and substantial oxygen-wastage even in the absence of FFA in the perfusate.

    “increased catecholamines have directly detrimental effects on the heart, which cause marked enzyme loss as an index of diffuse myocardial damage, and substantial oxygen-wastage even in the absence of FFA in the perfusate (Opie et al., 1979).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Opie et al., 1979

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  • May combine two claims.

    Premisecitation

    TBC1D4 inhibits the translocation of GLUT4 from intracellular vesicles to the plasma membrane, hence an increase in TBC1D4 phosphorylation would consequently enhance glucose uptake.

    “TBC1D4 inhibit the translocation of the glucose transporter type4 (GLUT4) from intracellular vesicles to the plasmamembrane, hence an increase in TBC1D4 phosphorylation would consequently enhance glucose uptake (Sakamoto and Holman, 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sakamoto and Holman, 2008

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  • May combine two claims.

    Premisecitation

    In vivo studies demonstrated a greater efficiency of carvedilol, a non-selective β-AR antagonist, in ameliorating myocardial insulin sensitivity and glucose extraction in animal model of heart failure as compared to metoprolol, a selective β1-AR antagonist, indicating that antagonism of β2AR positively regulates cardiac glucose metabolism in an animal model of heart failure.

    ““in vivo” studies demonstrated a greater efficiency of carvedilol, a non-selective β-AR antagonist, in ameliorating myocardial insulin sensitivity and glucose extraction in animal model of HF as compared to metoprolol, a selective β1-AR antagonist, indicating that antagonism of β2AR positively regulates cardiac glucose metabolism in an animal model HF (Nikolaidis et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nikolaidis et al., 2006

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    Premisecitation

    Ischemia causes acute cellular and mitochondrial accumulation of GRK2, an effect reverted by oxygen restoration, but it preserves ATP loss and induces mitochondria biogenesis after ischemia/reperfusion, indicating a protective effect of GRK2 for mitochondria after acute stress.

    “ischemia causes acute cellular and mitochondrial accumulation of GRK2 (Fusco et al., 2012), an effect reverted by oxygen restoration, but, surprisingly it preserves ATP loss and induces mitochondria biogenesis after ischemia/reperfusion, indicating a protective effect of GRK2 for mitochondria after acute stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fusco et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While acute activation of the receptor can favor glucose uptake by increasing GLUT4 translocation to the plasma membrane, chronic adrenergic stimulation, as seen during heart failure, would be rather detrimental by up or down regulation of specific intracellular molecules.

    “While acute activation of the receptor can favor glucose uptake by increasing GLUT4 translocation to the plasmamembrane, chronic adrenergic stimulation, as seen during HF, would be rather detrimental by up or down regulation of specific intracellular molecules.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Premisenone given

    Increased circulating catecholamine and activation of the different adrenergic receptors produce increased gluconeogenesis by the liver to provide substrate for the brain.

    “(2) increased gluconeogenesis by the liver to provide substrate for the brain”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    GRK2 is protective for the cell by increasing ATP production and promoting mitogenesis.

    “Fusco et al. have indicated that GRK2 is protective for the cell by increasing ATP production and promoting mitogenesis (Fusco et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fusco et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GRK2 affects myocardial glucose uptake at the early stages of the disease, before cardiac dilation and reduced function are evident, indicating that metabolic modifications are relevant in the progression of heart failure and to be the molecular link between over-activation of the adrenergic system and the altered glucose uptake during heart failure.

    “GRK2 is upregulated (Iaccarino et al., 2005) and affects myocardial glucose uptake at the early stages of the disease, before cardiac dilation and reduced function are evident, indicating that metabolic modifications are relevant in the progression of HF and to be the molecular link between over-activation of the adrenergic system and the altered glucose uptake during HF (Ciccarelli et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Iaccarino et al., 2005

      Not checked in the free run.

    • cites Ciccarelli et al., 2011

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

    Interpretationreasoning

    These conflicting results may rely on the different models used for studies and/or to differences in acute and chronic stimulation of the β2AR.

    “These conflicting results may rely on the different models used for studies and/or to differences in acute and chronic stimulation of the β2AR.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Current available compounds acting on the β adrenergic receptors seem to be effective for the goals of efficient metabolic supply and counteracting oxygen wastage and increased ROS in myocardial dysfunction.

    “Current available compounds acting on the β ARs seem to be effective for these goals”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These metabolic patterns are involved with a variable extent among different pathologies, but in general they are strictly correlated to the level of activation of the adrenergic system.

    “These patterns are involved with a variably extent among the different pathologies, however, they are in general strictly correlated to the level of activation of the adrenergic system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Increased circulating catecholamine and activation of the different adrenergic receptors produce moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation.

    “(3) moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation.”
    Quote in the paperNot a substantial claim
22 of 22

  • The paper relies on this without support.

    The mechanisms of adrenergic regulation of cardiac metabolism observed in animal and cell models apply to human heart failure.

    “Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.”
1 of 1

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?

  • Activation of the adrenergic system has profound effects on metabolism, and prolonged activation can lead to insulin resistance, alterations in glucose and fatty acid metabolism, and mitochondrial dysfunction.

    “Activation of the adrenergic system also has profound effect on metabolism and prolonged activation can lead to insulin resistance, alterations in glucose and fatty acid metabolism and mitochondrial dysfunction (Ciccarelli et al., 2013; Fu et al., 2017).”

    From A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors (2020) · cites this paper as Ciccarelli et al., 2013

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Two different articles are assigned the same DOI

    Minor

    The references assign DOI 10.1161/CIRCRESAHA.112.300754 to two articles with different titles, journals, and publication years. A DOI identifies a single publication, so both entries cannot be correct.

1 of 1

Cites

1 retracted

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1 of the 59 references couldn’t be matched to a known paper.

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Related

Authors
Ciccarelli, M., Santulli, G., Pascale, V., Trimarco, B., & Iaccarino, G.
Affiliations
  • University of Salerno (IT)
  • University of Naples Federico II (IT)
Corresponding author
Ciccarelli, Michele
ORCID
Venue
Frontiers in Physiology
Publisher
Frontiers Media SA
Published
2013
Volume
4
Pages
265-265
ISSN
1664-042X (ISSN-L)
DOI
10.3389/fphys.2013.00265
PMC
PMC3789271
OpenAlex
W2019786374
Semantic Scholar
489d6a6b203e081a82d47796ebaa168486207b89
Cited by
89
References
59
Citations by year
2026: 6 · 2025: 5 · 2024: 13 · 2023: 9 · 2022: 10 · 2021: 7 · 2020: 5 · 2019: 10 · 2018: 3 · 2017: 6 · 2016: 6 · 2015: 5 · 2014: 4
FWCI
0.47
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Physiology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
adrenergic receptors, catecholamines, cardiovascular disease, heart failure, lipolysis, gluconeogenesis, insulin resistance, mitochondrial dysfunction, fatty acid oxidation, chronic stress, glucose metabolism, lipid metabolism

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