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Cited by 38Regulation of Appetite and ObesityNeuropeptides and Animal PhysiologyBlood Pressure and Hypertension Studies

Role of the brain melanocortins in blood pressure regulation

Open access
do Carmo, Jussara M., da Silva, Alexandre A., Wang, Zhen, Fang, Taolin, Aberdein, Nicola, Perez de Lara, Cecilia E., Hall, John E.·2017·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
DOI 10.1016/j.bbadis.2017.03.003PMC PMC5587353
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Abstract

Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals. In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity. Activation of the central nervous system (CNS) pro-opiomelanocortin (POMC)–MC4R pathway appears to be an important link between obesity, SNS activation and hypertension. Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function. In this review we discuss the importance of the brain POMC-MC4R system in regulating SNS activity and BP in obesity and other forms of hypertension. We also highlight potential mechanisms and brain circuitry by which the melanocortin system regulates cardiovascular function.

AI snapshot

Written from the paper’s full text.

TL;DR

The brain POMC–MC4R melanocortin pathway is a key regulator of sympathetic nervous system activity and blood pressure, linking obesity to hypertension. Blocking MC4R lowers blood pressure in several high-sympathetic models, while chronic MC4R activation can raise blood pressure, complicating therapeutic use of MC4R agonists for obesity and diabetes.

Key findings

  • Central POMC–MC4R activation increases SNS activity and BP; MC4R blockade reduces BP in experimental hypertension with high SNS activity despite causing hyperphagia and obesity.
  • Humans with MC4R deficiency have lower BP, reduced 24-hr norepinephrine excretion, and reduced prevalence of hypertension despite severe obesity; POMC or MC4R mutations are estimated to account for as much as 5–6% of early-onset obesity.
  • MC4R antagonism lowers BP in spontaneously hypertensive rats (SHR) and in L-NAME–induced hypertension, but not in angiotensin II–induced hypertension; 12-day CNS MC4R blockade caused greater BP reduction in SHR than in normotensive Sprague-Dawley or Wistar-Kyoto rats.
  • MC4R agonists can reduce food intake and body weight but may raise BP/HR: LY2112688 caused dose-dependent BP and HR increases sustained over 7 days, whereas RM-493 caused a 35% transient decrease in food intake with no significant BP/HR increases over 8 weeks in obese nonhuman primates, and setmelanotide produced 51.0 kg loss after 42 weeks and 20.5 kg after 12 weeks in two POMC-deficient patients without significant BP/HR increases.

Methods

  • Narrative review synthesizing published experimental animal and human studies on POMC-derived melanocortins, MC3R/MC4R, SNS activity, and BP regulation.
  • No primary data collection, systematic search strategy, or meta-analysis is described; evidence is presented qualitatively from cited literature.

Limitations

  • Stated: the specific brain regions and neuronal populations mediating MC4R effects on SNS activity and BP are still largely unknown; downstream mediators of MC4R cardiovascular actions remain unclear; long-term protective actions and whether targeting MC4R is effective in shock are poorly understood.
  • Evident: as a narrative review, it lacks systematic search and quality appraisal, and conclusions rely on heterogeneous animal models with limited human data.
  • Evident: many mechanistic claims derive from acute pharmacological injections, and the paper itself notes that the physiological significance of acute γ-MSH pressor actions is unclear.

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

Integrity signals

Registry

Crossref · 10.1016/j.bbadis.2017.03.003

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 169 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Subjects with melanocortin-4 receptor deficiency exhibit reductions in heart rate compared to obese subjects with normal melanocortin-4 receptor function despite severe obesity.

    “Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Greenfield JR Melanocortin signalling and the regulation of blood pressure in human obesity J Neuroendocrinol 2011 23 2 186 93 21062377 source

      Not checked in the free run.

  • Premisecitation

    ACTH-induced hypertension depends on intact adrenal gland function since adrenal insufficiency or adrenalectomy prevents increased blood pressure in subjects with high levels of ACTH.

    “ACTH-induced hypertension depends on intact adrenal gland function since adrenal insufficiency or adrenalectomy prevents increased BP in subjects with high levels of ACTH [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Whitworth JA Species variability in cardiovascular research: the example of adrenocorticotrophin-induced hypertension Clin Exp Pharmacol Physiol 2006 33 9 887 91 16922827 source

      Not checked in the free run.

  • Premisenone given

    Some melanocortins such as ACTH and γ-MSH function as circulating hormones to influence blood pressure regulation via multiple neurohumoral and renal mechanisms.

    “Some of the melanocortins such as ACTH and γ-MSH function as circulating hormones to influence BP regulation via multiple neurohumoral and renal mechanisms.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The melanocortin system also plays an important role in regulating sympathetic nervous system activity and blood pressure besides its effects on food intake and body weight regulation.

    “Besides its effects on food intake and body weight regulation, the melanocortin system also plays an important role in regulating SNS activity and BP.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [2] Corander MP Fenech M Coll AP Science of self-preservation: how melanocortin action in the brain modulates body weight, blood pressure, and ischemic damage Circulation 2009 120 22 2260 8 19948994 PMC2880450 source

      Not checked in the free run.

    • cites [5] Tsatmali M Skin POMC peptides: their actions at the human MC-1 receptor and roles in the tanning response Pigment Cell Res 2000 13 Suppl 8 125 9 11041369 source

      Not checked in the free run.

    • cites [6] Torda C Wolff HG Effects of adrenocorticotrophic hormone, cortisone acetate, and 17-hydroxycorticosterone-21-acetate on acetylcholine metabolism Am J Physiol 1952 169 1 150 8 14923875 source

      Not checked in the free run.

    • cites [7] Cheung WW Mak RH Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease Am J Physiol Renal Physiol 2012 303 9 F1315 24 22914778 PMC3518185 source

      Not checked in the free run.

    • cites [8] Bariohay B Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control Endocrinology 2009 150 6 2646 53 19179431 source

      Not checked in the free run.

    • cites [9] Hall JE Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins J Biol Chem 2010 285 23 17271 6 20348094 PMC2878489 source

      Not checked in the free run.

  • Premisecitation

    ACTH greatly enhances the chronic blood pressure effects of norepinephrine or angiotensin II through mechanisms that are independent of increased glucocorticoids.

    “ACTH also greatly enhances the chronic BP effects of norepinephrine or angiotensin II through mechanisms that are independent of increased glucocorticoids [12].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Woods LL Mizelle HL Hall JE Control of sodium excretion in NE-ACTH hypertension: role of pressure natriuresis Am J Physiol 1988 255 6 Pt 2 R894 900 2849322

      Not checked in the free run.

  • May combine two claims. 19
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Melanocortins play an important role in regulating blood pressure and sympathetic nervous system activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals.

    “Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [2] Corander MP Fenech M Coll AP Science of self-preservation: how melanocortin action in the brain modulates body weight, blood pressure, and ischemic damage Circulation 2009 120 22 2260 8 19948994 PMC2880450 source

      Not checked in the free run.

    • cites [5] Tsatmali M Skin POMC peptides: their actions at the human MC-1 receptor and roles in the tanning response Pigment Cell Res 2000 13 Suppl 8 125 9 11041369 source

      Not checked in the free run.

    • cites [6] Torda C Wolff HG Effects of adrenocorticotrophic hormone, cortisone acetate, and 17-hydroxycorticosterone-21-acetate on acetylcholine metabolism Am J Physiol 1952 169 1 150 8 14923875 source

      Not checked in the free run.

    • cites [7] Cheung WW Mak RH Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease Am J Physiol Renal Physiol 2012 303 9 F1315 24 22914778 PMC3518185 source

      Not checked in the free run.

    • cites [8] Bariohay B Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control Endocrinology 2009 150 6 2646 53 19179431 source

      Not checked in the free run.

    • cites [9] Hall JE Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins J Biol Chem 2010 285 23 17271 6 20348094 PMC2878489 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    γ-MSH has pro-hypertensive as well as antihypertensive actions.

    “Previous studies have suggested that γ-MSH has pro-hypertensive as well as antihypertensive actions [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Humphreys MH Ni XP Pearce D Cardiovascular effects of melanocortins Eur J Pharmacol 2011 660 1 43 52 21199648 PMC3086937 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic pharmacological activation of central nervous system MC4R in rats increased blood pressure while reducing appetite and body weight.

    “Chronic pharmacological activation of CNS MC4R in rats increased BP while reducing appetite and body weight [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Kuo JJ Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation Hypertension 2004 43 2 370 5 14707160 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute intracerebroventricular injections of α-MSH increase sympathetic nervous system activity and blood pressure.

    “Several previous studies have shown that acute ICV injections of α-MSH increase SNS activity and BP [19, 23, 24].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Ni XP Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones J Hypertens 2006 24 11 2239 46 17053546 source

      Not checked in the free run.

    • cites [23] Matsumura K Central alpha-melanocyte-stimulating hormone acts at melanocortin-4 receptor to activate sympathetic nervous system in conscious rabbits Brain Res 2002 948 1–2 145 8 12383966 source

      Not checked in the free run.

    • cites [24] Hill C Dunbar JC The effects of acute and chronic alpha melanocyte stimulating hormone (alphaMSH) on cardiovascular dynamics in conscious rats Peptides 2002 23 9 1625 30 12217423 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chronic physiological or pathophysiological stimulation of MC4R, which is activated mainly by α-MSH, generally increases blood pressure and is thought to play a key role in several forms of hypertension associated with increased sympathetic nervous system activity, including obesity-induced hypertension.

    “However, as discussed below, chronic physiological/pathophysiological stimulation of MC4R, which is activated mainly by α-MSH, generally increases BP and is thought to play a key role in several forms of hypertension associated with increased SNS activity, including obesity-induced hypertension.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The effects of α-MSH on blood pressure are mediated mainly by direct actions on the central nervous system since intravenous injections of α-MSH have no measurable effect on blood pressure.

    “The effects of α-MSH on BP are mediated mainly by direct actions on the CNS since i.v. injections of α-MSH have no measureable effect on BP [23, 24].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Matsumura K Central alpha-melanocyte-stimulating hormone acts at melanocortin-4 receptor to activate sympathetic nervous system in conscious rabbits Brain Res 2002 948 1–2 145 8 12383966 source

      Not checked in the free run.

    • cites [24] Hill C Dunbar JC The effects of acute and chronic alpha melanocyte stimulating hormone (alphaMSH) on cardiovascular dynamics in conscious rats Peptides 2002 23 9 1625 30 12217423 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blockade of central nervous system MC4R in rodents reduces blood pressure despite increasing appetite and causing rapid weight gain.

    “Blockade of CNS MC4R in rodents reduces BP despite increasing appetite and causing rapid weight gain which would normally increase BP [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] da Silva AA Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats Hypertension 2008 51 4 884 90 18285617 PMC2803054 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Injections of γ-MSH into the nucleus tractus solitarius lower blood pressure and heart rate.

    “Injections of γ-MSH (i.v. or ICV) have been reported to raise BP and HR, although injections into the NTS lower BP and HR [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Humphreys MH Ni XP Pearce D Cardiovascular effects of melanocortins Eur J Pharmacol 2011 660 1 43 52 21199648 PMC3086937 source

      Not checked in the free run.

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

    Premisecitation

    MC4R appears to be the dominant efferent arm of the actions of the brain melanocortin system on regulation of food intake and body weight.

    “Also, MC4R appears to be the dominant efferent arm of the actions of the brain melanocortin system on regulation of food intake and body weight [27, 28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Tallam LS da Silva AA Hall JE Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin Hypertension 2006 48 1 58 64 16754792 source

      Not checked in the free run.

    • cites [28] do Carmo JM Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice Am J Physiol Regul Integr Comp Physiol 2009 297 3 R803 12 19605765 PMC2739784 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Humans with leptin deficiency are generally not hypertensive and do not have increased sympathetic activity despite severe obesity, hyperinsulinemia, insulin resistance and most other characteristics of the metabolic syndrome.

    “Although leptin’s effects on SNS activity and BP in humans have not been extensively studied, humans with leptin deficiency are generally not hypertensive and do not have increased sympathetic activity despite severe obesity, hyperinsulinemia, insulin resistance and most other characteristics of the metabolic syndrome [49].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Ozata M Ozdemir IC Licinio J Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects J Clin Endocrinol Metab 1999 84 10 3686 95 10523015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with whole-body MC4R deficiency are completely unresponsive to the effects of leptin to reduce appetite and to raise blood pressure.

    “Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels [27, 28, 52]; moreover, these mice are completely unresponsive to the effects of leptin to reduce appetite and to raise BP [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Tallam LS da Silva AA Hall JE Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin Hypertension 2006 48 1 58 64 16754792 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In obese humans and obese rodents functional MC4Rs may be required for normal sympathetic responses to acute stress as well as increases in sympathetic nervous system activity and blood pressure.

    “These observations suggest that in obese humans and obese rodents functional MC4Rs may be required for normal sympathetic responses to acute stress as well as increases in SNS activity and BP.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Greenfield JR Melanocortin signalling and the regulation of blood pressure in human obesity J Neuroendocrinol 2011 23 2 186 93 21062377 source

      Not checked in the free run.

    • cites [55] Sayk F Sympathetic function in human carriers of melanocortin-4 receptor gene mutations J Clin Endocrinol Metab 2010 95 4 1998 2002 20147580 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels.

    “Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels [27, 28, 52]; moreover, these mice are completely unresponsive to the effects of leptin to reduce appetite and to raise BP [27].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Tallam LS da Silva AA Hall JE Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin Hypertension 2006 48 1 58 64 16754792 source

      Not checked in the free run.

    • cites [28] do Carmo JM Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice Am J Physiol Regul Integr Comp Physiol 2009 297 3 R803 12 19605765 PMC2739784 source

      Not checked in the free run.

    • cites [52] da Silva AA do Carmo JM Hall JE Role of leptin and central nervous system melanocortins in obesity hypertension Curr Opin Nephrol Hypertens 2013 22 2 135 40 23299052 PMC3905446 source

      Not checked in the free run.

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

    Premisecitation

    Mutations of the POMC gene or the MC4R are estimated to account for as much as 5-6% of early onset obesity in humans.

    “Mutations of the POMC gene or the MC4R are estimated to account for as much as 5–6% of early onset obesity in humans (48, 64).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Lim K Burke SL Head GA Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits Hypertension 2013 61 3 628 34 23339171 source

      Not checked in the free run.

    • cites [64] Nicholson JR Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function J Neuroendocrinol 2007 19 12 974 82 18001327 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The brain melanocortin system plays a key role in maintenance of sympathetic nervous system activity and blood pressure in normotensive subjects as well as in non-obese forms of hypertension that have increased sympathetic activity.

    “These findings highlight the key role of the brain melanocortin system in maintenance of SNS activity and BP in normotensive subjects as well as in non-obese forms of hypertension that have increased sympathetic activity [41, 42, 57, 58].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [41] Kuo JJ Silva AA Hall JE Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function Hypertension 2003 41 3 Pt 2 768 74 12623994 source

      Not checked in the free run.

    • cites [42] da Silva AA Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats Hypertension 2008 51 4 884 90 18285617 PMC2803054 source

      Not checked in the free run.

    • cites [57] da Silva AA Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion Hypertension 2015 65 1 171 7 25287400 PMC4267912 source

      Not checked in the free run.

    • cites [58] do Carmo JM Systemic but not central nervous system nitric oxide synthase inhibition exacerbates the hypertensive effects of chronic melanocortin-3/4 receptor activation Hypertension 2011 57 3 428 34 21263126 PMC3073740 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leptin receptor deletion specifically in POMC neurons completely abolished the chronic effects of leptin to raise blood pressure and to reduce plasma glucose and insulin levels.

    “Leptin receptor (LR) deletion specifically in POMC neurons completely abolished the chronic effects of leptin to raise BP and to reduce plasma glucose and insulin levels but did not markedly attenuate the effects of leptin on food intake [50].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] do Carmo JM Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons Hypertension 2011 57 5 918 26 21422382 PMC3092393 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blockade of central nervous system MC4R for 12 consecutive days caused a much greater reduction in blood pressure in spontaneously hypertensive rats than in normotensive Sprague-Dawley or Wistar-Kyoto rats despite causing marked hyperphagia, weight gain, and insulin resistance.

    “Blockade of CNS MC4R for 12 consecutive days caused a much greater reduction in BP in SHR than in normotensive Sprague-Dawley or Wistar-Kyoto rats despite causing marked hyperphagia, weight gain, and insulin resistance [42, 56].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] da Silva AA Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats Hypertension 2008 51 4 884 90 18285617 PMC2803054 source

      Not checked in the free run.

    • cites [56] da Silva AA Kuo JJ Hall JE Role of hypothalamic melanocortin 3/4-receptors in mediating chronic cardiovascular, renal, and metabolic actions of leptin Hypertension 2004 43 6 1312 7 15123576 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Leptin receptor activation in POMC neurons is critical for leptin's ability to increase blood pressure and improve glucose homeostasis but not for its effect to reduce food intake.

    “These findings suggest that LR activation in POMC neurons is critical for leptin’s ability to increase BP and improve glucose homeostasis but not for its effect to reduce food intake.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] do Carmo JM Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons Hypertension 2011 57 5 918 26 21422382 PMC3092393 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MC4R is a G protein-coupled 7 transmembrane receptor that increases cAMP phosphorylation and activates protein kinase A.

    “The MC4R is a G protein-coupled 7 transmembrane receptor that increases cAMP phosphorylation and activates protein kinase A (PKA) [3, 26, 63]; therefore, blockade of these intracellular pathways attenuates MC4R actions [3, 63].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Tao YX The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology Endocr Rev 2010 31 4 506 43 20190196 PMC3365848 source

      Not checked in the free run.

    • cites [26] Tai MH Role of nitric oxide in alpha-melanocyte-stimulating hormone-induced hypotension in the nucleus tractus solitarii of the spontaneously hypertensive rats J Pharmacol Exp Ther 2007 321 2 455 61 17283224 source

      Not checked in the free run.

    • cites [63] Li P Melanocortin 4 receptors in the paraventricular nucleus modulate the adipose afferent reflex in rat PLoS One 2013 8 11 e80295 24244673 PMC3823614 source

      Not checked in the free run.

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

    Premisecitation

    Melanocortins can regulate apoptosis.

    “Previous studies showed that melanocortins can regulate myocyte contractility, hypertrophy, apoptosis and cardiac metabolism [70, 71].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Abel ED Litwin SE Sweeney G Cardiac remodeling in obesity Physiol Rev 2008 88 2 389 419 18391168 PMC2915933 source

      Not checked in the free run.

    • cites [71] Ottani A Protective effects of the melanocortin analog NDP-alpha-MSH in rats undergoing cardiac arrest Eur J Pharmacol 2014 745 108 16 25446929 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The central nervous system regions with the greatest abundance of MC4R are the hypothalamus and hindbrain preganglionic sympathetic neurons of the nucleus tractus solitarius, dorsal motor nucleus of the vagus and intermediolateral nucleus, which are important sites for autonomic regulation.

    “The CNS regions with the greatest abundance of MC4R are the hypothalamus and hindbrain preganglionic sympathetic neurons of the NTS, DMV and IML [35] (Figure 3) which are important sites for autonomic regulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Rossi J Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis Cell Metab 2011 13 2 195 204 21284986 PMC3033043 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α-MSH and γ1-MSH have protective effects in a rat model of transient myocardial infarction followed by reperfusion and in a rat model of permanent coronary artery occlusion.

    “For instance, α-MSH and γ1-MSH have protective effects in a model of transient myocardial infarction (MI) followed by reperfusion as well as in a model of permanent coronary artery occlusion in rats [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Chitravanshi VC Bhatt S Sapru HN Microinjections of alpha-melanocyte stimulating hormone into the nucleus ambiguus of the rat elicit vagally mediated bradycardia Am J Physiol Regul Integr Comp Physiol 2009 296 5 R1402 11 19297540 PMC2689839 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Understanding how cardiovascular and metabolic functions are differentially regulated by this complex system may lead to novel therapies that reduce the burden of obesity and associated metabolic disorders without causing adverse cardiovascular effects.

    “Understanding how cardiovascular and metabolic functions are differentially regulated by this complex system may lead to novel therapies that reduce the burden of obesity and associated metabolic disorders without causing adverse cardiovascular effects.”
    Quote in the paperNot a substantial claim
23 of 23

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?

  • A key central nervous system pathway that links adipokines and hormones with blood pressure control is the brain POMC-MC4R system.

    “A key CNS pathway that links adipokines and hormones with BP control is the brain POMC-melanocortin 4 receptor (MC4R) system6,189,190.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [189]

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References 80 · Cited by 38

Authors
do Carmo, J. M., da Silva, A. A., Wang, Z., Fang, T., Aberdein, N., Perez de Lara, C. E., & Hall, J. E.
Affiliations
University of Mississippi Medical Center (US)
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
2017-10
Volume
1863
Issue
10
Pages
2508-2514
ISSN
0925-4439 (ISSN-L)
DOI
10.1016/j.bbadis.2017.03.003
PMC
PMC5587353
OpenAlex
W2593556740
Semantic Scholar
6514b8848be34d7da4606debdf145d0816750931
Cited by
38
References
80
Citations by year
2026: 5 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 7 · 2017: 1
FWCI
0.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • SHURA (Sheffield Hallam University Research Archive) (Sheffield Hallam University) (acceptedVersion)
Funders
  • National Heart, Lung and Blood Institute (PO1HL51971)
  • National Institute of General Medical Sciences (P20GM104357)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
melanocortin peptides, melanocortin-4 receptor, proopiomelanocortin, blood pressure regulation, sympathetic nervous system, obesity, hypertension, hyperphagia, energy balance, catecholamines, cold stress response, brain circuits, cardiovascular function
MeSH terms
Animals, Blood Pressure, Brain, Humans, Hypertension, Obesity, Pro-Opiomelanocortin, Sympathetic Nervous System, Receptor, Melanocortin, Type 4, Melanocortins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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