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Cited by 1,360Blood Pressure and Hypertension StudiesRenin-Angiotensin System StudiesHormonal Regulation and Hypertension

Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms

Open access
Hall, John E., do Carmo, Jussara M., da Silva, Alexandre A., Wang, Zhen, Hall, Michael E.·2015·Circulation Research
DOI 10.1161/circresaha.116.305697PMC PMC4363087
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Abstract

Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin–angiotensin–aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin–angiotensin–aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

AI snapshot

Written from the paper’s full text.

TL;DR

Excess weight gain, especially visceral adiposity, is a major cause of primary hypertension, accounting for 65–75% of risk, through impaired renal-pressure natriuresis driven by kidney compression, RAAS activation, and increased sympathetic nervous system activity. Obesity hypertension becomes harder to control as renal injury and chronic kidney disease develop, and current therapies mainly treat consequences rather than the underlying obesity.

Key findings

  • Excess weight gain is estimated to account for 65–75% of the risk for human primary hypertension; Framingham data suggest 78% of primary hypertension in men and 65% in women can be ascribed to excess weight gain.
  • Obesity impairs renal-pressure natriuresis via at least three major mechanisms: physical compression of the kidneys by visceral, retroperitoneal, and renal sinus fat; RAAS activation including mineralocorticoid receptor activation independent of aldosterone; and SNS activation, especially increased renal sympathetic nerve activity.
  • Renal compression is supported by elevated intra-abdominal pressures as high as 35–40 mmHg in visceral obesity and renal interstitial fluid hydrostatic pressure of 19 mmHg in obese dogs versus 9–10 mmHg in lean dogs; fatty kidneys are associated with more than a 2-fold higher risk for hypertension after adjustment for BMI and visceral fat.
  • Renal denervation lowered office BP by 25–30 mmHg systolic and 10–12 mmHg diastolic for up to 24 months in obese patients with resistant hypertension, with ambulatory BP reductions averaging −11/−7 mmHg in a subgroup, though a recent trial failed to find a major effect versus sham controls.

Methods

  • Narrative review; no new primary data are reported.
  • Synthesizes experimental animal studies (dogs, rabbits, rodents) and human clinical, population, and trial evidence on obesity-induced hypertension.
  • Main analysis is qualitative mechanistic synthesis linking neurohumoral, renal, and cardiovascular findings rather than a systematic review or meta-analysis.

Limitations

  • The paper states that the pathophysiological mechanisms are complex and not fully elucidated; mechanisms for SNS activation in obesity have not been fully elucidated; the importance of natriuretic peptide abnormalities and adipose RAAS is still unclear; and data on leptin’s chronic BP effects in humans are limited.
  • The paper states there have been no large-scale clinical studies comparing RAAS blockers in obese versus lean hypertensive patients, and whether renal denervation reduces SNA to other organs besides the kidneys remains uncertain.
  • Evident from the text: as a narrative review, it does not use a systematic search or quantitative synthesis, and many mechanistic conclusions rely heavily on animal models, with some human evidence from small trials or subgroups.

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

Integrity signals

Registry

Crossref · 10.1161/circresaha.116.305697

Cites

147 of 147 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 108 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    A highly reproducible rise in BP is observed with excess weight gain induced by a high fat diet in dogs and rabbits.

    “A highly reproducible rise in BP is observed with excess weight gain induced by a high fat diet in dogs and rabbits.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Higher aortic pulse-wave velocity, a measure of aortic stiffness, strongly correlates with increases in BMI, waist circumference and waist-hip ratio independent of systolic blood pressure, race, and sex.

    “Moreover, higher aortic pulse-wave velocity, a measure of aortic stiffness, strongly correlates with increases in BMI, waist circumference and waist-hip ratio independent of systolic blood pressure, race, and sex19,20.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Wildman RP Mackey RH Bostom A Thompson T Sutton-Tyrrell K Measures of obesity are associated with vascular stiffness in young and older adults Hypertension 2003 42 468 473 12953016 source

      Not checked in the free run.

    • cites [20] Lyon CJ Law RE Hsueh WA Minireview: adiposity, inflammation, and atherogenesis Endocrinology 2003 144 2195 2200 12746274 source

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  • Findingcitation

    Obese subjects, especially those with visceral obesity, often have mild to moderate increases in plasma renin activity (PRA), angiotensinogen, ACE activity, AngII, and aldosterone.

    “Obese subjects, especially those with visceral obesity, often have mild to moderate increases in plasma renin activity (PRA), angiotensinogen, ACE activity, AngII, and aldosterone40.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Engeli S Sharma AM The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension J Mol Med (Berl) 2001 79 21 29 11327100 source

      Not checked in the free run.

  • Findingcitation

    Renal interstitial fluid hydrostatic pressure was elevated to 19 mmHg in obese dogs compared to only 9-10 mmHg in lean dogs.

    “Supporting the concept that visceral obesity compresses the kidneys is the observation that renal interstitial fluid hydrostatic pressure was elevated to 19 mmHg in obese dogs compared to only 9–10 mmHg in lean dogs34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Hall JE Brands MW Henegar JR Mechanisms of hypertension and kidney disease in obesity Ann N Y Acad Sci 1999 892 91 107 10842655 source

      Not checked in the free run.

  • Findingcitation

    Blood flows of tissues such as the kidneys, skeletal muscle, and heart are increased in obese subjects even when flow is expressed per gram tissue weight.

    “However, blood flows of tissues such as the kidneys, skeletal muscle, and heart are increased in obese subjects even when flow is expressed per gram tissue weight13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Carroll JF Huang M Hester RL Cockrell K Mizelle HL Hemodynamic alterations in hypertensive obese rabbits Hypertension 1995 26 465 470 7649583 source

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  • May combine two claims. 41
  • Classified as probably not a substantial claim. 1
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    11β-HSD2 is markedly down-regulated in kidneys of obese dogs, providing a potential mechanism by which cortisol might activate the MR.

    “We found that 11β-HSD2 is markedly down-regulated in kidneys of obese dogs, providing a potential mechanism by which cortisol might activate the MR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In patients with visceral obesity, intra-abdominal pressure rises in proportion to sagittal abdominal diameter, reaching levels as high as 35-40 mmHg.

    “In patients with visceral obesity, intra-abdominal pressure rises in proportion to sagittal abdominal diameter, reaching levels as high as 35–40 mmHg27.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Sugerman H Windsor A Bessos M Wolfe L Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity J Intern Med 1997 241 71 79 9042096 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Levels of natriuretic peptides are inappropriately low in obese subjects, and their release in response to volume loading is impaired.

    “Not only are levels of natriuretic peptides inappropriately low in obese subjects23, but their release in response to volume loading is impaired24.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Wang TJ Larson MG Levy D Benjamin EJ Leip EP Wilson PW Vasan RS Impact of obesity on plasma natriuretic peptide levels Circulation 2004 109 594 600 14769680 source

      Not checked in the free run.

    • cites [24] Savoia C Volpe M Alonzo A Rossi C Rubattu S Natriuretic peptides and cardiovascular damage in the metabolic syndrome: molecular mechanisms and clinical implications Clin Sci (Lond) 2010 118 231 240 19886866 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In obese Zucker rats there is increased sensitivity to the BP effects of AngII and RAAS blockade lowers BP to a greater extent than in lean rats despite lower PRA.

    “In obese Zucker rats there is increased sensitivity to the BP effects of AngII and RAAS blockade lowers BP to a greater extent than in lean rats despite lower PRA45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Alonso-Galicia M Brands MW Zappe DH Hall JE Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity Hypertension 1996 28 1047 1054 8952595 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Administration of α/β-adrenergic blockers or clonidine prevents most of the obesity-induced rise in BP in obese animals, and α/β-adrenergic blockade reduces ambulatory BP significantly more in obese than in lean hypertensive patients.

    “administration of α/β-adrenergic blockers or clonidine, which stimulates central α-2 adrenergic receptors and reduces SNS activity, prevents most of the obesity-induced rise in BP in obese animals10,62 and α/β-adrenergic blockade reduces ambulatory BP significantly more in obese than in lean hypertensive patients63”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Hall JE Crook ED Jones DW Wofford MR Dubbert PM Mechanisms of obesity-associated cardiovascular and renal disease Am J Med Sci 2002 324 127 137 12240710 source

      Not checked in the free run.

    • cites [62] Carlyle M Jones OB Kuo JJ Hall JE Chronic cardiovascular and renal actions of leptin: role of adrenergic activity Hypertension 2002 39 496 501 11882597 source

      Not checked in the free run.

    • cites [63] Wofford MR Anderson DC Jr Brown CA Jones DW Miller ME Hall JE Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects Am J Hypertens 2001 14 694 698 11465655 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Administration of MR antagonists provides significant antihypertensive benefit in treatment resistant obese patients, although there was no correlation between plasma aldosterone levels and BP responses to MR blockade.

    “Administration of MR antagonists provides significant antihypertensive benefit in treatment resistant obese patients, although there was no correlation between plasma aldosterone levels and BP responses to MR blockade52,53.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] de SF Muxfeldt E Fiszman R Salles G Efficacy of spironolactone therapy in patients with true resistant hypertension Hypertension 2010 55 147 152 19858405 source

      Not checked in the free run.

    • cites [53] Calhoun DA Hyperaldosteronism as a common cause of resistant hypertension Annu Rev Med 2013 64 233 247 23092384 source

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  • May combine two claims.

    Premisecitation

    Clinical studies indicate that maintenance of a BMI < 25 kg/m2 is effective in primary prevention of hypertension and that weight loss reduces BP in most hypertensive subjects.

    “Clinical studies indicate that maintenance of a BMI < 25 kg/m2 is effective in primary prevention of hypertension and that weight loss reduces BP in most hypertensive subjects8,9.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Jones DW Miller ME Wofford MR Anderson DC Jr Cameron ME Willoughby DL Adair CT King NS The effect of weight loss intervention on antihypertensive medication requirements in the hypertension Optimal Treatment (HOT) study Am J Hypertens 1999 12 1175 1180 10619579 source

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    • cites [9] Stevens VJ Obarzanek E Cook NR Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II Ann Intern Med 2001 134 1 11 11187414 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Excess weight gain shifts the BP frequency distribution toward higher levels, increasing the probability that a person's BP will register in the hypertensive range.

    “It is clear, however, that excess weight gain shifts the BP frequency distribution toward higher levels increasing the probability that a person’s BP will register in the hypertensive range (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Even obese "normotensives" have higher BP than they would at a lower body weight, and weight loss lowers BP in "normotensive" and "hypertensive" obese subjects.

    “However, even those who are classified as obese “normotensives” have higher BP than they would at a lower body weight and weight loss lowers BP in “normotensive” and “hypertensive” obese subjects10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Hall JE Crook ED Jones DW Wofford MR Dubbert PM Mechanisms of obesity-associated cardiovascular and renal disease Am J Med Sci 2002 324 127 137 12240710 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims. The quote only partly states this claim.

    Interpretationnone given

    Unless effective anti-obesity drugs are developed, the impact of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

    “the impact of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The prevalence of obesity will continue to increase.

  • May combine two claims.

    Premisecitation

    Increased renal sodium reabsorption plays a major role in initiating the rise in BP associated with excess weight gain, and obese subjects require higher than normal BP to maintain sodium balance, indicating impaired renal-pressure natriuresis.

    “Increased renal sodium reabsorption plays a major role in initiating the rise in BP associated with excess weight gain and obese subjects require higher than normal BP to maintain sodium balance, indicating impaired renal-pressure natriuresis21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Hall JE Mechanisms of abnormal renal sodium handling in obesity hypertension Am J Hypertens 1997 10 49S 55S 9160781 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity is associated with extracellular fluid volume expansion and increased blood flow in many tissues, which increases venous return and cardiac output.

    “Obesity is associated with extracellular fluid volume expansion and increased blood flow in many tissues which, in turn, increases venous return and cardiac output15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Hall JE Brands MW Dixon WN Smith MJ Jr Obesity-induced hypertension. Renal function and systemic hemodynamics Hypertension 1993 22 292 299 8349321 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity generally decreases parasympathetic tone and increases sympathetic activity.

    “Obesity generally decreases parasympathetic tone and increases sympathetic activity.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Hall JE da Silva AA do Carmo JM Dubinion J Hamza S Munusamy S Smith G Stec DE Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins J Biol Chem 2010 285 17271 17276 20348094 PMC2878489 source

      Not checked in the free run.

    • cites [57] Van Vliet BN Hall JE Mizelle HL Montani JP Smith MJ Jr Reduced parasympathetic control of heart rate in obese dogs Am J Physiol 1995 269 H629 H637 7653627 source

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    • cites [58] Lohmeier TE Iliescu R The sympathetic nervous system in obesity hypertension Curr Hypertens Rep 2013 15 409 416 23677623 PMC3714347 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    CKD may over a much longer time amplify the BP effects of these mechanisms, making obesity-associated hypertension more difficult to control and less easily reversed by weight loss.

    “Also, CKD may over a much longer time, amplify the BP effects of these mechanisms, making obesity-associated hypertension more difficult to control and less easily reversed by weight loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Excess fat accumulation in and around the kidneys is associated with increased intrarenal pressures, impaired pressure natriuresis, and hypertension.

    “Excess fat accumulation in and around the kidneys is associated with increased intrarenal pressures, impaired pressure natriuresis, and hypertension12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Hall ME do Carmo JM da Silva AA Juncos LA Wang Z Hall JE Obesity, hypertension, and chronic kidney disease Int J Nephrol Renovasc Dis 2014 7 75 88 24600241 PMC3933708 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PTP1B deletion raised BP by SNS activation even in the absence of high levels of leptin, suggesting that this pathway may also modulate SNA through other mechanisms besides leptin signaling.

    “The finding that PTP1B deletion raised BP by SNS activation, even in the absence of high levels of leptin, suggests that this pathway may also modulate SNA through other mechanisms besides leptin signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The chronic hypertensive effect of leptin in lean rodents is modest, and some investigators have reported no changes in BP during leptin infusions.

    “The chronic hypertensive effect of leptin in lean rodents is modest and some investigators have reported no changes in BP during leptin infusions89.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Belin de Chantemele EJ Muta K Mintz J Tremblay ML Marrero MB Fulton DJ Stepp DW Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function Circulation 2009 120 753 763 19687357 PMC2736363 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Current data suggest that leptin, at levels comparable to those found in obesity, raises BP and RSNA in experimental animals and increases SNS activity in humans, although no studies directly demonstrate that leptin administration raises BP in humans.

    “Overall, the current data suggest that leptin, at levels comparable to those found in obesity, raises BP and RSNA in experimental animals and increases SNS activity in humans, although there are no studies directly demonstrating that leptin administration raises BP in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    STAT3 signaling contributes to leptin's chronic effects on BP, and deletion of STAT3 specifically in POMC neurons attenuates leptin's effect to raise BP.

    “Deletion of STAT3 specifically in POMC neurons attenuated leptin’s effect to raise BP but had only minor effects on food intake and energy expenditure106.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Dubinion JH do Carmo JM Adi A Hamza S da Silva AA Hall JE Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin Hypertension 2013 61 1066 1074 23529161 PMC3678380 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Obesity causes resistance to leptin signaling, likely related to a post-receptor defect.

    “However, obese subjects have higher cerebrospinal fluid (CSF) leptin levels compared to lean subjects102 suggesting that obesity also causes resistance to leptin signaling, likely related to a post-receptor defect103.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Caro JF Kolaczynski JW Nyce MR Ohannesian JP Opentanova I Goldman WH Lynn RB Zhang PL Sinha MK Considine RV Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance Lancet 1996 348 159 161 8684156 source

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    • cites [103] Munzberg H Myers MG Jr Molecular and anatomical determinants of central leptin resistance Nat Neurosci 2005 8 566 570 15856064 source

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  • May combine two claims.

    Premisecitation

    Mice with leptin deficiency (ob/ob) have severe obesity, insulin resistance, hyperinsulinemia, and dyslipidemia but lower BP and reduced SNS activity compared to lean mice.

    “Mice with leptin deficiency (ob/ob) mice have severe obesity, insulin resistance, hyperinsulinemia, and dyslipidemia but lower BP and reduced SNS activity compared to lean mice112.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Mark AL Shaffer RA Correia ML Morgan DA Sigmund CD Haynes WG Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice J Hypertens 1999 17 1949 1953 10703894 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SOCS3 deficiency increases leptin sensitivity and attenuates obesity development in mice fed a high fat diet.

    “SOCS3 deficiency increases leptin sensitivity and attenuates obesity development in mice fed a high fat diet111.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Mori H Hanada R Hanada T Aki D Mashima R Nishinakamura H Torisu T Chien KR Yasukawa H Yoshimura A Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity Nat Med 2004 10 739 743 15208705 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IRS2-PI3K signaling contributes modestly to body weight regulation but mediates at least part of leptin's effects on SNS activity and BP.

    “These observations suggest that IRS2-PI3K signaling contributes modestly to body weight regulation but mediates at least part of leptin’s effects on SNS activity and BP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Leptin-mediated increases in BP occur gradually over several days, consistent with modest increases in SNS activity sufficient to increase renal sodium reabsorption.

    “Leptin-mediated increases in BP occur gradually over several days, consistent with modest increases in SNS activity that are not sufficient to directly cause vasoconstriction but sufficient to increase renal sodium reabsorption.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Leptin stimulates NO production, which opposes increases in BP.

    “Moreover, leptin stimulates NO production which opposes increases in BP.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [80] da Silva AA do Carmo JM Wang Z Hall JE The brain melanocortin system, sympathetic control, and obesity hypertension Physiology (Bethesda) 2014 29 196 202 24789984 PMC4046815 source

      Not checked in the free run.

    • cites [86] Kuo JJ Jones OB Hall JE Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin Hypertension 2001 37 670 676 11230354 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Several brain regions may coordinate SNS responses to leptin, and leptin's effects on SNS activity in various organs can be differentially controlled by activation of LepR in multiple brain regions.

    “Taken together, these studies suggest that several brain regions may coordinate SNS responses to leptin and that leptin’s effects on SNS activity in various organs and tissues can be differentially controlled by activation of LepR in multiple brain regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Genetic deletion of PTP1B enhances leptin sensitivity and protects against obesity but exacerbates leptin's BP effects.

    “Genetic deletion of PTP1B enhances leptin sensitivity and protects against obesity but exacerbates leptin’s BP effects89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Belin de Chantemele EJ Muta K Mintz J Tremblay ML Marrero MB Fulton DJ Stepp DW Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function Circulation 2009 120 753 763 19687357 PMC2736363 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute injections of leptin have little effect on BP despite increasing SNS activity.

    “acute injections of leptin have little effect on BP despite increasing SNS activity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [80] da Silva AA do Carmo JM Wang Z Hall JE The brain melanocortin system, sympathetic control, and obesity hypertension Physiology (Bethesda) 2014 29 196 202 24789984 PMC4046815 source

      Not checked in the free run.

    • cites [86] Kuo JJ Jones OB Hall JE Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin Hypertension 2001 37 670 676 11230354 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In obese mice, leptin's anorexic effects were blunted whereas the acute effects to increase RSNA were preserved.

    “In obese mice, leptin’s anorexic effects were blunted whereas the acute effects to increase RSNA were preserved104.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Rahmouni K Morgan DA Morgan GM Mark AL Haynes WG Role of selective leptin resistance in diet-induced obesity hypertension Diabetes 2005 54 2012 2018 15983201 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early in development of obesity and even in obese children, there is often interstitial fibrosis, microalbuminuria or proteinuria, expansion of mesangial matrix, glomerulomegaly, focal segmental glomerular sclerosis, and podocyte disorder associated with glomerular hyperfiltration.

    “Early in development of obesity and even in obese children, there is often interstitial fibrosis, microalbuminuria or proteinuria, expansion of mesangial matrix, glomerulomegaly, focal segmental glomerular sclerosis, and podocyte disorder associated with glomerular hyperfiltration142–144.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [142] Amann K Benz K Structural renal changes in obesity and diabetes Semin Nephrol 2013 33 23 33 23374891 source

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    • cites [143] Hall JE Henegar JR Dwyer TM Liu J Da Silva AA Kuo JJ Tallam L Is obesity a major cause of chronic kidney disease? Adv Ren Replace Ther 2004 11 41 54 14730537 source

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    • cites [144] Henegar JR Bigler SA Henegar LK Tyagi SC Hall JE Functional and structural changes in the kidney in the early stages of obesity J Am Soc Nephrol 2001 12 1211 1217 11373344 source

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  • May combine two claims.

    Interpretationreasoning

    The CNS POMC-MC4R pathway regulates appetite, energy expenditure, autonomic nervous system activity and cardiovascular responses to stress.

    “Thus, the CNS POMC-MC4R pathway regulates appetite, energy expenditure, autonomic nervous system activity and cardiovascular responses to stress, among many other important functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Leptin-deficient humans generally are not hypertensive and do not have increased SNS activity.

    “Although BP and SNS activity have been assessed in only a few leptin-deficient humans, they generally are not hypertensive and do not have increased SNS activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] 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 3686 3695 10523015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Obesity may eventually cause CKD that amplifies hypertension and makes it more difficult to control.

    “In addition to increasing BP by renal compression and activation of the RAAS and SNS, obesity may eventually cause CKD that amplifies the hypertension and makes it more difficult to control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Excess weight gain and visceral obesity are major causes of hypertension, perhaps accounting for as much as 65-75% of the risk for human essential hypertension.

    “There is overwhelming evidence that excess weight gain and visceral obesity are major causes of hypertension, perhaps accounting for as much as 65–75% of the risk for human essential hypertension.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a retrospective analysis of 320,252 adults followed for 15-35 years, the rate of ESRD increased stepwise as BMI increased and this relationship remained after adjustment for BP, diabetes, smoking, age, and several other variables.

    “In a retrospective analysis of 320,252 adults followed for 15–35 years, the rate of ESRD increased stepwise as BMI increased and this relationship remained after adjustment for BP, diabetes, smoking, age, and several other variables141.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Hsu CY McCulloch CE Iribarren C Darbinian J Go AS Body mass index and risk for end-stage renal disease Ann Intern Med 2006 144 21 28 16389251 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In humans and rodents, chronic activation of MC4R raises BP and a functional POMC-MC4R system appears necessary for obesity to increase SNS activity and BP.

    “Thus, in humans and rodents, chronic activation of MC4R raises BP and a functional POMC-MC4R system appears to be necessary for obesity to increase SNS activity and BP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The POMC-MC4R pathway may contribute to SNS activation during acute stress as well as during chronic increases in SNS activity, and this system plays a more fundamental role controlling SNS activity and BP than previously appreciated.

    “These observations support the concept the POMC-MC4R pathway may contribute to SNS activation during acute stress as well as during chronic increases in SNS activity, and that this system plays a more fundamental role controlling SNS activity and BP than previously appreciated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Blockade of CNS MC4R in rodents causes voracious feeding, rapid weight gain, and reduces rather than increases BP.

    “Conversely, blockade of CNS MC4R in rodents causes voracious feeding, rapid weight gain, and reduces rather than increases BP123.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] da Silva AA do Carmo JM Kanyicska B Dubinion J Brandon E Hall JE Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats Hypertension 2008 51 884 890 18285617 PMC2803054 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic pharmacological activation of CNS MC4R in rats increases BP while reducing appetite and body weight, and the rise in BP is abolished after α/β-adrenergic blockade.

    “Chronic pharmacological activation of CNS MC4R in rats increases BP while reducing appetite and body weight121. The rise in BP after chronic activation of MC4R is abolished after α/β-adrenergic blockade indicating that it is due to increased adrenergic activity122.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] Kuo JJ Silva AA Hall JE Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function Hypertension 2003 41 768 774 12623994 source

      Not checked in the free run.

    • cites [122] Kuo JJ da Silva AA Tallam LS Hall JE Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation Hypertension 2004 43 370 375 14707160 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clinical and experimental observations support a role for leptin as a link between obesity, increased SNS activity and elevated BP although data on leptin's chronic BP effects in humans are still limited.

    “Collectively, clinical and experimental observations support a role for leptin as a link between obesity, increased SNS activity and elevated BP although data on leptin’s chronic BP effects in humans are still limited.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    MC4R activation contributes to tonic SNS activation and may be necessary for rapid weight gain to increase BP.

    “These observations suggest that MC4R activation contributes to tonic SNS activation and may be necessary for rapid weight gain to increase BP.”
    Quote in the paperSubstantial claim
41 of 41

  • The paper relies on this without support.

    The prevalence of obesity will continue to increase.

    “as the prevalence of obesity continues to increase.”

  • The paper relies on this without support.

    SNS activation in obesity requires leptin and activation of the brain melanocortin system.

    “The mechanisms for SNS activation in obesity have not been fully elucidated but appear to require leptin and activation of the brain melanocortin system.”
2 of 2

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?

  • Additional evidence confirms that obesity is a contributing factor for type 2 diabetes, hypertension, and thrombotic episodes, as well as conditions linked to inflammation such as heart failure with preserved ejection fraction.

    “Additional evi dence confirms that obesity is a contributing factor for type 2 diabetes, hypertension, and thrombotic ep isodes, as well as conditions linked to inflammation such as heart failure with preserved ejection frac tion. 2-7”

    From Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide (2026) · cites this paper as [6]

    The Introduction identifies obesity as a cause of hypertension and links it to the development of diabetes; the CKD section specifically associates obesity with type II diabetes. The passages on inflammation and cardiovascular effects do not support the more specific claims about thrombotic episodes or heart failure with preserved ejection fraction. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A nearly linear relationship exists between blood pressure and indices of obesity, including BMI, in every population examined, including white, black, Hispanic and Asian populations.

    “A nearly linear relationship exists between BP and indices of obesity, including BMI, in every population examined, including white, black, Hispanic and Asian populations6,25.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [6]

  • Other cardiovascular, renal, endocrine and sympathetic nervous system changes that are associated with obesity caused by a high-fat diet in dogs and rabbits closely mimic those found in people who are obese.

    “Other cardiovascular, renal, endocrine and sympathetic nervous system (SNS) changes that are associated with obesity caused by an HFD in dogs and rabbits closely mimic those found in people who are obese6.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [6]

  • Feeding a chronic high-fat diet causes reproducible rises in blood pressure in rabbits and dogs, although smaller and less consistent blood pressure increases are observed in rodents.

    “Feeding a chronic high-fat diet (HFD) causes reproducible rises in BP in rabbits and dogs, although smaller and less consistent BP increases are observed in rodents6.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [6]

  • Excessive adipose deposition around the kidneys, such as renal sinus fat and perirenal fat, may be associated with hypertension even after adjustment for traditional risk factors, including overall adiposity and BMI.

    “Evidence suggests that excessive adipose deposition around the kidneys (for example, renal sinus fat (RSF) and perirenal fat (PRF)) may be associated with hypertension even after adjustment for traditional risk factors, including overall adiposity and BMI6,19–21.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [6]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 10.1097/01.hjh.0000084718.53355.69 · DOI

Cited by

Sorted by citations

Related

Authors
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z., & Hall, M. E.
Affiliations
  • University of Mississippi Medical Center (US)
  • From the Departments of Physiology and Biophysics (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), Medicine (M.E.H.), Mississippi Center for Obesity Research (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), and Cardiovascular-Renal Research Center (J.E.H., J.M.d.C., A.A.d.S., Z.W., M.E.H.), University of Mississippi Medical Center, Jackson.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-03-13
Volume
116
Issue
6
Pages
991-1006
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.116.305697
PMC
PMC4363087
OpenAlex
W2151009383
Semantic Scholar
a5da0ccc20ef38542b949ef56293f5130a57a7db
Cited by
1,360
References
147
Citations by year
2026: 175 · 2025: 185 · 2024: 135 · 2023: 131 · 2022: 129 · 2021: 130 · 2020: 119 · 2019: 113 · 2018: 86 · 2017: 69 · 2016: 63 · 2015: 15 · 2014: 6 · 2013: 1 · 2012: 1
FWCI
56.53
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (P01-HL-51971, P01HL051971)
  • National Institute of General Medical Sciences (P20GM104357)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K08DK099415)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
obesity-related hypertension, visceral fat, tubular sodium reabsorption, pressure natriuresis, renal compression, renin-angiotensin-aldosterone system, sympathetic activation, leptin, melanocortin system, target organ damage, kidney injury, insulin resistance, diabetes mellitus, dyslipidemia, inflammation, anti-obesity drugs
MeSH terms
Aldosterone, Animals, Antihypertensive Agents, Heart Conduction System, Hemodynamics, Humans, Hypertension, Insulin Resistance, Kidney, Models, Cardiovascular, Natriuresis, Obesity, Organ Specificity, Parasympathetic Nervous System, Pressure, Pro-Opiomelanocortin, Renin-Angiotensin System, Sodium, Sympathetic Nervous System, Prevalence, Leptin, Models, Animal, Metabolic Syndrome, Intra-Abdominal Fat, Dyslipidemias, Renal Insufficiency, Chronic, Receptors, Leptin

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.

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