Obesity, kidney dysfunction and hypertension: mechanistic links

Dorsal root ganglionectomy from T10 to L2 did not blunt the rise in blood pressure during development of obesity-induced hypertension in obese hypertensive dogs.

“This procedure did not blunt the rise in BP during development of obesity-induced hypertension, indicating that the BP effects of RDN are due to ablation of renal sympathetic efferent fibres rather than sensory afferent nerves.”

• cites [173] Zappe, D. H. et al. Role of renal afferent nerves in obesity-induced hypertension. Am. J. Hypertens. 9, 20A (1996). sourceNot checked yet

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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.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [25] Jones, D. W., Kim, J. S., Andrew, M. E., Kim, S. J. & Hong, Y. P. Body mass index and blood pressure in Korean men and women: the Korean National Blood Pressure Survey. J. Hypertens. 12, 1433–1437 (1994). sourceNot checked yet

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A 1 s.d. increase in BMI over a 5-year period led to a 30% increase in risk of hypertension compared with people whose weight did not change.

“A study in individuals aged 25–74 years reported that a 1 s.d. increase in BMI over a 5-year period led to a 30% increase in risk of hypertension compared with people whose weight did not change28.”

• cites [28] Nyamdorj, R. et al. Comparison of body mass index with waist circumference, waist-to-hip ratio, and waist-to-stature ratio as a predictor of hypertension incidence in Mauritius. J. Hypertens. 26, 866–870 (2008). sourceNot checked yet

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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.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension.

“Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension.”

Studies in primary care settings report that 60-76% of patients who are overweight or obese have hypertension.

“Studies in primary care settings report that 60–76% of patients who are overweight or obese have hypertension, defined as BP >140/90 mmHg 26.”

• cites [26] Bramlage, P. et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am. J. Hypertens. 17, 904–910 (2004). sourceNot checked yet

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Several haemodynamic, renal and neurohormonal changes occur during the development of obesity-induced hypertension in humans and in experimental animal models of obesity caused by overfeeding.

“Several haemodynamic, renal and neurohormonal changes occur during the development of obesity-induced hypertension in humans and in experimental animal models of obesity caused by overfeeding (TABLE 1).”

The risk of developing hypertension increases with obesity duration.

“Thus, the risk of developing hypertension increases with obesity duration.”

Obesity in young adults conferred a threefold greater risk of hypertension after 46 years of follow-up, even after accounting for changes in lifestyle factors over the life course.

“In the Johns Hopkins Precursors Study, obesity in young adults conferred a threefold greater risk of hypertension after 46 years of follow-up, even after accounting for changes in lifestyle factors over the life course30.”

• cites [30] Shihab, H. M. et al. Body mass index and risk of incident hypertension over the life course: the Johns Hopkins Precursors Study. Circulation 126, 2983–2989 (2012). sourceNot checked yet

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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.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [19] Chughtai, H. L. et al. Renal sinus fat and poor blood pressure control in middle-aged and elderly individuals at risk for cardiovascular events. Hypertension 56, 901–906 (2010). sourceNot checked yet

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• cites [20] Foster, M. C. et al. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58, 784–790 (2011). sourceNot checked yet

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• cites [21] Chandra, A. et al. The relationship of body mass and fat distribution with incident hypertension: observations from the dallas heart study. J. Am. Coll. Cardiol. 64, 997–1002 (2014). sourceNot checked yet

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People who are obese and considered to be normotensive often experience a reduction in blood pressure when they reduce their overall adiposity by losing weight.

“people who are obese and considered to be normotensive often experience a reduction in BP when they reduce their overall adiposity by losing weight35.”

• cites [35] Hall, J. E., Crook, E. D., Jones, D. W., Wofford, M. R. & Dubbert, P. M. Mechanisms of obesity-associated cardiovascular and renal disease. Am. J. Med. Sci. 324, 127–137 (2002). sourceNot checked yet

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Excessive adiposity raises blood pressure.

“Excessive adiposity raises blood pressure and accounts for 65–75% of primary hypertension”

Excessive adiposity accounts for 65-75% of primary hypertension.

“Epidemiology studies indicate that 65–75% of primary (essential) hypertension is due to overweight or obesity7.”

• cites [7] Garrison, R. J., Kannel, W. B., Stokes, J. III & Castelli, W. P. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev. Med. 16, 235–251 (1987). sourceNot checked yet

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In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension.

“In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension”

Body weight remained the strongest predictor of blood pressure in Pima Indians.

“However, body weight remained the strongest predictor of BP in Pima Indians34.”

• cites [34] de Courten, M. P., Pettitt, D. J. & Knowler, W. C. Hypertension in Pima Indians: prevalence and predictors. Public Health Rep. 111 (Suppl. 2), 40–43 (1996).Not checked yet

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The search for genetic and epigenetic contributions to obesity-induced hypertension has been disappointing, explaining only a tiny fraction of hypertension.

“However, the search for genetic and epigenetic contributions to obesity-induced hypertension has been disappointing, explaining only a tiny fraction of hypertension31.”

• cites [31] Harrap, S. B. & Charchar, F. J. Genetics of blood pressure: time to curate the collection. J. Hypertens. 35, 1360–1362 (2017). sourceNot checked yet

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Visceral adipose tissue reduction following bariatric surgery rapidly decreases blood pressure.

“VAT reduction following bariatric surgery (for example, vertical sleeve gastrectomy or Roux-en-Y gastric bypass) rapidly decreases BP16,17.”

• cites [16] Schiavon, C. A. et al. Effects of bariatric surgery in obese patients with hypertension: the GATEWAY randomized trial (gastric bypass to treat obese patients with steady hypertension). Circulation 137, 1132–1142 (2018). sourceNot checked yet

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• cites [17] Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy for diabetes — 5-year outcomes. N. Engl. J. Med. 376, 641–651 (2017). sourceNot checked yet

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Excess visceral adipose tissue conveys a higher risk of cardiometabolic disorders, including hypertension and type 2 diabetes mellitus, than excess subcutaneous adipose tissue.

“Substantial evidence indicates that excess visceral adipose tissue (VAT) conveys a higher risk of cardiometabolic disorders, including hypertension and T2DM, than does excess subcutaneous adipose tissue (SAT)”

• cites [13] Neeland, I. J., Poirier, P. & Despres, J. P. Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management. Circulation 137, 1391–1406 (2018). sourceNot checked yet

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• cites [14] Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). sourceNot checked yet

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The frequency distribution for blood pressure seems to be displaced to higher levels by visceral obesity, increasing the likelihood that blood pressure will be considered hypertensive.

“the frequency distribution for BP seems to be displaced to higher levels by visceral obesity, increasing the likelihood that BP will be considered hypertensive (FIG. 1).”

Increases in body weight during 10 years of follow-up were associated with higher risk of hypertension, even within a range of BMIs that were considered normal.

“In the Nurses’ Health Study and the Health Professionals Follow-up Study, increases in body weight during 10 years of follow-up were associated with higher risk of hypertension, even within a range of BMIs that were considered normal29.”

• cites [29] Field, A. E. et al. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch. Intern. Med. 161, 1581–1586 (2001). sourceNot checked yet

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Among obese individuals with similar BMI or total body adiposity, those with greater visceral and ectopic fat generally have higher cardiometabolic risk than those with less visceral adipose tissue.

“among obese individuals with similar BMI or total body adiposity, those with greater visceral and ectopic fat generally have higher cardiometabolic risk than those with less VAT13.”

• cites [13] Neeland, I. J., Poirier, P. & Despres, J. P. Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management. Circulation 137, 1391–1406 (2018). sourceNot checked yet

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These differences can limit the translation of results from rodent models to the understanding of obesity-induced cardiorenal changes in humans.

“These differences can limit the translation of results from rodent models to the understanding of obesity-induced cardiorenal changes in humans.”

Many commonly used genetic models of obesity, such as ob/ob and db/db mice and Zucker fatty rats, have derangements of adipokine signalling and/or nervous system networks that mediate sympathetic hyperactivity and hypertension in obesity.

“many commonly used genetic models of obesity, such as ob/ob and db/db mice and Zucker fatty rats, have derangements of adipokine (for example, leptin) signalling and/or nervous system networks (for example, proopiomelanocortin (POMC)-melanocortin signalling) that mediate sympathetic hyperactivity and hypertension in obesity6.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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Rodents with genetic or diet-induced obesity do not show adherence of fat to the renal capsule and resulting kidney compression as occurs in obese dogs, rabbits and humans.

“rodents with genetic or diet-induced obesity do not show adherence of fat to the renal capsule and resulting kidney compression as occurs in obese dogs, rabbits and humans6.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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Excessive weight gain increases heart rate and cardiac output in experimental animals and in humans.

“Excessive weight gain increases heart rate (HR) and cardiac output (CO) in experimental animals and in humans35,36 (TABLE 1).”

• cites [35] Hall, J. E., Crook, E. D., Jones, D. W., Wofford, M. R. & Dubbert, P. M. Mechanisms of obesity-associated cardiovascular and renal disease. Am. J. Med. Sci. 324, 127–137 (2002). sourceNot checked yet

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• cites [36] Alpert, M. A., Karthikeyan, K., Abdullah, O. & Ghadban, R. Obesity and cardiac remodeling in adults: mechanisms and clinical implications. Prog. Cardiovasc. Dis. 61, 114–123 (2018). sourceNot checked yet

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Haemodynamic changes in obesity, including hypertension, increased venous return and increased cardiac output levels, predispose the heart to left ventricular hypertrophy with increased wall thickness and chamber size.

“Haemodynamic changes in obesity, including hypertension, increased venous return and increased CO levels, predispose the heart to left ventricular hypertrophy (LVH) with increased wall thickness and chamber size.”

Blockade of nitric oxide synthesis abrogated glomerular hyperfiltration in dogs with aldosterone-induced hypertension.

“blockade of NO synthesis abrogated glomerular hyperfiltration in dogs with aldosterone-induced hypertension50.”

• cites [50] Granger, J. P. et al. Role of nitric oxide in modulating renal function and arterial pressure during chronic aldosterone excess. Am. J. Physiol. 276, R197–R202 (1999).Not checked yet

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Excessive sodium reabsorption by the kidneys initiates the sodium retention, increased extracellular fluid volume and elevated blood pressure that are associated with excess weight gain.

“Excessive sodium reabsorption by the kidneys initiates the sodium retention, increased extracellular fluid volume and elevated BP that are associated with excess weight gain.”

Obesity-induced glomerular hyperfiltration is associated with vasodilation of renal afferent arterioles and increased glomerular hydrostatic pressure, similar to that observed in diabetes mellitus and hyperglycaemia.

“Obesity-induced glomerular hyperfiltration is associated with vasodilation of renal afferent arterioles and increased glomerular hydrostatic pressure, similar to that observed in diabetes mellitus and hyperglycaemia35,42.”

• cites [35] Hall, J. E., Crook, E. D., Jones, D. W., Wofford, M. R. & Dubbert, P. M. Mechanisms of obesity-associated cardiovascular and renal disease. Am. J. Med. Sci. 324, 127–137 (2002). sourceNot checked yet

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• cites [42] Tonneijck, L. et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J. Am. Soc. Nephrol. 28, 1023–1039 (2017). sourceNot checked yet

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Mineralocorticoid receptor blockade markedly attenuated glomerular hyperfiltration in obese dogs fed a high-fat diet.

“We showed that MR blockade markedly attenuated glomerular hyperfiltration in obese dogs fed an HFD47.”

• cites [47] de Paula, R. B., da Silva, A. A. & Hall, J. E. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 43, 41–47 (2004). sourceNot checked yet

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Individuals who gain excess adiposity maintain sodium balance at higher blood pressures than when they were lean, indicating impaired renal-pressure natriuresis.

“individuals who gain excess adiposity maintain sodium balance at higher BPs than when they were lean, indicating impaired renal-pressure natriuresis16,51.”

• cites [16] Schiavon, C. A. et al. Effects of bariatric surgery in obese patients with hypertension: the GATEWAY randomized trial (gastric bypass to treat obese patients with steady hypertension). Circulation 137, 1132–1142 (2018). sourceNot checked yet

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• cites [51] Hall, J. E. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension. Circulation 133, 894–906 (2016). sourceNot checked yet

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Increased renal blood flow contributes to increases in venous return and cardiac output in individuals with obesity.

“Increased RBF also contributes to increases in venous return and CO in individuals with obesity6.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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Cross-sectional studies may not reveal time-dependent cardiorenal changes that initiate the development of obesity-induced hypertension.

“Thus, crosssectional studies may not reveal time-dependent cardiorenal changes that initiate the development of obesity-induced hypertension.”

Pressure in the abdominal cavity may be elevated to >40 cm H20 in patients with large sagittal abdominal diameters.

“Pressure in the abdominal cavity may be elevated to >40 cm H20 in patients with large sagittal abdominal diameters52.”

• cites [52] Sugerman, H., Windsor, A., Bessos, M. & Wolfe, L. Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity. J. Intern. Med. 241, 71–79 (1997). sourceNot checked yet

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In obesity, chronic elevations in resting heart rate are caused mainly by reduced parasympathetic tone rather than by increases in sympathetic activity or intrinsic heart rate.

“In obesity, chronic elevations in resting HR are caused mainly by reduced parasympathetic tone rather than by increases in sympathetic activity or intrinsic HR6,37.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [37] Van Vliet, B. N., Hall, J. E., Mizelle, H. L., Montani, J. P. & Smith, M. J. Jr. Reduced parasympathetic control of heart rate in obese dogs. Am. J. Physiol. 269, H629–H637 (1995).Not checked yet

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Obesity is associated with eccentric and concentric left ventricular hypertrophy.

“Thus, obesity is associated with eccentric and concentric LVH36,41.”

• cites [36] Alpert, M. A., Karthikeyan, K., Abdullah, O. & Ghadban, R. Obesity and cardiac remodeling in adults: mechanisms and clinical implications. Prog. Cardiovasc. Dis. 61, 114–123 (2018). sourceNot checked yet

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• cites [41] Lavie, C. J., Arena, R., Alpert, M. A., Milani, R. V. & Ventura, H. O. Management of cardiovascular diseases in patients with obesity. Nat. Rev. Cardiol. 15, 45–56 (2018). sourceNot checked yet

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Obesity enhances blood pressure sensitivity to angiotensin II.

“For reasons that are still unclear, obesity enhances BP sensitivity to AngII62.”

• cites [62] Alonso-Galicia, M., Brands, M. W., Zappe, D. H. & Hall, J. E. Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity. Hypertension 28, 1047–1054 (1996). sourceNot checked yet

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In dogs fed a high-fat diet to produce obesity, MR antagonism with eplerenone blunted sodium retention, glomerular hyperfiltration, and the development of hypertension by more than 50%.

“In dogs fed an HFD to produce obesity, MR antagonism with eplerenone blunted sodium retention, glomerular hyperfiltration and the development of hypertension by >50%47.”

• cites [47] de Paula, R. B., da Silva, A. A. & Hall, J. E. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 43, 41–47 (2004). sourceNot checked yet

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Blockade of the RAAS with angiotensin II receptor blockers, ACE inhibitors, or renin inhibitors reduces blood pressure in patients with obesity and hypertension.

“As mentioned above, blockade of the RAAS with AngII receptor blockers, angiotensin-converting enzyme (ACE) inhibitors or renin inhibitors reduces BP in patients with obesity and hypertension64–66.”

• cites [64] Dorresteijn, J. A. et al. Differential effects of renin-angiotensin-aldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension: a double-blind, placebo-controlled cross-over trial. J. Hypertens. 31, 393–403 (2013). sourceNot checked yet

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• cites [65] Grassi, G. et al. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J. Hypertens. 21, 1761–1769 (2003). sourceNot checked yet

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• cites [66] Reisin, E. et al. Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) study group. Hypertension 30, 140–145 (1997). sourceNot checked yet

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Antagonism of the RAAS with ACE inhibitors or angiotensin II receptor blockers attenuates, but may not completely halt, the progression of kidney injury in patients with obesity, hypertension, and type 2 diabetes mellitus.

“Antagonism of the RAAS with ACE inhibitors or AngII receptor blockers also attenuates, but may not completely halt, the progression of kidney injury in patients with obesity, hypertension and T2DM67,68.”

• cites [67] Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001). sourceNot checked yet

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• cites [68] Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001). sourceNot checked yet

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In patients with primary hypertension, treatment with the aldosterone synthase inhibitor LCI699 reduced serum aldosterone levels and blood pressure.

“A randomized controlled trial in patients with primary hypertension showed that treatment with the aldosterone synthase inhibitor LCI699 reduced serum aldosterone levels and BP79.”

• cites [79] Calhoun, D. A. et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 124, 1945–1955 (2011). sourceNot checked yet

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Stimulation of the renin-angiotensin-aldosterone system in obesity occurs despite sodium retention and increased blood pressure, which normally inhibit renin secretion, angiotensin II formation and aldosterone secretion.

“Stimulation of the RAAS in obesity occurs despite sodium retention and increased BP, which normally inhibit renin secretion, AngII formation and aldosterone secretion.”

In patients with obesity and hypertension, MR antagonism with spironolactone reduced blood pressure and urinary albumin excretion even after long-term blockade of angiotensin II formation with ACE inhibitors.

“In patients with obesity and hypertension, MR antagonism with spironolactone reduced BP and urinary albumin excretion even after long-term blockade of AngII formation with ACE inhibitors72.”

• cites [72] Bomback, A. S., Muskala, P., Bald, E., Chwatko, G. & Nowicki, M. Low-dose spironolactone, added to long-term ACE inhibitor therapy, reduces blood pressure and urinary albumin excretion in obese patients with hypertensive target organ damage. Clin. Nephrol. 72, 449–456 (2009). sourceNot checked yet

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Experimental animals and people with obesity generally have modest increases in most components of the renin-angiotensin-aldosterone system, including angiotensin II and aldosterone.

“Experimental animals and people with obesity generally have modest increases in most components of the RAAS, including angiotensin II (AngII) and aldosterone6,59.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [59] Engeli, S. & Sharma, A. M. The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension. J. Mol. Med. 79, 21–29 (2001). sourceNot checked yet

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In 2,923 participants from the Framingham Heart Study, high renal sinus fat levels conveyed a 2.2-fold increased risk of hypertension.

“In 2,923 participants from the Framingham Heart Study, high RSF levels (fatty kidney) conveyed a 2.2-fold increased risk of hypertension20.”

• cites [20] Foster, M. C. et al. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58, 784–790 (2011). sourceNot checked yet

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Mild elevations in angiotensin II levels in obesity are driven largely by increased renal renin secretion due to sympathetic nervous system activation, kidney compression, and other factors such as adipokines.

“Current evidence suggests that mild elevations in AngII levels in obesity are driven largely by increased renal renin secretion due to SNS activation, kidney compression and perhaps other factors such as adipokines51,60.”

• cites [51] Hall, J. E. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension. Circulation 133, 894–906 (2016). sourceNot checked yet

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• cites [60] Cabandugama, P. K., Gardner, M. J. & Sowers, J. R. The renin angiotensin aldosterone system in obesity and hypertension: roles in the cardiorenal metabolic syndrome. Med. Clin. North Am. 101, 129–137 (2017). sourceNot checked yet

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High levels of renal sinus fat were also associated with a 2.3-fold increased risk of chronic kidney disease after adjusting for visceral adipose tissue and BMI.

“High levels of RSF were also associated with a 2.3-fold increased risk of CKD after adjusting for VAT and BMI20.”

• cites [20] Foster, M. C. et al. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58, 784–790 (2011). sourceNot checked yet

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Increases in total tissue pressure and interstitial fluid hydrostatic pressure to −19 mmHg have been observed in obese dogs.

“Increases in total tissue pressure and interstitial fluid hydrostatic pressure to −19 mmHg have been observed in obese dogs56.”

• cites [56] Hall, J. E., Brands, M. W. & Henegar, J. R. Mechanisms of hypertension and kidney disease in obesity. Ann. NY Acad. Sci. 892, 91–107 (1999). sourceNot checked yet

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Preclinical studies in mice suggest that aldosterone synthase inhibition may amplify diet-induced hyperinsulinaemia and obesity.

“Preclinical studies in mice suggest that aldosterone synthase inhibition may amplify diet-induced hyperinsulinaemia and obesity81; such adverse effects have not been reported for MR antagonists.”

• cites [81] Liao, W. H. et al. Aldosterone deficiency in mice burdens respiration and accentuates diet-induced hyperinsulinemia and obesity. JCI Insight 3, 99015 (2018). sourceNot checked yet

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In patients with obesity and treatment-resistant hypertension treated with spironolactone, reductions in blood pressure did not correlate with plasma aldosterone concentration.

“Moreover, in patients with obesity and treatment-resistant hypertension who were treated with spironolactone, the resulting reductions in BP did not correlate with plasma aldosterone concentration73,74.”

• cites [73] Dudenbostel, T. & Calhoun, D. A. Use of aldosterone antagonists for treatment of uncontrolled resistant hypertension. Am. J. Hypertens. 30, 103–109 (2017). sourceNot checked yet

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• cites [74] de Souza, F., Muxfeldt, E., Fiszman, R. & Salles, G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension 55, 147–152 (2010). sourceNot checked yet

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In the Dallas Heart Study, increased visceral adipose tissue, but not total or subcutaneous adiposity, was strongly associated with incident hypertension during a median follow-up of 7 years.

“In the Dallas Heart Study, increased VAT, but not total or subcutaneous adiposity, was strongly associated with incident hypertension during a median follow-up of 7 years21.”

• cites [21] Chandra, A. et al. The relationship of body mass and fat distribution with incident hypertension: observations from the dallas heart study. J. Am. Coll. Cardiol. 64, 997–1002 (2014). sourceNot checked yet

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In obese rabbits, dogs and humans, the levels of renal medullary glycosaminoglycans, especially hyaluronan, were markedly elevated compared with lean controls.

“In obese rabbits, dogs and humans, the levels of renal medullary glycosaminoglycans, especially hyaluronan, which is an important component of the ECM and is often associated with tissue inflammation and oedema, were markedly elevated compared with lean controls53–55.”

• cites [53] Hall, J. E. Louis, K. Dahl Memorial Lecture. Renal and cardiovascular mechanisms of hypertension in obesity. Hypertension 23, 381–394 (1994). sourceNot checked yet

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• cites [54] Alonso-Galicia, M., Dwyer, T. M., Herrera, G. A. & Hall, J. E. Increased hyaluronic acid in the inner renal medulla of obese dogs. Hypertension 25, 888–892 (1995). sourceNot checked yet

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• cites [55] Dwyer, T. M. et al. Distribution of renal medullary hyaluronan in lean and obese rabbits. Kidney Int. 58, 721–729 (2000). sourceNot checked yet

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Excessive renal sinus fat and perirenal fat may also cause lipotoxicity owing to the accumulation of intracellular triglycerides and toxic metabolites such as ceramides.

“Excessive RSF and PRF may also cause lipotoxicity owing to the accumulation of intracellular triglycerides and toxic metabolites such as ceramides57,58.”

• cites [57] Adeosun, S. O. et al. Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells. Am. J. Physiol. Renal Physiol. 315, F323–F331 (2018). sourceNot checked yet

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• cites [58] Unger, R. H. & Scherer, P. E. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol. Metab. 21, 345–352 (2010). sourceNot checked yet

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Increases in perirenal fat and renal sinus fat increased the risk of hypertension independent of BMI and visceral adipose tissue.

“increases in PRF and RSF increased the risk of hypertension independent of BMI and VAT.”

Pharmacological RAAS blockade blunts sodium retention and hypertension in obesity.

“Although obesity causes only modest increases in AngII formation, pharmacological RAAS blockade blunts sodium retention and hypertension in obesity6.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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Aldosterone synthase inhibitors attenuate cardiac and renal injury in models of experimental hypertension such as spontaneously hypertensive rats and uninephrectomized rats fed a high-salt diet.

“Aldosterone synthase inhibitors have been shown to attenuate cardiac and renal injury in models of experimental hypertension, such as spontaneously hypertensive rats (SHRs) and uninephrectomized rats fed a high-salt diet77,78, but their efficacy in obesity-induced hypertension is unclear.”

• cites [77] Andersen, K. Aldosterone synthase inhibition in hypertension. Curr. Hypertens. Rep. 15, 484–488 (2013). sourceNot checked yet

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• cites [78] Namsolleck, P. & Unger, T. Aldosterone synthase inhibitors in cardiovascular and renal diseases. Nephrol. Dial. Transplant. 29, i62–i68 (2014). sourceNot checked yet

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Rac1 inhibitors ameliorated proteinuria and kidney injury in obese rodents and in rodents with salt-sensitive hypertension.

“In addition, Racl inhibitors amelio-rated proteinuria and kidney injury in obese rodents and in rodents with salt-sensitive hypertension82.”

• cites [82] Fujita, T. Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems. J. Am. Soc. Nephrol. 25, 1148–1155 (2014). sourceNot checked yet

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MR antagonism is an important therapy for obesity-induced hypertension and its associated cardiorenal abnormalities even in the absence of hyperaldosteronism.

“These studies indicate that MR antagonism is an important therapy for obesity-induced hypertension and its associated cardiorenal abnormalities even in the absence of hyperaldosteronism.”

Genetically engineered mice with increased circulating levels of ANP and BNP showed beiging of white adipocytes and increased thermogenesis compared with wild-type mice.

“In addition, genetically engineered mice with increased circulating levels of ANP and BNP (owing to a lack of receptors that promote clearance of these NPs) showed ‘beiging of white adipocytes and increased thermogenesis compared with wild-type mice99.”

• cites [99] Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012). sourceNot checked yet

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An altered gut microbiota may be, in part, secondary to increased blood pressure or activation of the RAAS and sympathetic nervous system.

“These findings suggest that an altered GM may be, in part, secondary to increased BP or activation of the RAAS and SNS, which are known to contribute to hypertension in SHRs.”

The MR antagonist spironolactone is effective for treating patients with resistant hypertension who are usually overweight or obese and already on at least three antihypertensive drugs.

“The landmark PATHWAY-2 trial85,86 clearly established that the MR antagonist spironolactone is effective for treating patients with resistant hypertension who are usually overweight or obese and already on at least three antihypertensive drugs87.”

• cites [85] Williams, B. et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 6, 464–475 (2018). sourceNot checked yet

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• cites [86] Williams, B. et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 386, 2059–2068 (2015). sourceNot checked yet

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• cites [87] Carey, R. M. et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension 72, e53–e90 (2018). sourceNot checked yet

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The pathogenic role of visceral adipose tissue may be related to secretion of cytokines such as tumour necrosis factor and interleukin-6 that contribute to inflammation, insulin resistance, and increased blood pressure.

“The pathogenic role of VAT, beyond its contributions to overall adiposity, may be related to secretion of cytokines such as tumour necrosis factor (TNF) and IL-6 14 that contribute to inflammation, insulin resistance and increased BP.”

• cites [14] Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). sourceNot checked yet

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In spontaneously hypertensive rats, blood pressure reduction as a result of ACE inhibition had beneficial effects on gut pathology, including reductions in mucosal permeability, inflammation, and dysbiosis.

“In SHRs, BP reduction as a result of ACE inhibition had beneficial effects on gut pathology (for example, reductions in mucosal permeability, inflammation and dysbiosis)105.”

• cites [105] Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017). sourceNot checked yet

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Transgenic mice that overexpressed brain natriuretic peptide were protected against diet-induced obesity and insulin resistance.

“Consistent with this hypothesis, transgenic mice that overexpressed BNP were protected against diet-induced obesity and insulin resistance98.”

• cites [98] Miyashita, K. et al. Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes 58, 2880–2892 (2009). sourceNot checked yet

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Limited direct evidence exists for a cause-and-effect relationship between short-chain fatty acids and blood pressure regulation in obesity-induced hypertension.

“Although production of SCFAs provides a plausible link between the GM and BP regulation, limited direct evidence exists for a cause-and-effect relationship in obesity-induced hypertension.”

Men with obesity and hypertension had lower plasma pro-ANP levels than normotensive lean men despite greater sodium intake and larger left atria.

“Men with obesity and hypertension had lower plasma pro ANP levels than normotensive lean men despite greater sodium intake and larger left atria90,91.”

• cites [90] Asferg, C. L. et al. Relative atrial natriuretic peptide deficiency and inadequate renin and angiotensin II suppression in obese hypertensive men. Hypertension 62, 147–153 (2013). sourceNot checked yet

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• cites [91] Asferg, C. L., Andersen, U. B., Linneberg, A., Goetze, J. P. & Jeppesen, J. L. Obese hypertensive men have lower circulating proatrial natriuretic peptide concentrations despite greater left atrial size. Am. J. Hypertens. 31, 645–650 (2018). sourceNot checked yet

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Increases in natriuretic peptides associated with high salt intake and volume loading are diminished in obese compared with lean individuals.

“Increases in NPs associated with high salt intake and volume loading are also diminished in obese compared with lean individuals90–92.”

• cites [90] Asferg, C. L. et al. Relative atrial natriuretic peptide deficiency and inadequate renin and angiotensin II suppression in obese hypertensive men. Hypertension 62, 147–153 (2013). sourceNot checked yet

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• cites [91] Asferg, C. L., Andersen, U. B., Linneberg, A., Goetze, J. P. & Jeppesen, J. L. Obese hypertensive men have lower circulating proatrial natriuretic peptide concentrations despite greater left atrial size. Am. J. Hypertens. 31, 645–650 (2018). sourceNot checked yet

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• cites [92] 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. 118, 231–240 (2010). sourceNot checked yet

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Increased visceral and subcutaneous adipose tissue volume and reduced adipose tissue quality assessed as reduced attenuation on CT are associated with increased cardiovascular risk that is not explained by increased BMI.

“Increased VAT and SAT volume as well as reduced adipose tissue quality (assessed indirectly as reduced attenuation in Hounsfield units on CT) were reported to be associated with increased cardiovascular risk that was not explained by increased BMI111.”

• cites [111] Abraham, T. M., Pedley, A., Massaro, J. M., Hoffmann, U. & Fox, C. S. Association between visceral and subcutaneous adipose depots and incident cardiovascular disease risk factors. Circulation 132, 1639–1647 (2015). sourceNot checked yet

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The mineralocorticoid receptor can be activated by glucocorticoids in the setting of 11β-hydroxysteroid dehydrogenase type 2 deficiency.

“MR can also be activated by glucocorticoids in the setting of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) deficiency83.”

• cites [83] Chapman, K., Holmes, M. & Seckl, J. 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol. Rev. 93, 1139–1206 (2013). sourceNot checked yet

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The GLP1 agonist liraglutide and dipeptidyl peptidase 4 inhibitors lower blood pressure in obese animals and in patients with hypertension and type 2 diabetes mellitus.

“The GLP1 agonist liraglutide and dipeptidyl peptidase 4 (DPP4) inhibitors, which attenuate degradation of GLP1, lower BP in obese animals and in patients with hypertension and T2DM108.”

• cites [108] Afsar, B., Vaziri, N. D., Aslan, G., Tarim, K. & Kanbay, M. Gut hormones and gut microbiota: implications for kidney function and hypertension. J. Am. Soc. Hypertens. 10, 954–961 (2016). sourceNot checked yet

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Adipocytes secrete many bioactive substances that influence metabolic and cardiovascular functions, including blood pressure.

“Adipocytes are much more than just energy-storage depots — they secrete many bioactive substances that influence metabolic and cardiovascular functions, including BP110.”

• cites [110] Zhu, Q. & Scherer, P. E. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat. Rev. Nephrol. 14, 105–120 (2018). sourceNot checked yet

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In the Framingham Heart Study, participants with obesity had lower circulating amino-terminal pro-ANP concentrations than those with normal BMI.

“In the Framingham Heart Study, participants with obesity had lower circulating amino-terminal pro-ANP concentrations than those who had normal BMI93.”

• cites [93] Wang, T. J. et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 109, 594–600 (2004). sourceNot checked yet

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Digestion of dietary fibre by the gut microbiota produces short-chain fatty acids including acetate, propionate, and butyrate.

“In particular, digestion of dietary fibre by the GM produces short-chain fatty acids (SCFAs) including acetate, propionate and butyrate.”

Increased levels of neprilysin and upregulation of NPR-C in obesity could contribute to a relative natriuretic peptide deficiency and impaired NaCl homeostasis despite increased cardiac filling pressures and volume loading.

“Thus, increased levels of neprilysin and upregulation of NPR-C in obesity could contribute to a relative NP deficiency and impaired NaCl homeostasis despite increased cardiac filling pressures and volume loading.”

The leptin receptor is expressed in multiple regions of the forebrain and hindbrain, including the hypothalamus, brainstem vasomotor centres, and intermediolateral nucleus of the spinal cord.

“The LepR is expressed in multiple regions of the forebrain and hindbrain, including the hypothalamus, brainstem vasomotor centres and intermediolateral nucleus (IML) of the spinal cord119,135,138 (FIG. 5a).”

• cites [119] Pan, W. W. & Myers, M. G. Jr. Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19, 95–105 (2018). sourceNot checked yet

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• cites [135] Munzberg, H. & Myers, M. G. Jr. Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8, 566–570 (2005). sourceNot checked yet

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• cites [138] Mark, A. L. et al. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension 53, 375–380 (2009). sourceNot checked yet

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Leptin infusions in rodents over several days cause mild, gradual increases in blood pressure and heart rate.

“Leptin infusions in rodents over several days also cause mild, gradual increases in BP and HR125–127.”

• cites [125] Shek, E. W., Brands, M. W. & Hall, J. E. Chronic leptin infusion increases arterial pressure. Hypertension 31, 409–414 (1998). sourceNot checked yet

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• cites [126] Mark, A. L. Selective leptin resistance revisited. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R566–R581 (2013). sourceNot checked yet

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• cites [127] Kuo, J. J., Jones, O. B. & Hall, J. E. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 37, 670–676 (2001). sourceNot checked yet

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Adiponectin supplementation reduced blood pressure in salt-fed adiponectin-knockout mice and in KKAy mice, which develop obesity via ectopic expression of agouti protein.

“Adiponectin supplementation reduced BP in salt-fed, adiponectin-knockout mice and in KKAy mice, which develop obesity via ectopic expression of agouti protein117.”

• cites [117] Ohashi, K. et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47, 1108–1116 (2006). sourceNot checked yet

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Leptin-deficient individuals displayed evidence of autonomic dysfunction, including postural hypotension, reduced blood pressure responses to cold pressor stimuli, and diminished RAAS responses to upright posture.

“Moreover, these leptin-deficient individuals displayed evidence of autonomic dysfunction, including postural hypotension, reduced BP responses to cold pressor stimuli and diminished RAAS responses to upright posture.”

• cites [134] Ozata, M., Ozdemir, I. C. & 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. 84, 3686–3695 (1999). sourceNot checked yet

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Leptin may act as a link between obesity, sympathetic nerve activity, and hypertension.

“These observations, together with the findings in rodents discussed above, are consistent with the concept that leptin may act as a link between obesity, SNA and hypertension.”

Plasma leptin concentration is highly correlated with sympathetic nerve activity.

“Plasma leptin concentration is highly correlated with SNA activity123, and acute leptin infusions increase SNA in the brown adipose tissue, adrenal glands and kidneys of rodents124.”

• cites [123] Snitker, S., Pratley, R. E., Nicolson, M., Tataranni, P. A. & Ravussin, E. Relationship between muscle sympathetic nerve activity and plasma leptin concentration. Obes. Res. 5, 338–340 (1997). sourceNot checked yet

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Acute leptin administration stimulates sympathetic nerve activity in humans.

“Similar to findings in rodents, acute leptin administration stimulates SNA in humans132.”

• cites [132] Machleidt, F. et al. Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans. J. Clin. Endocrinol. Metab. 98, E491–E496 (2013). sourceNot checked yet

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The chronic hypertensive effects of leptin were greatly potentiated after inhibition of nitric oxide synthesis despite weight loss that was associated with decreased food intake.

“The chronic hypertensive effects of leptin were greatly potentiated after inhibition of NO synthesis despite weight loss that was associated with decreased food intake127.”

• cites [127] Kuo, J. J., Jones, O. B. & Hall, J. E. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 37, 670–676 (2001). sourceNot checked yet

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Leptin is secreted in increasing amounts as adipocytes enlarge.

“In contrast to adiponectin, leptin is secreted in increasing amounts as adipocytes enlarge119,120.”

• cites [119] Pan, W. W. & Myers, M. G. Jr. Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19, 95–105 (2018). sourceNot checked yet

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• cites [120] Schwartz, M. W. et al. Central nervous system control of food intake. Nature 404, 661–671 (2000). sourceNot checked yet

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The anorexic effects of acute leptin injections are attenuated in individuals with obesity.

“The anorexic effects of acute leptin injections are attenuated in individuals with obesity135.”

• cites [135] Munzberg, H. & Myers, M. G. Jr. Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8, 566–570 (2005). sourceNot checked yet

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Leptin infusion in ob/ob mice raised their blood pressure despite causing significant weight loss.

“Leptin infusion in ob/ob mice raised their BP despite causing significant weight loss131.”

• cites [131] Aizawa-Abe, M. et al. Pathophysiological role of leptin in obesity-related hypertension. J. Clin. Invest. 105, 1243–1252 (2000). sourceNot checked yet

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The sympathetic nervous system effects of leptin may involve multiple neuronal populations.

“Thus, the SNS effects of leptin may involve multiple neuronal populations.”

Deletion of leptin receptor in the hypothalamic arcuate nucleus of mice blocked much of the elevated renal sympathetic nerve activity that was evoked by leptin.

“Deletion of LepR in the hypothalamic arcuate nucleus (ARC) of mice blocked much of the elevated RSNA that was evoked by leptin139.”

• cites [139] Harlan, S. M. et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ. Res. 108, 808–812 (2011). sourceNot checked yet

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Acute leptin infusions increase sympathetic nerve activity in brown adipose tissue, adrenal glands, and kidneys of rodents.

“Plasma leptin concentration is highly correlated with SNA activity123, and acute leptin infusions increase SNA in the brown adipose tissue, adrenal glands and kidneys of rodents124.”

• cites [124] Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L. & Sivitz, W. I. Receptor-mediated regional sympathetic nerve activation by leptin. J. Clin. Invest. 100, 270–278 (1997). sourceNot checked yet

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Leptin receptor antagonism decreased blood pressure and sympathetic nerve activity in obese rabbits.

“The observation that LepR antagonism decreased BP and SNA in obese rabbits supports the importance of leptin in obesity hypertension129.”

• cites [129] Lim, K., Burke, S. L. & Head, G. A. Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits. Hypertension 61, 628–634 (2013). sourceNot checked yet

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Selective leptin receptor deletion in POMC neurons of the arcuate nucleus and brainstem abolished blood pressure increases in mice during chronic leptin infusions.

“Selective LepR deletion in POMC neurons of the ARC and brainstem also abolished BP increases in mice during chronic leptin infusions140.”

• cites [140] do Carmo, J. M. et al. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57, 918–926 (2011). sourceNot checked yet

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In a study of four patients with leptin deficiency due to gene mutations, three had normal blood pressure and one had high blood pressure.

“A study that included four patients with leptin deficiency due to gene mutations found that despite severe obesity, three of these patients had normal BP and only one had high BP, possibly owing to unexplained high levels of adrenocorticotropic hormone, which can increase plasma cortisol levels as well as BP134.”

• cites [134] Ozata, M., Ozdemir, I. C. & 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. 84, 3686–3695 (1999). sourceNot checked yet

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Administration of recombinant leptin for 12 weeks failed to increase blood pressure in overweight or obese adults.

“Although the effect of chronic leptin infusion on SNA in humans has not yet been reported, administration of recombinant leptin for 12 weeks failed to increase BP in overweight or obese adults133.”

• cites [133] Zelissen, P. M. et al. Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial. Diabetes Obes. Metab. 7, 755–761 (2005). sourceNot checked yet

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Renal sympathetic nerve activity, assessed by kidney noradrenaline spillover, is higher in individuals with obesity than in those who are non-obese and normotensive.

“RSNA, assessed by kidney noradrenaline spillover, is also higher in individuals with obesity than in those who are non-obese and normotensive152,154.”

• cites [152] Grassi, G., Mark, A. & Esler, M. The sympathetic nervous system alterations in human hypertension. Circ. Res. 116, 976–990 (2015). sourceNot checked yet

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• cites [154] Esler, M. et al. Obesity paradox in hypertension: is this because sympathetic activation in obesity-hypertension takes a benign form? Hypertension 71, 22–33 (2018). sourceNot checked yet

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Sympathetic blockade in patients with obesity or in experimental animals with dietary-induced obesity consistently reduces blood pressure.

“However, sympathetic blockade in patients with obesity or in experimental animals with dietary-induced obesity consistently reduces BP6,158.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [158] Wofford, M. R. et al. Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects. Am. J. Hypertens. 14, 694–698 (2001). sourceNot checked yet

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In contrast to skeletal muscle and kidneys, heart sympathetic nerve activity may be within the normal range, or perhaps even reduced, in patients with obesity and hypertension.

“In contrast to skeletal muscle and kidneys, heart SNA may be within the normal range, or perhaps even reduced, in patients with obesity and hypertension152”

• cites [152] Grassi, G., Mark, A. & Esler, M. The sympathetic nervous system alterations in human hypertension. Circ. Res. 116, 976–990 (2015). sourceNot checked yet

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Part of the variability in sympathetic nerve activity and blood pressure among individuals with obesity may relate to differences in visceral adipose tissue, which seems to be more closely correlated with increased sympathetic nerve activity and hypertension than overall adiposity.

“Part of this variability may relate to differences in VAT, which seems to be more closely correlated with increased SNA and hypertension than does overall adiposity156.”

• cites [156] Davy, K. P. & Hall, J. E. Obesity and hypertension: two epidemics or one? Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R803–R813 (2004). sourceNot checked yet

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Obesity elicits complex alterations in renal, sympathetic nervous system, endothelial, and vascular function that may augment the effects of leptin on sympathetic nerve activity and blood pressure.

“In summary, obesity elicits complex alterations in renal, SNS, endothelial and vascular function that may augment the effects of leptin on SNA and BP.”

In rabbits, renal sympathetic nerve activity increases within a few days of starting a high-fat diet.

“In rabbits, RSNA increases within a few days of starting an HFD155.”

• cites [155] Armitage, J. A. et al. Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet. Hypertension 60, 163–171 (2012). sourceNot checked yet

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Renal nerves may mediate most of the blood pressure effects of sympathetic activation in obesity.

“The renal nerves may mediate most of the BP effects of sympathetic activation in obesity.”

Increased renal sympathetic nerve activity in individuals with obesity contributes to increases in renin secretion, sodium reabsorption and blood pressure.

“Increased RSNA in individuals with obesity contributes to increases in renin secretion, sodium reabsorption and BP159–161.”

• cites [159] Kassab, S. et al. Endothelin-A receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats. Hypertension 31, 397–402 (1998). sourceNot checked yet

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• cites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). sourceNot checked yet

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• cites [161] Henegar, J. R. et al. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am. J. Hypertens. 27, 1285–1292 (2014). sourceNot checked yet

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In humans, skeletal muscle sympathetic nerve activity measured by microneurography increases even with modest weight gain.

“In humans, skeletal MSNA, measured by microneurography, increases even with modest weight gain153.”

• cites [153] Gentile, C. L., Orr, J. S., Davy, B. M. & Davy, K. P. Modest weight gain is associated with sympathetic neural activation in nonobese humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1834–R1838 (2007). sourceNot checked yet

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Increased sympathetic activity is an important contributor to the development and maintenance of obesity-induced hypertension.

“These findings indicate that increased sympathetic activity is an important contributor to the development and maintenance of obesity-induced hypertension.”

The role of the sympathetic nervous system in linking obesity with elevated blood pressure has been well documented in experimental models and in humans.

“The role of the SNS in linking obesity with elevated BP has been well documented in experimental models and in humans121,152.”

• cites [121] Hall, J. E. et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J. Biol. Chem. 285, 17271–17276 (2010). sourceNot checked yet

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• cites [152] Grassi, G., Mark, A. & Esler, M. The sympathetic nervous system alterations in human hypertension. Circ. Res. 116, 976–990 (2015). sourceNot checked yet

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The acute stimulatory effect of leptin on renal sympathetic nerve activity in anaesthetized mice was nearly abolished by pharmacological inhibition of PI3K.

“The acute stimulatory effect of leptin on RSNA in anaesthetized mice was nearly abolished by pharmacological inhibition of PI3K143.”

• cites [143] Rahmouni, K., Haynes, W. G., Morgan, D. A. & Mark, A. L. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 41, 763–767 (2003). sourceNot checked yet

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The IRS2-PI3K pathway contributes to the effects of leptin on sympathetic nerve activity and blood pressure.

“The IRS2-PI3K pathway also contributes to the effects of leptin on SNA and BP.”

• cites [143] Rahmouni, K., Haynes, W. G., Morgan, D. A. & Mark, A. L. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 41, 763–767 (2003). sourceNot checked yet

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• cites [144] do Carmo, J. M., da Silva, A. A. & Hall, J. E. Leptin reduces food intake but fails to raise blood pressure in mice with deficiency of insulin receptor substrate 2 (IRS2) in the entire brain or specifically in POMC neurons. Hypertension 60, A27 (2012). sourceNot checked yet

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Targeted deletion of SHP2 in the forebrain or in POMC neurons markedly attenuated increases in blood pressure and lowering of glucose levels in response to chronic leptin infusion, indicating an important role for SHP2 signalling in these cardiometabolic functions.

“Moreover, targeted deletion of SHP2 in the forebrain or in POMC neurons markedly attenuated increases in BP and lowering of glucose levels in response to chronic leptin infusion, indicating an important role for SHP2 signalling in these cardiometabolic functions146,147.”

• cites [146] do Carmo, J. M. et al. Shp2 signaling in POMC neurons is important for leptin’s actions on blood pressure, energy balance, and glucose regulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R1438–R1447 (2014). sourceNot checked yet

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• cites [147] do Carmo, J. M. et al. Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin. Int. J. Obes. 38, 775–783 (2014). sourceNot checked yet

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Considerable variability exists in sympathetic nerve activity and blood pressure among individuals with obesity of similar age, sex, and BMI.

“Considerable variability exists in SNA and BP among individuals with obesity of similar age, sex and BMI.”

Similar results of impaired baroreflexes were found in rabbits fed a high-fat diet.

“Similar results were found in rabbits fed an HFD155.”

• cites [155] Armitage, J. A. et al. Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet. Hypertension 60, 163–171 (2012). sourceNot checked yet

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In overweight patients with hypertension who were not taking antihypertensive medications, endovascular ultrasound renal denervation caused significantly greater reductions in 24-hour ambulatory systolic blood pressure at 2 months than did a sham procedure.

“In overweight patients with hypertension who were not taking antihypertensive medications, endovascular ultrasound RDN caused significantly greater reductions in 24-hour ambulatory systolic BP at 2 months than did a sham procedure166.”

• cites [166] Azizi, M. et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 391, 2335–2345 (2018). sourceNot checked yet

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In dogs, the reductions in cardiac baroreflex sensitivity and heart rate variability intensified with progressive weight gain and hypertension.

“In dogs, marked reductions in 24-hour cardiac baroreflex sensitivity and HR variability occurred within a few days of starting an HFD, before appreciable weight gain or large BP increases, although these responses intensified with progressive weight gain and hypertension179.”

• cites [179] Iliescu, R., Tudorancea, I., Irwin, E. D. & Lohmeier, T. E. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am. J. Physiol. Heart Circ. Physiol. 305, H1080–H1088 (2013). sourceNot checked yet

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Even under optimal conditions, catheter-based renal denervation methods ablate only 40-50% of renal nerves unless nerves running along the renal segmental arteries are also ablated.

“Even under optimal conditions, catheter-based RDN methods ablate only 40–50% of renal nerves unless nerves running along the renal segmental arteries are also ablated167.”

• cites [167] Henegar, J. R. et al. Catheter-based radiofrequency renal denervation: location effects on renal norepinephrine. Am. J. Hypertens. 28, 909–914 (2015). sourceNot checked yet

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The rapid onset of impaired baroreflexes with overfeeding suggests that factors associated with increased caloric intake may contribute to this impairment.

“The rapid onset of impaired baroreflexes with overfeeding suggests that factors associated with increased caloric intake may contribute to this impairment, but definite mediators have not been identified.”

In the SYMPLICITY HTN clinical trials, renal denervation decreased 24-hour ambulatory systolic/diastolic blood pressure by −11/−7 mmHg.

“In the SYMPLICITY HTN clinical trials, RDN also decreased 24-hour ambulatory systolic/diastolic BP by −11/−7mmHg 164.”

• cites [164] Hering, D. et al. Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension. Hypertension 64, 118–124 (2014). sourceNot checked yet

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Renal denervation nearly normalized blood pressure in dogs with established obesity-induced hypertension.

“RDN also nearly normalized BP in dogs with established obesity-induced hypertension160,162 (FIG. 6).”

• cites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). sourceNot checked yet

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• cites [162] Iliescu, R., Lohmeier, T. E., Tudorancea, I., Laffin, L. & Bakris, G. L. Renal denervation for the treatment of resistant hypertension: review and clinical perspective. Am. J. Physiol. Renal Physiol. 309, F583–F594 (2015). sourceNot checked yet

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This trial was limited because the extent of renal denervation was not assessed.

“However, this trial was also limited because the extent of RDN was not assessed.”

In patients receiving medical treatment for moderate, uncontrolled hypertension, renal denervation extending into branch arteries caused significant, clinically relevant reductions in blood pressure compared with sham controls.

“A study of patients receiving medical treatment for moderate, uncontrolled hypertension indicated that RDN extending into branch arteries caused significant, clinically relevant reductions in BP compared with sham controls168.”

• cites [168] Kandzari, D. E. et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 391, 2346–2355 (2018). sourceNot checked yet

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Renal denervation slightly decreased muscle sympathetic nerve activity and blood pressure in patients with obesity and hypertension.

“Another study reported that RDN slightly decreased MSNA and BP in patients with obesity and hypertension171.”

• cites [171] Hering, D. et al. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension 61, 457–464 (2013). sourceNot checked yet

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The blood pressure effects of renal denervation are due to ablation of renal sympathetic efferent fibres rather than sensory afferent nerves.

“This procedure did not blunt the rise in BP during development of obesity-induced hypertension, indicating that the BP effects of RDN are due to ablation of renal sympathetic efferent fibres rather than sensory afferent nerves.”

• cites [173] Zappe, D. H. et al. Role of renal afferent nerves in obesity-induced hypertension. Am. J. Hypertens. 9, 20A (1996). sourceNot checked yet

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• AssumptionRests on an assumption: Renal denervation removes both sympathetic efferent and sensory afferent renal nerves.

The first randomized, sham-controlled renal denervation trial, SYMPLICITY HTN-3, failed to prove superiority of renal denervation for blood pressure lowering compared with a sham control procedure.

“The first randomized, sham-controlled RDN trial, SYMPLICITY HTN-3, failed to prove superiority of RDN for BP lowering compared with a sham control procedure165.”

• cites [165] Bhatt, D. L. et al. A controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 370, 1393–1401 (2014). sourceNot checked yet

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Cardiac and renal sympathetic nerve activity baroreflex sensitivity is depressed after rapid weight gain and in the setting of long-standing obesity in experimental animals and humans.

“Studies in experimental animals and humans indicate that cardiac and RSNA baroreflex sensitivity is depressed after rapid weight gain and in the setting of long-standing obesity37,155,179.”

• cites [37] Van Vliet, B. N., Hall, J. E., Mizelle, H. L., Montani, J. P. & Smith, M. J. Jr. Reduced parasympathetic control of heart rate in obese dogs. Am. J. Physiol. 269, H629–H637 (1995).Not checked yet

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• cites [155] Armitage, J. A. et al. Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet. Hypertension 60, 163–171 (2012). sourceNot checked yet

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• cites [179] Iliescu, R., Tudorancea, I., Irwin, E. D. & Lohmeier, T. E. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am. J. Physiol. Heart Circ. Physiol. 305, H1080–H1088 (2013). sourceNot checked yet

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Increased vascular stiffness associated with chronic obesity-induced hypertension could contribute to impaired baroreflex sensitivity by limiting pressure-induced distension of the arterial wall where baroreceptor sensory endings are located.

“Increased vascular stiffness associated with chronic obesity-induced hypertension could contribute to impaired baroreflex sensitivity by limiting pressure-induced distension of the arterial wall where baroreceptor sensory endings are located.”

In dogs, marked reductions in 24-hour cardiac baroreflex sensitivity and heart rate variability occurred within a few days of starting a high-fat diet, before appreciable weight gain or large blood pressure increases.

“In dogs, marked reductions in 24-hour cardiac baroreflex sensitivity and HR variability occurred within a few days of starting an HFD, before appreciable weight gain or large BP increases, although these responses intensified with progressive weight gain and hypertension179.”

• cites [179] Iliescu, R., Tudorancea, I., Irwin, E. D. & Lohmeier, T. E. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am. J. Physiol. Heart Circ. Physiol. 305, H1080–H1088 (2013). sourceNot checked yet

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Sensory afferent fibres convey signals from renal chemoreceptors and mechanoreceptors to the central nervous system.

“However, sensory afferent fibres convey signals from renal chemoreceptors and mechanoreceptors to the CNS and are thought to contribute to increased BP in some forms of experimental hypertension169.”

• cites [169] DiBona, G. F. Sympathetic nervous system and hypertension. Hypertension 61, 556–560 (2013). sourceNot checked yet

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The blood pressure-lowering effects of renal denervation may be attenuated by prior antihypertensive therapy, especially RAAS blockade.

“However, the BP-lowering effects of RDN may be attenuated by prior antihypertensive therapy, especially RAAS blockade.”

Carotid sinus stimulation decreased plasma noradrenaline concentration in obese dogs.

“Carotid sinus stimulation also decreased plasma noradrenaline concentration, suggesting global sympathoinhibition, whereas RDN did not have this effect.”

• cites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). sourceNot checked yet

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In overweight or obese patients with resistant hypertension, catheter-based radiofrequency renal denervation lowered office systolic/diastolic blood pressure by −25 to −30/−10 to −12 mmHg for up to 24 months.

“In overweight or obese patients with resistant hypertension, catheter-based radiofrequency RDN lowered office systolic/diastolic BP by −25 to −30/−10 to −12 mmHg for up to 24 months164.”

• cites [164] Hering, D. et al. Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension. Hypertension 64, 118–124 (2014). sourceNot checked yet

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Sensory afferent fibres are thought to contribute to increased blood pressure in some forms of experimental hypertension.

“However, sensory afferent fibres convey signals from renal chemoreceptors and mechanoreceptors to the CNS and are thought to contribute to increased BP in some forms of experimental hypertension169.”

• cites [169] DiBona, G. F. Sympathetic nervous system and hypertension. Hypertension 61, 556–560 (2013). sourceNot checked yet

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In obese dogs fed a high-fat diet, renal denervation greatly attenuated sodium retention and increases in blood pressure.

“In obese dogs fed an HFD, RDN greatly attenuated sodium retention and increases in BP159.”

• cites [159] Kassab, S. et al. Endothelin-A receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats. Hypertension 31, 397–402 (1998). sourceNot checked yet

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The lack of effect of surgical renal denervation on plasma noradrenaline or heart rate suggests that sensory afferent signals from the kidneys to the brain may not make an important contribution to increases in sympathetic activity or cardiac autonomic dysfunction of obesity.

“In obese dogs, surgical RDN reduced renal tissue noradrenaline concentration by over 96% and almost completely abolished hypertension but did not lower plasma noradrenaline levels or HR, suggesting that sensory afferent signals from the kidneys to the brain may not make an important contribution to increases in sympathetic activity or cardiac autonomic dysfunction of obesity160.”

• cites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). sourceNot checked yet

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In patients and experimental animals with obesity hypertension, renal denervation lowers blood pressure if the nerves are ablated along the branches as well as the main renal artery.

“Thus, in patients and in experimental animals with obesity hypertension, RDN lowers BP if the nerves are ablated along the branches as well as the main renal artery.”

• AssumptionRests on an assumption: Renal denervation removes both sympathetic efferent and sensory afferent renal nerves.

Chemoreflex-induced sympathetic responses to hypoxia are exaggerated in patients with obesity and obstructive sleep apnoea compared with individuals without obesity exposed to hypoxia.

“Chemoreflex-induced sympathetic responses to hypoxia are exaggerated in patients with obesity and OSA compared with individuals without obesity exposed to hypoxia182,183.”

• cites [182] Mansukhani, M. P., Kara, T., Caples, S. M. & Somers, V. K. Chemoreflexes, sleep apnea, and sympathetic dysregulation. Curr. Hypertens. Rep. 16, 476 (2014). sourceNot checked yet

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• cites [183] Mansukhani, M. P., Wang, S. & Somers, V. K. Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp. Physiol. 100, 130–135 (2015). sourceNot checked yet

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Carotid body chemoreceptors are believed to have a pivotal role in sympathetic dysregulation in obstructive sleep apnoea.

“Carotid body chemoreceptors are believed to have a pivotal role in sympathetic dysregulation in OSA, although other mechanisms may also contribute183,184.”

• cites [183] Mansukhani, M. P., Wang, S. & Somers, V. K. Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp. Physiol. 100, 130–135 (2015). sourceNot checked yet

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• cites [184] Floras, J. S. Sleep apnea and cardiovascular disease: an enigmatic risk factor. Circ. Res. 122, 1741–1764 (2018). sourceNot checked yet

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In rodents, MC4R signalling seems to be essential for obesity to increase sympathetic nerve activity and blood pressure.

“Thus, in rodents, MC4R signalling seems to be essential for obesity to increase SNA and BP.”

Obesity is associated with a heightened central chemoreflex response to hypercapnia in the absence of coexisting disease.

“Obesity is also associated with a heightened central chemoreflex response to hypercapnia in the absence of coexisting disease182,183.”

• cites [182] Mansukhani, M. P., Kara, T., Caples, S. M. & Somers, V. K. Chemoreflexes, sleep apnea, and sympathetic dysregulation. Curr. Hypertens. Rep. 16, 476 (2014). sourceNot checked yet

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• cites [183] Mansukhani, M. P., Wang, S. & Somers, V. K. Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp. Physiol. 100, 130–135 (2015). sourceNot checked yet

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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.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [189] do Carmo, J. M. et al. Role of the brain melanocortins in blood pressure regulation. Biochim. Biophys. Acta 1863, 2508–2514 (2017). sourceNot checked yet

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• cites [190] da Silva, A. A., do Carmo, J. M., Wang, Z. & Hall, J. E. The brain melanocortin system, sympathetic control, and obesity hypertension. Physiology 29, 196–202 (2014). sourceNot checked yet

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Renal denervation did not decrease plasma noradrenaline concentration in obese dogs.

“Carotid sinus stimulation also decreased plasma noradrenaline concentration, suggesting global sympathoinhibition, whereas RDN did not have this effect.”

• cites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). sourceNot checked yet

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In the arcuate nucleus and brainstem, POMC-expressing neurons project to second-order neurons involved in blood pressure regulation, where their axons release α-melanocyte-stimulating hormone, the endogenous ligand for MC4R.

“In the ARC and brainstem, POMC-expressing neurons project to second-order neurons involved in BP regulation (for example, in the paraventricular nucleus (PVN)), where their axons release a-melanocyte-stimulating hormone (aMSH), the endogenous ligand for MC4R191 (FIG. 5a).”

• cites [191] Tao, Y. X. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 31, 506–543 (2010). sourceNot checked yet

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The POMC-MC4R system is a major regulator of energy balance.

“The POMC-MC4R system is a major regulator of energy balance.”

• cites [191] Tao, Y. X. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 31, 506–543 (2010). sourceNot checked yet

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• cites [192] Cone, R. D. Studies on the physiological functions of the melanocortin system. Endocr. Rev. 27, 736–749 (2006). sourceNot checked yet

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MC4R activation may also increase blood pressure in people with obesity.

“MC4R activation may also increase BP in people with obesity.”

The blood pressure-reducing effects of MC4R blockade are enhanced in spontaneously hypertensive rats and other models of hypertension associated with increased sympathetic nerve activity.

“The BP-reducing effects of MC4R blockade are enhanced in SHRs and other models of hypertension that are associated with increased SNA197.”

• cites [197] da Silva, A. A. et al. Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats. Hypertension 51, 884–890 (2008). sourceNot checked yet

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Obesity-induced hypoxaemia may stimulate peripheral chemoreceptors, causing compensatory increases in ventilation and sympathetic nerve activity that contribute to hypertension.

“Thus, obesity-induced hypoxaemia may stimulate peripheral chemoreceptors, causing compensatory increases in ventilation and SNA that contribute to hypertension.”

• AssumptionRests on an assumption: Hypoxaemia may occur in obesity without obstructive sleep apnoea.

Studies in experimental animals suggest that chronic intermittent hypoxia produces sustained increases in sympathetic nerve activity and blood pressure.

“Studies in experimental animals suggest that chronic intermittent hypoxia produces sustained increases in SNA and BP186.”

• cites [186] Iturriaga, R., Oyarce, M. P. & Dias, A. C. R. Role of carotid body in intermittent hypoxia-related hypertension. Curr. Hypertens. Rep. 19, 38 (2017). sourceNot checked yet

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Increased efferent renal sympathetic nerve activity is important in mediating obesity-induced hypertension.

“These observations highlight the importance of increased efferent RSNA in mediating obesity-induced hypertension and the capacity of baroreflex activation and RDN to abrogate renal sympathoexcitation160.”

• cites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). sourceNot checked yet

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• AssumptionRests on an assumption: Renal denervation removes both sympathetic efferent and sensory afferent renal nerves.
• AssumptionRests on an assumption: Increased stimulation of renal sympathetic efferent nerves increases renin secretion, renal tubular sodium reabsorption and blood pressure.

These changes in obese dogs were attenuated by chronic electrical stimulation of the carotid baroreflex or carotid body denervation.

“These changes were attenuated by chronic electrical stimulation of the carotid baroreflex or carotid body denervation.”

• cites [188] Lohmeier, T. E. et al. Chronic interactions between carotid baroreceptors and chemoreceptors in obesity hypertension. Hypertension 68, 227–235 (2016). sourceNot checked yet

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The blood pressure-increasing effects of neuronostatin and nesfatin 1 were diminished by MC4R blockade.

“The BP-increasing effects of the hormones neuronostatin and nesfatin 1, which are elevated in obesity, were diminished203,204, and hypertension induced by inhibition of NO synthesis was attenuated by MC4R blockade205.”

• cites [203] Yosten, G. L., Pate, A. T. & Samson, W. K. Neuronostatin acts in brain to biphasically increase mean arterial pressure through sympatho-activation followed by vasopressin secretion: the role of melanocortin receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1194–R1199 (2011). sourceNot checked yet

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• cites [204] Yosten, G. L. & Samson, W. K. Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306, R722–R727 (2014). sourceNot checked yet

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Multiple factors can activate central nervous system POMC-MC4R signalling to mediate sympathetic nerve activation and increased blood pressure in obesity.

“Together, these observations indicate that multiple factors can activate CNS POMC-MC4R signalling to mediate SNS activation and increased BP in obesity.”

In mice with defective MC4R signalling in the central nervous system, restoration of MC4R expression on POMC neurons partially restored blood pressure responses to acute stress.

“In mice with defective MC4R signalling in the CNS, restoration of MC4R expression on POMC neurons partially restored BP responses to acute stress, suggesting that activation of MC4R might sensitize POMC neurons to other stimuli that influence sympathetic activity209.”

• cites [209] do Carmo, J. M., da Silva, A. A., Rushing, J. S., Pace, B. & Hall, J. E. Differential control of metabolic and cardiovascular functions by melanocortin-4 receptors in proopiomelanocortin neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R359–R368 (2013). sourceNot checked yet

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Treatment with synthetic MC4R agonists raises blood pressure and heart rate despite causing weight loss in people with obesity.

“Similar to their effects in rodents, treatment with synthetic MC4R agonists raises BP and HR despite causing weight loss in people with obesity; these effects limit the use of MC4R agonists in the treatment of obesity199.”

• cites [199] Greenfield, J. R. et al. Modulation of blood pressure by central melanocortinergic pathways. N. Engl. J. Med. 360, 44–52 (2009). sourceNot checked yet

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Patients with obesity and MC4R mutations showed a substantial reduction in apnoea-induced increases in muscle sympathetic nerve activity compared with control individuals with obesity and intact MC4R signalling.

“Moreover, patients with obesity and MC4R mutations showed a substantial reduction in apnoea-induced increases in MSNA compared with control individuals with obesity and intact MC4R signalling206.”

• cites [206] Sayk, F. et al. Sympathetic function in human carriers of melanocortin-4 receptor gene mutations. J. Clin. Endocrinol. Metab. 95, 1998–2002 (2010). sourceNot checked yet

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Hypertension induced by inhibition of nitric oxide synthesis was attenuated by MC4R blockade.

“The BP-increasing effects of the hormones neuronostatin and nesfatin 1, which are elevated in obesity, were diminished203,204, and hypertension induced by inhibition of NO synthesis was attenuated by MC4R blockade205.”

• cites [205] da Silva, A. A. et al. Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion. Hypertension 65, 171–177 (2014). sourceNot checked yet

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MC4R is a transmembrane G protein-coupled receptor found in greatest abundance in central nervous system neuronal populations important for autonomic regulation, including the nucleus of the solitary tract, dorsal motor nucleus of the vagus, paraventricular nucleus, lateral hypothalamus and preganglionic sympathetic neurons of the intermediolateral cell column.

“MC4R is a transmembrane G protein-coupled receptor that is found in greatest abundance in CNS neuronal populations that are important for autonomic regulation, including the NTS, dorsal motor nucleus of the vagus, PVN, lateral hypothalamus and preganglionic sympathetic neurons of the IML192,207 (FIG. 5a).”

• cites [192] Cone, R. D. Studies on the physiological functions of the melanocortin system. Endocr. Rev. 27, 736–749 (2006). sourceNot checked yet

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• cites [207] Rossi, J. et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 13, 195–204 (2011). sourceNot checked yet

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Considerable evidence from studies in experimental animals and humans indicates a major role of stimulation of the sympathetic nervous system in obesity-induced hypertension.

“Although the complex pathophysiology of obesity-induced hypertension continues to be intensively investigated, considerable evidence from studies in experimental animals and humans indicates a major role of renal compression due to excess PRF, RSF and VAT squeezing the kidneys; activation of the RAAS; and stimulation of the SNS, which together mediate increased renal sodium reabsorption.”

Excess adiposity, especially when localized in visceral regions and around the kidneys, accounts for 65-75% of the risk of primary hypertension.

“Excess adiposity, especially when localized in visceral regions and around the kidneys, accounts for 65–75% of the risk of primary hypertension6,7.”

• cites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). sourceNot checked yet

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• cites [7] Garrison, R. J., Kannel, W. B., Stokes, J. III & Castelli, W. P. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev. Med. 16, 235–251 (1987). sourceNot checked yet

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BDNF may be a downstream effector of MC4R.

“In rats, injection of anti-brain-derived neurotrophic factor (BDNF) antibody into the CNS blunted the anorexic effect of MC4R activation, suggesting that BDNF may be a downstream effector of MC4R211.”

• cites [211] Bariohay, B. et al. 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 150, 2646–2653 (2009). sourceNot checked yet

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Activation of MC4R might sensitize POMC neurons to other stimuli that influence sympathetic activity.

“In mice with defective MC4R signalling in the CNS, restoration of MC4R expression on POMC neurons partially restored BP responses to acute stress, suggesting that activation of MC4R might sensitize POMC neurons to other stimuli that influence sympathetic activity209.”

• cites [209] do Carmo, J. M., da Silva, A. A., Rushing, J. S., Pace, B. & Hall, J. E. Differential control of metabolic and cardiovascular functions by melanocortin-4 receptors in proopiomelanocortin neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R359–R368 (2013). sourceNot checked yet

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Evidence suggests that cholinergic preganglionic parasympathetic and sympathetic neuronal MC4R may contribute to elevated blood pressure in obesity.

“However, evidence suggests that cholinergic preganglionic parasympathetic and sympathetic neuronal MC4R may contribute to elevated BP in obesity208.”

• cites [208] Sohn, J. W. et al. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell 152, 612–619 (2013). sourceNot checked yet

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Insulin might also activate POMC neurons.

“In obese Zucker rats, which exhibit defective LepR signalling, CNS blockade of MC4R reduced BP201 and attenuated the sympathetic response to insulin, suggesting that insulin might also activate POMC neurons202.”

• cites [202] Ward, K. R., Bardgett, J. F., Wolfgang, L. & Stocker, S. D. Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus. Hypertension 57, 435–441 (2011). sourceNot checked yet

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MC4R signals mainly through phosphorylation of cAMP and activation of protein kinase A.

“MC4R signals mainly through phosphorylation of cAMP and activation of protein kinase A (PKA)191.”

• cites [191] Tao, Y. X. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 31, 506–543 (2010). sourceNot checked yet

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In rats, injection of anti-brain-derived neurotrophic factor antibody into the central nervous system blunted the anorexic effect of MC4R activation.

“In rats, injection of anti-brain-derived neurotrophic factor (BDNF) antibody into the CNS blunted the anorexic effect of MC4R activation, suggesting that BDNF may be a downstream effector of MC4R211.”

• cites [211] Bariohay, B. et al. 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 150, 2646–2653 (2009). sourceNot checked yet

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Renal compression, renin-angiotensin-aldosterone system activation and sympathetic nervous system stimulation together mediate increased renal sodium reabsorption in obesity-induced hypertension.

“Although the complex pathophysiology of obesity-induced hypertension continues to be intensively investigated, considerable evidence from studies in experimental animals and humans indicates a major role of renal compression due to excess PRF, RSF and VAT squeezing the kidneys; activation of the RAAS; and stimulation of the SNS, which together mediate increased renal sodium reabsorption.”

These effects limit the use of MC4R agonists in the treatment of obesity.

“Similar to their effects in rodents, treatment with synthetic MC4R agonists raises BP and HR despite causing weight loss in people with obesity; these effects limit the use of MC4R agonists in the treatment of obesity199.”

• cites [199] Greenfield, J. R. et al. Modulation of blood pressure by central melanocortinergic pathways. N. Engl. J. Med. 360, 44–52 (2009). sourceNot checked yet

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Adipokines, including leptin, may also contribute to obesity-induced hypertension by activation of the renin-angiotensin-aldosterone system and sympathetic nervous system.

“Adipokines, including leptin, may also contribute to obesity-induced hypertension by activation of the RAAS and SNS.”

Considerable evidence from studies in experimental animals and humans indicates a major role of activation of the renin-angiotensin-aldosterone system in obesity-induced hypertension.

“Although the complex pathophysiology of obesity-induced hypertension continues to be intensively investigated, considerable evidence from studies in experimental animals and humans indicates a major role of renal compression due to excess PRF, RSF and VAT squeezing the kidneys; activation of the RAAS; and stimulation of the SNS, which together mediate increased renal sodium reabsorption.”

In obese Zucker rats, central nervous system blockade of MC4R attenuated the sympathetic response to insulin.

“In obese Zucker rats, which exhibit defective LepR signalling, CNS blockade of MC4R reduced BP201 and attenuated the sympathetic response to insulin, suggesting that insulin might also activate POMC neurons202.”

• cites [202] Ward, K. R., Bardgett, J. F., Wolfgang, L. & Stocker, S. D. Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus. Hypertension 57, 435–441 (2011). sourceNot checked yet

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In obese Zucker rats with defective leptin receptor signalling, central nervous system blockade of MC4R reduced blood pressure.

“In obese Zucker rats, which exhibit defective LepR signalling, CNS blockade of MC4R reduced BP201 and attenuated the sympathetic response to insulin, suggesting that insulin might also activate POMC neurons202.”

• cites [201] do Carmo, J. M., da Silva, A. A., Rushing, J. S. & Hall, J. E. Activation of the central melanocortin system contributes to the increased arterial pressure in obese Zucker rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R561–R567 (2012). sourceNot checked yet

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Considerable evidence from studies in experimental animals and humans indicates a major role of renal compression due to excess perirenal fat, renal sinus fat and visceral adipose tissue squeezing the kidneys in obesity-induced hypertension.

“Although the complex pathophysiology of obesity-induced hypertension continues to be intensively investigated, considerable evidence from studies in experimental animals and humans indicates a major role of renal compression due to excess PRF, RSF and VAT squeezing the kidneys; activation of the RAAS; and stimulation of the SNS, which together mediate increased renal sodium reabsorption.”