Obesity, kidney dysfunction and hypertension: mechanistic links

In the paper

“Obesity and prediabetes also cause endothelial dysfunction, which is reversible with weight loss if severe vascular injury has not occurred38,39.”

What the sources say

• Partly supported

  The Discussion (page not provided) says obesity is associated with endothelial dysfunction and reports improved endothelial-dependent vasodilation after six weeks of weight reduction in overweight adults. It also links that improvement to lower plasma glucose, but does not establish that prediabetes causes endothelial dysfunction or that reversibility depends on the absence of severe vascular injury. (LLM, conf=0.88)

  cites [38] Raitakari, M. et al. Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler. Thromb. Vasc. Biol. 24, 124–128 (2004). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and 'Endothelial Vasodilator Dysfunction in Prediabetes' section link obesity and prediabetes to endothelial dysfunction. The Abstract calls weight loss a mainstay of treatment, but the passages found do not say that weight loss reverses endothelial dysfunction or make reversibility conditional on the absence of severe vascular injury. (LLM, conf=0.84)

  cites [39] Wasserman, D. H., Wang, T. J. & Brown, N. J. The vasculature in prediabetes. Circ. Res. 122, 1135–1150 (2018). sourceExperimental — accuracy not yet measured

In the paper

“The observation that PTP1B deficiency increases BP via SNS stimulation, even when leptin concentrations are not elevated148, indicates that this pathway influences SNA and BP through mechanisms other than leptin signalling.”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [148] Belin de Chantemele, E. J. et al. Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. Circulation 120, 753–763 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Targeted STAT3 deletion in POMC neurons markedly blunted the BP effect of leptin in mice but caused only small reductions in energy expenditure and increases in food intake142.”

What the sources say

• Partly supported

  The Abstract and Discussion report that POMC-neuron Stat3 deletion abolished the blood-pressure rise during chronic leptin treatment in male mice. The Discussion also describes mild hyperphagia, supporting the food-intake part. It does not report a general reduction in energy expenditure: it says oxygen consumption and heat production had no major alterations, while the Results report higher heat production in female mice. Page numbers were not available in our copy. (LLM, conf=0.86)

  cites [142] Dubinion, J. H. et al. Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin. Hypertension 61, 1066–1074 (2013). sourceExperimental — accuracy not yet measured

In the paper

“We found that in rodents, HFD-induced obesity blunts the acute anorexic effects of leptin but does not cause resistance to the chronic CNS effects of leptin on BP or HR137.”

What the sources say

• Not checked yetcites [137] Dubinion, J. H., da Silva, A. A. & Hall, J. E. Chronic blood pressure and appetite responses to central leptin infusion in rats fed a high fat diet. J. Hypertens. 29, 758–762 (2011). source

In the paper

“Pima Indians have a high prevalence of obesity but relatively low rates of hypertension compared with white individuals32.”

What the sources say

• Not checked yetcites [32] Saad, M. F. et al. Racial differences in the relation between blood pressure and insulin resistance. N. Engl. J. Med. 324, 733–739 (1991). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity.”

In the paper

“Surgical removal of excess SAT (for example, large-volume liposuction) does not reduce BP or improve insulin resistance15.”

What the sources say

• Not checked yetcites [15] Mohammed, B. S., Cohen, S., Reeds, D., Young, V. L. & Klein, S. Long-term effects of large-volume liposuction on metabolic risk factors for coronary heart disease. Obesity 16, 2648–2651 (2008). source

In the paper

“leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway”

In the paper

“Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin.”

In the paper

“Muscle sympathetic nervous system activity (MSNA) was also lower in Pima Indians than in white individuals and did not track well with adiposity33.”

What the sources say

• Not checked yetcites [33] Weyer, C. et al. Ethnic differences in insulinemia and sympathetic tone as links between obesity and blood pressure. Hypertension 36, 531–537 (2000). source

In the paper

“kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation”

In the paper

“most population studies have not measured VAT, RSF and PRF, which are better predictors of increased BP than are BMI or overall adiposity.”

In the paper

“regional body fat distribution is strongly influenced by genetics and in turn may influence susceptibility to cardiometabolic disorders, including hypertension14.”

What the sources say

• Not checked yetcites [14] Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source

In the paper

“excess PRF encapsulating the kidneys and excess RSF may squeeze the kidneys and increase intrarenal pressures10,35.”

What the sources say

• Not checked yetcites [10] Hall, M. E. et al. Obesity, hypertension, and chronic kidney disease. Int. J. Nephrol. Renovasc. Dis. 7, 75–88 (2014). source
• Not checked yetcites [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). source

In the paper

“These cardiac changes markedly increase the risk of heart failure and arrhythmias.”

In the paper

“Enlargement of the atria also occurs in obesity and is related, in part, to volume expansion, increased venous return and cardiac preload36.”

What the sources say

• Not checked yetcites [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). source

In the paper

“Accelerated vascular stiffening also occurs in obesity, leading to increases in pulse wave velocity and systolic BP40.”

What the sources say

• Not checked yetcites [40] Wildman, R. P., Mackey, R. H., Bostom, A., Thompson, T. & Sutton-Tyrrell, K. Measures of obesity are associated with vascular stiffness in young and older adults. Hypertension 42, 468–473 (2003). source

In the paper

“in chronic obesity, increases in BP, glomerular hyperfiltration, neurohumoral activation and metabolic changes may cause renal injury and increased salt sensitivity of BP.”

In the paper

“These changes tend to increase fractional NaCl reabsorption in the loop of Henle and decrease delivery of NaCl to the macula densa, causing feedback-mediated reductions in afferent arteriolar resistance, increases in RBF and GFR and stimulation of renin secretion from juxtaglomerular cells10.”

What the sources say

• Not checked yetcites [10] Hall, M. E. et al. Obesity, hypertension, and chronic kidney disease. Int. J. Nephrol. Renovasc. Dis. 7, 75–88 (2014). source

In the paper

“Excessive weight gain initially causes renal vasodilation and increases in RBF and GFR before nephron injury35.”

What the sources say

• Not checked yetcites [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). source

In the paper

“obesity may lead to compression of the kidneys, resulting in increased intrarenal pressures and tending to reduce blood flow rates in the vasa recta and loop of Henle35,45 (FIG. 2).”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [45] Hall, J. E. et al. Obesity-associated hypertension and kidney disease. Curr. Opin. Nephrol. Hypertens. 12, 195–200 (2003). source

In the paper

“In the early phases of obesity, BP may not be salt-sensitive; therefore, hypertension may not be greatly exacerbated by high salt intake10.”

What the sources say

• Not checked yetcites [10] Hall, M. E. et al. Obesity, hypertension, and chronic kidney disease. Int. J. Nephrol. Renovasc. Dis. 7, 75–88 (2014). source

In the paper

“In rabbits, dogs and humans, obesity increases extracellular fluid volume and blood flow in the gastrointestinal tract, skeletal muscles, heart, kidney and several other tissues, leading to elevated venous return and CO levels35.”

What the sources say

• Not checked yetcites [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). source

In the paper

“An increase in NaCl reabsorption in the renal tubules before or at the macula densa cells results in a decrease in NaCl concentration at these cells, which, in turn, send signals to the renal afferent arterioles that cause vasodilation as well as increases in GFR and RBF.”

In the paper

“At least three mechanisms have important roles in causing the increased renal sodium reabsorption and hypertension that are associated with rapid increases in adiposity and excessive weight gain: renal compression; stimulation of the renin-angiotensin-aldosterone system (RAAS) and renal MR activation; and stimulation of the SNS (FIG. 3).”

In the paper

“Excessive VAT initiates several effects that may compress the kidneys, increase renal sodium reabsorption and raise BP.”

In the paper

“Multiple factors could contribute to renal vasodilation in obesity, including compression of the renal tubules, hyperglycaemia, high protein intake, hyperinsulinaemia and increased BP combined with impaired renal autoregulation6,43,44.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [43] Carlstrom, M., Wilcox, C. S. & Arendshorst, W. J. Renal autoregulation in health and disease. Physiol. Rev. 95, 405–511 (2015). source
• Not checked yetcites [44] Woods, L. L., Mizelle, H. L. & Hall, J. E. Control of renal hemodynamics in hyperglycemia: possible role of tubuloglomerular feedback. Am. J. Physiol. 252, F65–F73 (1987).

In the paper

“renal vasodilation, increases in renal blood flow (RBF) and glomerular hyperfiltration occur early after weight gain but are later followed by declines in RBF and glomerular filtration rate (GFR) as a result of kidney injury and gradual loss of nephrons10.”

What the sources say

• Not checked yetcites [10] Hall, M. E. et al. Obesity, hypertension, and chronic kidney disease. Int. J. Nephrol. Renovasc. Dis. 7, 75–88 (2014). source

In the paper

“aldosterone activates MRs expressed on macula densa cells and increases their production of NO, which induces renal vasodilation and glomerular hyperfiltration48,49.”

What the sources say

• Not checked yetcites [48] Hall, J. E., Granger, J. P., Smith, M. J. Jr & Premen, A. J. Role of renal hemodynamics and arterial pressure in aldosterone “escape”. Hypertension 6, I183–I192 (1984). source
• Not checked yetcites [49] Fu, Y. et al. Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors. Hypertension 59, 599–606 (2012). source

In the paper

“After accounting for other body fat depots and risk factors for hypertension, RSF volume was highly correlated with the number of BP medications and with stage II hypertension19.”

What the sources say

• Not checked yetcites [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). source

In the paper

“In addition, MR antagonism improved brachial artery flow-mediated dilation (an index of vascular endothelial function)75 and left ventricular function in patients with obesity and left ventricular diastolic dysfunction76.”

What the sources say

• Not checked yetcites [75] Hwang, M. H. et al. Mineralocorticoid receptors modulate vascular endothelial function in human obesity. Clin. Sci. 125, 513–520 (2013). source
• Not checked yetcites [76] Kosmala, W., Przewlocka-Kosmala, M., Szczepanik-Osadnik, H., Mysiak, A. & Marwick, T. H. Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade. Heart 99, 320–326 (2013). source

In the paper

“Another study in patients with resistant hypertension and an average BMI of −32 kg/m2 reported that aldosterone synthase inhibition using LC1699 reduced plasma aldosterone concentration but caused minimal reductions in BP that were substantially less than those achieved with an MR antagonist80.”

What the sources say

• Not checked yetcites [80] Karns, A. D., Bral, J. M., Hartman, D., Peppard, T. & Schumacher, C. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J. Clin. Hypertens. 15, 186–192 (2013). source

In the paper

“Although obesity is often associated with only mild increases in plasma aldosterone levels, MR blockade effectively reduces BP and attenuates injury in target organs including the kidneys.”

In the paper

“such pressure increases could compress the vasa recta and thin loops of Henle, resulting in reduced blood flow in the kidney medulla and contributing to increases in fractional NaCl reabsorption, renin secretion and glomerular hyperfiltration (FIG. 2).”

In the paper

“Racl stimulates MR signalling, and the levels of Racl in renal epithelial cells were increased in obese rodents.”

What the sources say

• Not checked yetcites [82] Fujita, T. Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems. J. Am. Soc. Nephrol. 25, 1148–1155 (2014). source

In the paper

“The BP-lowering effect of LC1699 was not as impressive, however, as that observed with MR antagonism, and LC1699 therapy was associated with an important adverse effect of reduced cortisol synthesis.”

What the sources say

• Not checked yetcites [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). source

In the paper

“Kidney compression likely contributes to hypertension in obese rabbits, dogs and humans, but this mechanism is not important in obese rodents, which have little fat adherence to the kidney capsule or renal compression6.”

What the sources say

• Not checked yetcites [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). source

In the paper

“As NPs are known to reduce sodium reabsorption and BP, relative NP deficiency has been postulated as a contributor to the pathogenesis of obesity-induced hypertension.”

In the paper

“Individuals with obesity may have decreased bacterial diversity, and gut microbial dysbiosis is associated with metabolic disorders such as T2DM101.”

What the sources say

• Not checked yetcites [101] Aydin, O., Nieuwdorp, M. & Gerdes, V. The gut microbiome as a target for the treatment of type 2 diabetes. Curr. Diab Rep. 18, 55 (2018). source

In the paper

“Adiponectin is an adipocyte-secreted protein hormone that promotes glucose metabolism and fatty acid oxidation113.”

What the sources say

• Not checked yetcites [113] Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002). source

In the paper

“Other studies, however, found no correlation or even a positive correlation between BMI and plasma NP concentrations94,95.”

What the sources say

• Not checked yetcites [94] Grandi, A. M. et al. Natriuretic peptides as markers of preclinical cardiac disease in obesity. Eur. J. Clin. Invest. 34, 342–348 (2004). source
• Not checked yetcites [95] Abdulle, A. M. et al. Plasma N terminal pro-brain natriuretic peptide levels and its determinants in a multi-ethnic population. J. Hum. Hypertens. 21, 647–653 (2007). source

In the paper

“In obese dogs, kidney 11βHSD2 expression is reduced by 60–70%, supporting the possibility that glucocorticoids might contribute to MR activation in obesity6.”

What the sources say

• Not checked yetcites [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). source

In the paper

“Natriuretic peptides (NPs), including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are secreted from the heart in response to stretch of the atrial or ventricular cardiomyocytes and signal via cGMP-coupled receptors89.”

What the sources say

• Not checked yetcites [89] Jordan, J., Birkenfeld, A. L., Melander, O. & Moro, C. Natriuretic peptides in cardiovascular and metabolic crosstalk: implications for hypertension management. Hypertension 72, 270–276 (2018). source

In the paper

“The antihypertensive benefit of MR antagonism seems to be related largely to its natriuretic and diuretic effects86, which are consistent with the important role of MR activation in mediating obesity-associated sodium retention88.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [88] Calhoun, D. A. Fluid retention, aldosterone excess, and treatment of resistant hypertension. Lancet Diabetes Endocrinol. 6, 431–433 (2018). source

In the paper

“Ethnicity may be an important factor in determining the importance of hypoadiponectinaemia as decreased adiponectin levels are associated with hypertension in Asian individuals but not in white individuals116.”

What the sources say

• Not checked yetcites [116] Sabbatini, A. R., Fontana, V., Laurent, S. & Moreno, H. An update on the role of adipokines in arterial stiffness and hypertension. J. Hypertens. 33, 435–444 (2015). source

In the paper

“In addition, macrophages infiltrate VAT to a greater extent than SAT and secrete TNF and other pro-inflammatory molecules that could influence BP14.”

What the sources say

• Not checked yetcites [14] Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source

In the paper

“These observations suggest that NPs may protect against obesity and metabolic dysfunction, whereas NP deficiency could exacerbate obesity-induced metabolic disorders.”

In the paper

“A pilot study in normotensive, healthy humans reported that a high-salt diet for 14 days reduced intestinal survival of Lactobacillus and increased BP, although a cause-and-effect relationship between altered GM and BP was not established104.”

What the sources say

• Not checked yetcites [104] Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017). source

In the paper

“These SCFAs are thought to affect the function of the immune system, epithelial cells, blood vessels and nervous system and may underlie the reductions in hypertension risk that are associated with fibre-rich diets103,106.”

What the sources say

• Not checked yetcites [103] Yang, T., Richards, E. M., Pepine, C. J. & Raizada, M. K. The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. Nat. Rev. Nephrol. 14, 442–456 (2018). source
• Not checked yetcites [106] Riedl, R. A., Atkinson, S. N., Burnett, C. M. L., Grobe, J. L. & Kirby, J. R. The gut microbiome, energy homeostasis, and implications for hypertension. Curr. Hypertens. Rep. 19, 27 (2017). source

In the paper

“For example, glucagon-like peptide-1 (GLP1), which is generated from L-cells in the colon and ileum, increases insulin secretion and insulin sensitivity, reduces food intake and increases renal NaCl excretion109.”

What the sources say

• Not checked yetcites [109] Muskiet, M. H. A. et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat. Rev. Nephrol. 13, 605–628 (2017). source

In the paper

“Plasma adiponectin concentration is decreased in patients with obesity, especially those with excess visceral fat, and this downregulation is associated with insulin resistance, impaired glucose metabolism, decreased fatty acid metabolism and ectopic fat accumulation114,115.”

What the sources say

• Not checked yetcites [114] Ohashi, K., Ouchi, N. & Matsuzawa, Y. Adiponectin and hypertension. Am. J. Hypertens. 24, 263–269 (2011). source
• Not checked yetcites [115] Wang, Z. V. & Scherer, P. E. Adiponectin, cardiovascular function, and hypertension. Hypertension 51, 8–14 (2008). source

In the paper

“In mice, high salt intake altered the GM, and treatment with Lactobacillus murinus attenuated salt-induced increases in BP by ~5 mmHg 104.”

What the sources say

• Not checked yetcites [104] Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017). source

In the paper

“Although genetic deletion of these CNS signalling pathways may increase adiposity, only STAT3 deletion causes severe obesity and greatly attenuates the anorexic effect of leptin141.”

What the sources say

• Not checked yetcites [141] Gao, Q. et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc. Natl Acad. Sci. USA 101, 4661–4666 (2004). source

In the paper

“Although the suppressive effects of leptin on food intake are blunted in obesity, its acute stimulatory actions on RSNA seem to be preserved, suggesting selective leptin resistance126,136.”

What the sources say

• Not checked yetcites [126] Mark, A. L. Selective leptin resistance revisited. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R566–R581 (2013). source
• Not checked yetcites [136] Rahmouni, K., Morgan, D. A., Morgan, G. M., Mark, A. L. & Haynes, W. G. Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes 54, 2012–2018 (2005). source

In the paper

“In the CNS, leptin increases Janus tyrosine kinase 2 (JAK2) activity and activates three primary intracellular pathways: phosphorylation of LepR at Tyrl 138 recruits latent signal transducer and activator of transcription 3 (STAT3); phosphorylation of LepR at Tyr985 recruits Src homology 2 tyrosine phosphatase (SHP2) to activate mitogen-activated protein kinase (MAPK); and autophosphorylation of J”

What the sources say

• Not checked yetcites [119] Pan, W. W. & Myers, M. G. Jr. Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19, 95–105 (2018). source

In the paper

“The chronic hypertensive effects of leptin in non-obese rodents are modest; however, hyperleptinaemia also causes anorexia and stimulates NO production, effects that tend to decrease SNA and BP127.”

What the sources say

• Not checked yetcites [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). source

In the paper

“In addition, leptin-deficient (ob/ob) mice exhibit severe obesity, dyslipidaemia, insulin resistance and hyperinsulinaemia but reduced BP and SNA compared with lean control mice130.”

What the sources say

• Not checked yetcites [130] Mark, A. L. et al. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J. Hypertens. 17, 1949–1953 (1999). source

In the paper

“The role of adiponectin in cardiometabolic regulation was examined in adiponectin-knockout mice, which had normal BP when maintained on a normal salt intake117. By contrast, when fed a high-salt diet, these mice had greater increases in BP than did control mice, suggesting salt sensitivity of BP.”

What the sources say

• Not checked yetcites [117] Ohashi, K. et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47, 1108–1116 (2006). source

In the paper

“Combined blockade of both a-adrenergic and β-adrenergic receptors abolished the chronic effects of leptin on BP in male rats, suggesting that these effects were mediated by the SNS128.”

What the sources say

• Not checked yetcites [128] Carlyle, M., Jones, O. B., Kuo, J. J. & Hall, J. E. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 39, 496–501 (2002). source

In the paper

“Thus, current data, although sparse, suggest that leptin increases SNA in humans and that people with leptin deficiency may not be hypertensive or have increased SNA despite severe obesity, insulin resistance, hyperinsulinaemia and dyslipidaemia.”

In the paper

“Leptin is a hormone that is produced mainly by adipocytes and has been implicated in a wide variety of physiological functions, especially in the regulation of energy balance119,120.”

What the sources say

• Not checked yetcites [119] Pan, W. W. & Myers, M. G. Jr. Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19, 95–105 (2018). source
• Not checked yetcites [120] Schwartz, M. W. et al. Central nervous system control of food intake. Nature 404, 661–671 (2000). source

In the paper

“Together, these observations suggest that leptin increases sympathetic activity and BP in obese rodents.”

In the paper

“In addition to regulating energy stores, leptin increases sympathetic nerve activity (SNA) by binding to leptin receptors (LepRs) in the CNS and contributes to obesity-induced hypertension6,121,122.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [121] Hall, J. E. et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J. Biol. Chem. 285, 17271–17276 (2010). source
• Not checked yetcites [122] do Carmo, J. M. et al. Control of metabolic and cardiovascular function by the leptin-brain melanocortin pathway. IUBMB Life 65, 692–698 (2013). source

In the paper

“Acute leptin injections into the brainstem NTS doubled RSNA and significantly increased BP, suggesting that brainstem LepRs also contribute to the effect of leptin on SNA138.”

What the sources say

• Not checked yetcites [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). source

In the paper

“These observations suggest that PTP1B and SOCS3 may modulate the cardiometabolic effects of leptin, but their combined contribution to obesity-induced selective leptin resistance is still unknown.”

In the paper

“Increases in SNA that are associated with obesity are often modest, vary between organs and do not reduce tissue blood flow.”

In the paper

“Neuronal deletion of SHP2 signalling in mice led to hyperphagia, severe obesity and glucose dysregulation145.”

What the sources say

• Not checked yetcites [145] Krajewska, M. et al. Development of diabesity in mice with neuronal deletion of Shp2 tyrosine phosphatase. Am. J. Pathol. 172, 1312–1324 (2008). source

In the paper

“However, obesity also attenuates the effects of leptin on appetite, energy expenditure and glucose homeostasis.”

In the paper

“An important regulator of LepR signalling is protein tyrosine phosphatase IB (PTP1B), which dephosphorylates JAK2 (FIG. 5b).”

What the sources say

• Not checked yetcites [148] Belin de Chantemele, E. J. et al. Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. Circulation 120, 753–763 (2009). source

In the paper

“Sex and age-related variations in body fat distribution may also contribute to differences in SNA between women and men, and between younger and older adults157.”

What the sources say

• Not checked yetcites [157] Davy, K. P. & Orr, J. S. Sympathetic nervous system behavior in human obesity. Neurosci. Biobehav. Rev. 33, 116–124 (2009). source

In the paper

“Thus, IRS2-PI3K signalling has an important role in mediating the effects of leptin on SNA and BP, but it has much less effect on energy balance.”

In the paper

“Although obesity is generally associated with increased SNA, sympathetic stimulation is not uniform in different organs.”

In the paper

“Genetic disruption of PTP1B signalling enhances leptin signalling and attenuates diet-induced obesity but amplifies the effects of leptin on BP148.”

What the sources say

• Not checked yetcites [148] Belin de Chantemele, E. J. et al. Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. Circulation 120, 753–763 (2009). source

In the paper

“Surprisingly, POMC-specific PTP1B deficiency did not enhance BP and HR responses to hyperleptinaemia induced by an HFD but did improve glucose tolerance in male mice149.”

What the sources say

• Not checked yetcites [149] Aberdein, N. et al. Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 314, R478–R488 (2018). source

In the paper

“The extent to which selective leptin resistance occurs in obesity is unclear, but the net effect may be preservation or even amplification of leptin’s hypertensive effects and attenuation of its beneficial anorexic and antidiabetic actions that help to control body weight and prevent metabolic dysfunction.”

In the paper

“In addition, neuronal SOCS3 deficiency reduced body weight and food intake, amplified the effects of leptin on BP and attenuated the adverse metabolic effects of a high-fat, high-fructose diet in mice151.”

What the sources say

• Not checked yetcites [151] do Carmo, J. M. et al. Neuronal suppressor of cytokine signaling 3: role in modulating chronic metabolic and cardiovascular effects of leptin. Hypertension 71, 1248–1257 (2018). source

In the paper

“Thus, each of leptin’s three main cell signalling pathways mediate BP regulation; however, they have different actions on control of energy balance and glucose levels.”

In the paper

“Genetic deficiency of CNS IRS2 signalling greatly diminished the BP effects of chronic leptin infusion but elicited only mild increases in adiposity and failed to attenuate the anorexic effects of leptin in mice144.”

What the sources say

• Not checked yetcites [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). source

In the paper

“Suppressor of cytokine signalling 3 (SOCS3) deficiency also enhanced leptin signalling and reduced adiposity in mice maintained on an HFD150.”

What the sources say

• Not checked yetcites [150] Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739–743 (2004). source

In the paper

“Thus, leptin-mediated STAT3 activation in POMC neurons contributes to regulation of BP, whereas STAT3 signalling in other neurons seems to mediate most of the effects of leptin on energy expenditure and food intake.”

In the paper

“Studies in rodent models of obesity-induced hypertension also demonstrated reductions in BP and protection against target organ injury after RDN163.”

What the sources say

• Not checked yetcites [163] Asirvatham-Jeyaraj, N. et al. Renal denervation normalizes arterial pressure with no effect on glucose metabolism or renal inflammation in obese hypertensive mice. Hypertension 68, 929–936 (2016). source

In the paper

“These results indicate that reductions in BP cannot fully explain improvements in baroreflex sensitivity in obese dogs as BP was similarly reduced by RDN and chronic baroreflex activation (FIG. 6).”

In the paper

“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.”

What the sources say

• Not checked yetcites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). source

In the paper

“By contrast, RDN did not restore baroreflex sensitivity despite abolishing obesity-induced hypertension.”

What the sources say

• Not checked yetcites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). source

In the paper

“However, other investigators failed to observe sustained inhibition of MSNA after RDN and BP reductions were not associated with reduced MSNA in patients with difficult-to-control hypertension172.”

What the sources say

• Not checked yetcites [172] Brinkmann, J. et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Hypertension 60, 1485–1490 (2012). source

In the paper

“In obese dogs, chronic baroreflex activation via electrical stimulation of the carotid sinuses reduced BP, HR and HR variability and restored cardiac baroreflex sensitivity to control levels160.”

What the sources say

• Not checked yetcites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). source

In the paper

“Sustained obesity and hypertension also cause baroreflex dysfunction, which slowly regresses during chronic weight loss in individuals with obesity180,181.”

What the sources say

• Not checked yetcites [180] Seravalle, G. et al. Long-term sympathoinhibitory effects of surgically induced weight loss in severe obese patients. Hypertension 64, 431–437 (2014). source
• Not checked yetcites [181] Grassi, G. et al. Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans. Circulation 97, 2037–2042 (1998). source

In the paper

“Moreover, partial RDN, using a catheter-based radiofrequency method, reduced renal noradrenaline levels by only ~42% but substantially decreased BP in obese dogs161.”

What the sources say

• Not checked yetcites [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). source

In the paper

“The hypothesis that renal afferents mediate some of the BP effects of RDN in humans was sparked by the finding that whole-body noradrenaline spillover and MSNA were decreased in a single patient 1 year after RDN170.”

What the sources say

• Not checked yetcites [170] Schlaich, M. P., Sobotka, P. A., Krum, H., Lambert, E. & Esler, M. D. Renal sympathetic-nerve ablation for uncontrolled hypertension. N. Engl. J. Med. 361, 932–934 (2009). source

In the paper

“However, all of these clinical trials were confounded because the extent of RDN was not verified and patients were already on at least three BP medications, including antagonists of the RAAS, which contributes to the BP effect of RSNA.”

In the paper

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

What the sources say

• Not checked yetcites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). source

In the paper

“Mice with genetic disruption of MC4R signalling exhibit early-onset obesity, hyperphagia, insulin resistance, dyslipidaemia and other features of metabolic syndrome but have normal or reduced BP even when fed high-salt diets198.”

What the sources say

• Not checked yetcites [198] Tallam, L. S., da Silva, A. A. & Hall, J. E. Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Hypertension 48, 58–64 (2006). source

In the paper

“Obese dogs fed an HFD were hypoxaemic but eucapnic and appeared to have tonic activation of carotid chemoreceptors as well as increases in BP and respiratory rate188.”

What the sources say

• Not checked yetcites [188] Lohmeier, T. E. et al. Chronic interactions between carotid baroreceptors and chemoreceptors in obesity hypertension. Hypertension 68, 227–235 (2016). source

In the paper

“Although obesity-induced hypertension often occurs in the absence of OSA, the severity of hypertension is exacerbated when OSA coexists with obesity183,185.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [185] Javaheri, S. et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J. Am. Coll. Cardiol. 69, 841–858 (2017). source

In the paper

“Disruption of POMC-MC4R signalling causes hyperphagia and is the most common known genetic cause of morbid obesity in children193,194.”

What the sources say

• Not checked yetcites [193] Girardet, C. & Butler, A. A. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim. Biophys. Acta 1842, 482–494 (2014). source
• Not checked yetcites [194] Vaisse, C. et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253–262 (2000). source

In the paper

“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.”

What the sources say

• Not checked yetcites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). source