Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis

In the paper

“Rats fed high fat diet also exhibited a rapid increase in radiotelemetric lumbar sympathetic activity which progresses with time, in parallel with hemodynamic and metabolic changes (21).”

What the sources say

• Supported

  The Results report that lumbar sympathetic nerve activity in cafeteria-fed female Wistar rats increased over time and became significantly elevated by day 12. The study used radiotelemetry and also found higher overall heart rates and increased fat mass and leptin. Its Discussion notes that mean arterial pressure was not clearly elevated, but the claim does not specifically assert a blood-pressure increase. (LLM, conf=0.88)

  cites [21] Muntzel MS Al-Naimi OA Barclay A Ajasin D Cafeteria diet increases fat mass and chronically elevates lumbar sympathetic nerve activity in rats Hypertension 2012 60 1498 1502 23090774 PMC3535318 source

In the paper

“Given that excessive sympathetic activity is common in obesity, β-blockers appear as an obvious pharmacologic therapy to treat the hypertension associated with this condition, but treatment with β-blockers leads to metabolic complications including weight gain (16–18).”

What the sources say

• Supported

  The “Data That Support the Hypothesis” section reports weight gain during both short- and long-term β-blocker therapy, including a significant increase in β-blocker-treated patients in the HAPPHY trial. It also describes reduced thermogenesis as a possible mechanism. Page numbers were not supplied in our copy. (LLM, conf=0.92)

  cites [16] Julius S Valentini M Palatini P Overweight and hypertension - A 2-way street? Hypertension 2000 35 807 813 10720599 source
• Partly supported

  The Introduction says traditional β-blockers have been associated with weight gain and worsening insulin resistance. But it distinguishes nebivolol, which it says does not cause weight gain or adversely affect insulin resistance; the Discussion reports reduced weight gain in nebivolol-treated rats. The claim overgeneralizes this complication to β-blockers as a class. (LLM, conf=0.88)

  cites [17] Zhou X Ma L Habibi J Whaley-Connell A Hayden MR Tilmon RD Brown AN Kim JA Demarco VG Sowers JR Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat Hypertension 2010 55 880 888 20176997 PMC2841702 sourceExperimental — accuracy not yet measured
• Not checked yetcites [18] Jordan J Engeli S Boschmann M Weidinger G Luft FC Sharma AM Kreuzberg U Hemodynamic and metabolic responses to valsartan and atenolol in obese hypertensive patients J Hypertens 2005 23 2313 2318 16269974 source

In the paper

“Disruption of leptin receptor signaling in POMC neurons abolished the ability of exogenous leptin administration to increase blood pressure (39;41) which provides additional support to the notion that leptin is a critical hormone in coupling hypertension and obesity (Figure 1).”

What the sources say

• Supported

  The Discussion states that deleting leptin receptors in POMC neurons abolished leptin’s chronic effect on mean arterial pressure in mice. It also reports that chronic leptin infusion raised blood pressure in control mice but not in mice lacking those receptors. (LLM, conf=0.94)

  cites [39] do Carmo JM da Silva AA Cai ZW Lin SY Dubinion JH Hall JE Control of Blood Pressure, Appetite, and Glucose by Leptin in Mice Lacking Leptin Receptors in Proopiomelanocortin Neurons Hypertension 2011 57 918 926 21422382 PMC3092393 source
• Supported

  The Results section reports that seven days of leptin infusion raised blood pressure in control mice but produced no significant increase in mice lacking Stat3 signaling in POMC neurons. The Discussion likewise states that POMC-neuron Stat3 inactivation abolished the blood-pressure rise during chronic leptin treatment. The experiment disrupted this downstream signaling pathway, rather than deleting the leptin receptor itself. (LLM, conf=0.94)

  cites [41] Dubinion JH do Carmo JM Adi A Hamza S da Silva AA Hall JE Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin Hypertension 2013 61 1066 1074 23529161 PMC3678380 source

In the paper

“Obesity is associated with several other changes in the kidney that promote the development of hypertension as well as chronic kidney disease and end-stage renal disease.”

What the sources say

• Partly supported

  The Discussion (page not provided) describes obesity-related kidney changes and an association with hypertension and CKD. It treats the mechanisms by which those changes might contribute to disease as proposed rather than established, and our copy does not address end-stage renal disease. (LLM, conf=0.86)

  cites [63] Foster MC Hwang SJ Porter SA Massaro JM Hoffmann U Fox CS Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study Hypertension 2011 58 784 790 21931075 PMC3204377 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Renal Morphology; page not available) report structural kidney changes in obese mice. The Discussion (Potential mechanisms—Renal Injury; page not available) says kidney injury may be a result rather than a cause of impaired blood-pressure control. The paper does not establish that these changes promote hypertension, chronic kidney disease, or end-stage renal disease. (LLM, conf=0.86)

  cites [64] Belin de Chantemele EJ Ali MI Mintz JD Rainey WE Tremblay ML Fulton DJ Stepp DW Increasing peripheral insulin sensitivity by protein tyrosine phosphatase 1B deletion improves control of blood pressure in obesity Hypertension 2012 60 1273 1279 23045458 PMC3475734 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable in our copy) says obesity is frequently accompanied by elevated blood pressure and renal damage. It does not say that changes in the kidney promote hypertension, nor does it address chronic kidney disease or end-stage renal disease. (LLM, conf=0.85)

  cites [65] Beyer AM Raffai G Weinberg B Fredrich K Lombard JH Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity Hypertension 2012 60 404 410 22710645 PMC3444144 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports obesity-related kidney abnormalities in Bardet–Biedl syndrome (BBS) mouse models and says end-stage renal disease is frequent in BBS patients. But the paper does not establish that obesity-associated kidney changes promote hypertension or chronic kidney disease generally; the Discussion instead considers hypertension as a possible contributor to renal abnormalities. (LLM, conf=0.86)

  cites [66] Guo DF Beyer AM Yang BL Nishimura DY Sheffield VC Rahmouni K Inactivation of Bardet-Biedl syndrome genes causes kidney defects Am J Physiol Renal Physiol 2011 300 F574 F580 21106857 PMC3043995 sourceExperimental — accuracy not yet measured

In the paper

“This is based on the observation that female sheep are protected from adverse renal effects caused by obesity despite exhibiting similar metabolic and cardiovascular phenotypes as the male counterparts (67).”

What the sources say

• Supported

  The Discussion (page unavailable in our copy) explicitly reports similar metabolic and cardiovascular outcomes of juvenile obesity in both sexes, but adverse kidney-cell responses only in males. The paper also concludes that young female sheep were protected from adverse renal effects of obesity. (LLM, conf=0.94)

  cites [67] Bloor ID Sebert SP Mahajan RP Symonds ME The influence of sex on early stage markers of kidney dysfunction in response to juvenile obesity Hypertension 2012 60 991 997 22949537 source

In the paper

“The efficacy of chronic treatment with Ang 1–7, a peptide that negatively modulate RAS activity, in alleviating obesity-associated impairment in endothelium-dependent vasodilation supports further the pathophysiological role of the RAS in obesity-related endothelial dysfunction (73).”

What the sources say

• Supported

  The Discussion states that chronic Ang 1–7 treatment improved impaired endothelium-dependent vasodilation caused by obesity. It also identifies this finding as evidence of a protective vascular role for Ang 1–7 in obesity-associated endothelial dysfunction. (LLM, conf=0.94)

  cites [73] Beyer AM Guo DF Rahmouni K Prolonged treatment with angiotensin 1–7 improves endothelial function in diet-induced obesity J Hypertens 2013 31 4 730 738 23425706 PMC5684878 source

In the paper

“Interestingly, sympathetic overdrive was also found to be closely related to subclinical cardiovascular and renal alterations that develop in obese subjects even in the absence of hypertension (19).”

What the sources say

• Not checked yetcites [19] Lambert E Sari CI Dawood T Nguyen J McGrane M Eikelis N Chopra R Wong C Chatzivlastou K Head G Straznicky N Esler M Schlaich M Lambert G Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults Hypertension 2010 56 351 358 20625075 source

In the paper

“Moreover, obesity is a major risk factor for resistant hypertension, i.e. patients who have uncontrolled blood pressure despite being on three or more antihypertensive medications (7;8).”

What the sources say

• Not checked yetcites [7] Goodfriend TL Calhoun DA Resistant hypertension, obesity, sleep apnea, and aldosterone: theory and therapy Hypertension 2004 43 518 524 14732721 source
• Not checked yetcites [8] Persell SD Prevalence of resistant hypertension in the United States, 2003–2008 Hypertension 2011 57 1076 1080 21502568 source

In the paper

“Clinical and animal studies have documented that weight gain can raise arterial pressure whereas weight loss has a beneficial effect on blood pressure control (9–11).”

What the sources say

• Not checked yetcites [9] De CC Porteri E Rizzoni D Corbellini C La BE Boari GE Pilu A Mittempergher F Di BE Casella C Nascimbeni R Rosei CA Ruggeri G Caimi L Rosei EA Effects of weight loss on structural and functional alterations of subcutaneous small arteries in obese patients Hypertension 2011 58 29 36 21555677 source
• Not checked yetcites [10] Haufe S Utz W Engeli S Kast P Bohnke J Pofahl M Traber J Haas V Hermsdorf M Mahler A Busjahn A Wiesner S Otto C Mehling H Luft FC Boschmann M Schulz-Menger J Jordan J Left ventricular mass and function with reduced-fat or reduced-carbohydrate hypocaloric diets in overweight and obese subjects Hypertension 2012 59 70 75 22068866 source
• Not checked yetcites [11] Weisbrod RM Shiang T Al SL Fry JL Bajpai S Reinhart-King CA Lob HE Santhanam L Mitchell G Cohen RA Seta F Arterial stiffening precedes systolic hypertension in diet-induced obesity Hypertension 2013 62 1105 1110 24060894 PMC3951434 source

In the paper

“The close relationship between excess adipose mass and hypertension is well documented, with population-based studies showing excess adiposity as the strongest known risk factor for hypertension in male and female subjects of different ages and races (1–5).”

What the sources say

• Not checked yetcites [1] Jones A Charakida M Falaschetti E Hingorani AD Finer N Masi S Donald AE Lawlor DA Smith GD Deanfield JE Adipose and height growth through childhood and blood pressure status in a large prospective cohort study Hypertension 2012 59 919 925 22493074 PMC3428923 source
• Not checked yetcites [2] Suglia SF Clark CJ Gary-Webb TL Adolescent obesity, change in weight status, and hypertension: racial/ethnic variations Hypertension 2013 61 290 295 23248147 PMC3938160 source
• Not checked yetcites [3] Tu W Eckert GJ DiMeglio LA Yu Z Jung J Pratt JH Intensified effect of adiposity on blood pressure in overweight and obese children Hypertension 2011 58 818 824 21968752 PMC3433397 source
• Not checked yetcites [4] Selassie A Wagner CS Laken ML Ferguson ML Ferdinand KC Egan BM Progression is accelerated from prehypertension to hypertension in blacks Hypertension 2011 58 579 587 21911708 PMC3186683 source
• Not checked yetcites [5] Pausova Z Mahboubi A Abrahamowicz M Leonard GT Perron M Richer L Veillette S Gaudet D Paus T Sex differences in the contributions of visceral and total body fat to blood pressure in adolescence Hypertension 2012 59 572 579 22291448 source

In the paper

“In particular, patients with visceral or abdominal obesity are at the greatest risk of developing hypertension and other cardiovascular risks (5;6).”

What the sources say

• Not checked yetcites [5] Pausova Z Mahboubi A Abrahamowicz M Leonard GT Perron M Richer L Veillette S Gaudet D Paus T Sex differences in the contributions of visceral and total body fat to blood pressure in adolescence Hypertension 2012 59 572 579 22291448 source
• Not checked yetcites [6] Bombelli M Facchetti R Sega R Carugo S Fodri D Brambilla G Giannattasio C Grassi G Mancia G Impact of body mass index and waist circumference on the long-term risk of diabetes mellitus, hypertension, and cardiac organ damage Hypertension 2011 58 1029 1035 22025375 source

In the paper

“Clinical and animal studies have documented that weight gain can raise arterial pressure whereas weight loss has a beneficial effect on blood pressure control (9–11).”

What the sources say

• Not checked yetcites [9] De CC Porteri E Rizzoni D Corbellini C La BE Boari GE Pilu A Mittempergher F Di BE Casella C Nascimbeni R Rosei CA Ruggeri G Caimi L Rosei EA Effects of weight loss on structural and functional alterations of subcutaneous small arteries in obese patients Hypertension 2011 58 29 36 21555677 source
• Not checked yetcites [10] Haufe S Utz W Engeli S Kast P Bohnke J Pofahl M Traber J Haas V Hermsdorf M Mahler A Busjahn A Wiesner S Otto C Mehling H Luft FC Boschmann M Schulz-Menger J Jordan J Left ventricular mass and function with reduced-fat or reduced-carbohydrate hypocaloric diets in overweight and obese subjects Hypertension 2012 59 70 75 22068866 source
• Not checked yetcites [11] Weisbrod RM Shiang T Al SL Fry JL Bajpai S Reinhart-King CA Lob HE Santhanam L Mitchell G Cohen RA Seta F Arterial stiffening precedes systolic hypertension in diet-induced obesity Hypertension 2013 62 1105 1110 24060894 PMC3951434 source

In the paper

“This is based on the observation that patients carrying certain polymorphisms related to obesity and hypertension seems more likely to benefit from dietary interventions for weight loss and blood pressure control (12;13).”

What the sources say

• Not checked yetcites [12] Zhang X Qi Q Liang J Hu FB Sacks FM Qi L Neuropeptide Y promoter polymorphism modifies effects of a weight-loss diet on 2-year changes of blood pressure: the preventing overweight using novel dietary strategies trial Hypertension 2012 60 1169 1175 22966009 PMC3869086 source
• Not checked yetcites [13] Kostis WJ Cabrera J Hooper WC Whelton PK Espeland MA Cosgrove NM Cheng JQ Deng Y De SC Pyle M Maruthur N Reyes I Anderson CA Liu J Kostis JB Relationships between selected gene polymorphisms and blood pressure sensitivity to weight loss in elderly persons with hypertension Hypertension 2013 61 857 863 23438931 PMC4636329 source

In the paper

“The worldwide epidemic of excess body weight, including overweight and obesity, is associated with increased prevalence of cardiovascular risks comprising hypertension – a condition that promote stroke, heart disease and end-stage organ damage which are major causes of death and disability (1;2).”

What the sources say

• Not checked yetcites [1] Jones A Charakida M Falaschetti E Hingorani AD Finer N Masi S Donald AE Lawlor DA Smith GD Deanfield JE Adipose and height growth through childhood and blood pressure status in a large prospective cohort study Hypertension 2012 59 919 925 22493074 PMC3428923 source
• Not checked yetcites [2] Suglia SF Clark CJ Gary-Webb TL Adolescent obesity, change in weight status, and hypertension: racial/ethnic variations Hypertension 2013 61 290 295 23248147 PMC3938160 source

In the paper

“Strikingly, in obesity both phosphatidylinositol 3-kinase (PI3K) signaling and MC4R are required for the sympathetic control by leptin and insulin (Figure 1).”

In the paper

“These adverse cardiovascular effects of MC4R agonists detract from targeting this receptor for therapeutic use in the management of common human obesity despite its potent weight-reducing action.”

In the paper

“For instance, blocking the proinflammatory pathway in POMC neurons by ablation of the gene encoding the activator IκB kinase-β prevented the development of hypertension caused by high fat diet in mice (38).”

What the sources say

• Not checked yetcites [38] Purkayastha S Zhang G Cai DS Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-beta and NF-kappa B Nat Med 2011 17 883 887 21642978 PMC3134198 source

In the paper

“They found that in young healthy man intravenous bolus administration of leptin caused a gradual increase in muscle sympathetic nerve activity that persisted for over 2 hours.”

What the sources say

• Not checked yetcites [45] Machleidt F Simon P Krapalis AF Hallschmid M Lehnert H Sayk F Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans J Clin Endocrinol Metab 2013 98 E491 E496 23393176 source

In the paper

“An implantable device for bilateral electric baroreceptor stimulation that decreases sympathetic tone alleviates obesity-associated hypertension in experimental and clinical settings (22–24).”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source
• Not checked yetcites [23] Heusser K Tank J Engeli S Diedrich A Menne J Eckert S Peters T Sweep FC Haller H Pichlmaier AM Luft FC Jordan J Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients Hypertension 2010 55 619 626 20101001 source
• Not checked yetcites [24] Biaggioni I Interventional approaches to reduce sympathetic activity in resistant hypertension: to ablate or stimulate? Hypertension 2012 59 194 195 22184323 source

In the paper

“The ability of leptin to signal through various brain sites may also explain how this hormone can differentially alter baroreflex control of regional autonomic efferents (43).”

What the sources say

• Not checked yetcites [43] Li B Shi Z Cassaglia PA Brooks VL Leptin acts in the forebrain to differentially influence baroreflex control of lumbar, renal, and splanchnic sympathetic nerve activity and heart rate Hypertension 2013 61 812 819 23424232 PMC3823577 source

In the paper

“Indeed, the PI3K-MC4R axis mediates the preserved renal and lumbar sympathoexcitatory effects of leptin (52;53) and insulin (51), respectively.”

What the sources say

• Not checked yetcites [52] Morgan DA Thedens DR Weiss R Rahmouni K Mechanisms mediating renal sympathetic activation to leptin in obesity Am J Physiol Regul Integr Comp Physiol 2008 295 R1730 R1736 18815209 PMC2685291 source
• Not checked yetcites [53] Harlan SM Morgan DA Dellsperger DJ Myers MG Jr Mark AL Rahmouni K Cardiovascular and sympathetic effects of disrupting tyrosine 985 of the leptin receptor Hypertension 2011 57 627 632 21263121 PMC3072273 source
• Not checked yetcites [51] Morgan DA Rahmouni K Differential effects of insulin on sympathetic nerve activity in agouti obese mice J Hypertens 2010 28 1913 1919 20577122 PMC2920344 source

In the paper

“These findings indicate that adipose tissue may be the source of the elevated circulating aldosterone levels that is commonly found in obese patients.”

In the paper

“Finally, the increased aldosterone production by adipocytes in obesity was shown to contribute to the vascular changes associated with this condition (54).”

What the sources say

• Not checked yetcites [54] Briones AM Nguyen Dinh CA Callera GE Yogi A Burger D He Y Correa JW Gagnon AM Gomez-Sanchez CE Gomez-Sanchez EP Sorisky A Ooi TC Ruzicka M Burns KD Touyz RM Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction Hypertension 2012 59 1069 1078 22493070 source

In the paper

“For instance, adipocyte-derived aldosterone has emerged as a new paradigm in linking obesity with vascular disease (54).”

What the sources say

• Not checked yetcites [54] Briones AM Nguyen Dinh CA Callera GE Yogi A Burger D He Y Correa JW Gagnon AM Gomez-Sanchez CE Gomez-Sanchez EP Sorisky A Ooi TC Ruzicka M Burns KD Touyz RM Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction Hypertension 2012 59 1069 1078 22493070 source

In the paper

“In addition, these findings are consistent with the inability of leptin to increase renal sympathetic nerve traffic in mice bearing arcuate nucleus-specific deletion of the leptin receptor (40).”

What the sources say

• Not checked yetcites [40] Harlan SM Morgan DA Agassandian K Guo DF Cassell MD Sigmund CD Mark AL Rahmouni K Ablation of the Leptin Receptor in the Hypothalamic Arcuate Nucleus Abrogates Leptin-Induced Sympathetic Activation Circ Res 2011 108 808 812 21311043 PMC3072835 source

In the paper

“Together, these findings demonstrate that POMC neurons are critically involved in the development and maintenance of obesity hypertension.”

In the paper

“Leptin receptor signaling in the subfornical organ has also been involved in mediating renal sympathetic nerve activity in a selective manner (42).”

What the sources say

• Not checked yetcites [42] Young CN Morgan DA Butler SD Mark AL Davisson RL The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects Hypertension 2013 61 737 744 23357182 PMC3832948 source

In the paper

“Selective ablation of the renal nerves abolished the hypertension in obese dogs independently from changes in body weight (22).”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source

In the paper

“These data combined with previous findings (46) suggest that leptin may be a major driver of cardiovascular sympathetic activation in human obesity just like in experimental obesity.”

What the sources say

• Not checked yetcites [46] Eikelis N Schlaich M Aggarwal A Kaye D Esler M Interactions between leptin and the human sympathetic nervous system Hypertension 2003 41 1072 1079 12668587 source

In the paper

“These observations are also consistent with the beneficial effects of mineralocorticoid receptor blockade on blood pressure in obese subjects even in those displaying resistant hypertension (55).”

What the sources say

• Not checked yetcites [55] de SF Muxfeldt E Fiszman R Salles G Efficacy of spironolactone therapy in patients with true resistant hypertension Hypertension 2010 55 147 152 19858405 source

In the paper

“In particular, the brain melanocortinergic system has emerged as a crucial molecular pathway in the development of hypertension and other cardiovascular disorders in human obesity.”

In the paper

“Patients carrying loss-of-function mutations in MC4R were found to be protected from obesity-associated elevation in blood pressure, heart rate and sympathetic tone (36;37).”

What the sources say

• Not checked yetcites [36] Greenfield JR Miller JW Keogh JM Henning E Satterwhite JH Cameron GS Astruc B Mayer JP Brage S See TC Lomas DJ O’Rahilly S Farooqi IS Modulation of Blood Pressure by Central Melanocortinergic Pathways N Engl J Med 2009 360 44 52 19092146 source
• Not checked yetcites [37] Sayk F Heutling D Dodt C Iwen KA Wellhoner JP Scherag S Hinney A Hebebrand J Lehnert H Sympathetic Function in Human Carriers of Melanocortin-4 Receptor Gene Mutations J Clin Endocrinol Metab 2010 95 1998 2002 20147580 source

In the paper

“Adipocytes were found to possess the components necessary for aldosterone synthesis.”

What the sources say

• Not checked yetcites [54] Briones AM Nguyen Dinh CA Callera GE Yogi A Burger D He Y Correa JW Gagnon AM Gomez-Sanchez CE Gomez-Sanchez EP Sorisky A Ooi TC Ruzicka M Burns KD Touyz RM Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction Hypertension 2012 59 1069 1078 22493070 source

In the paper

“Moreover, in a recent blinded, sham-controlled study (SYMPLICITY HTN-3), after 6 months, the blood pressure lowering effect of renal denervation was not significantly different from that observed in the sham group (30).”

What the sources say

• Not checked yetcites [30] Bhatt DL Kandzari DE O’Neill WW D’Agostino R Flack JM Katzen BT Leon MB Liu M Mauri L Negoita M Cohen SA Oparil S Rocha-Singh K Townsend RR Bakris GL A Controlled Trial of Renal Denervation for Resistant Hypertension N Engl J Med 2014 370 1393 1401 24678939 source

In the paper

“Such possibility is consistent with the preserved ability of central action of insulin to increase lumbar, but not renal, sympathetic nerve traffic in obese mice (51).”

What the sources say

• Not checked yetcites [51] Morgan DA Rahmouni K Differential effects of insulin on sympathetic nerve activity in agouti obese mice J Hypertens 2010 28 1913 1919 20577122 PMC2920344 source

In the paper

“Moreover, this study revealed that adipocyte-derived aldosterone regulates vascular function in a paracrine manner.”

What the sources say

• Not checked yetcites [54] Briones AM Nguyen Dinh CA Callera GE Yogi A Burger D He Y Correa JW Gagnon AM Gomez-Sanchez CE Gomez-Sanchez EP Sorisky A Ooi TC Ruzicka M Burns KD Touyz RM Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction Hypertension 2012 59 1069 1078 22493070 source

In the paper

“Conversely, stimulation of the MC4R led to significant and dose-dependent increase in blood pressure in healthy overweight or obese subjects (36).”

What the sources say

• Not checked yetcites [36] Greenfield JR Miller JW Keogh JM Henning E Satterwhite JH Cameron GS Astruc B Mayer JP Brage S See TC Lomas DJ O’Rahilly S Farooqi IS Modulation of Blood Pressure by Central Melanocortinergic Pathways N Engl J Med 2009 360 44 52 19092146 source

In the paper

“The effectiveness of central administration of a leptin receptor antagonist in normalizing arterial pressure and renal sympathetic activity in obese rabbits provide direct evidence regarding the importance of leptin in driving hypertension and sympathetic overactivity in obesity (50).”

What the sources say

• Not checked yetcites [50] Lim K Burke SL Head GA Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits Hypertension 2013 61 628 634 23339171 source

In the paper

“This appears to occur through sympathetic vasomotor pathways subserving beds other than the kidneys.”

In the paper

“Several open-label trials have documented the efficacy of renal denervation in subjects with resistant hypertension many of whom are obese (24–28).”

What the sources say

• Not checked yetcites [24] Biaggioni I Interventional approaches to reduce sympathetic activity in resistant hypertension: to ablate or stimulate? Hypertension 2012 59 194 195 22184323 source
• Not checked yetcites [25] Lambert GW Hering D Esler MD Marusic P Lambert EA Tanamas SK Shaw J Krum H Dixon JB Barton DA Schlaich MP Health-related quality of life after renal denervation in patients with treatment-resistant hypertension Hypertension 2012 60 1479 1484 23071129 source
• Not checked yetcites [26] Hering D Lambert EA Marusic P Walton AS Krum H Lambert GW Esler MD Schlaich MP Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension Hypertension 2013 61 457 464 23172929 source
• Not checked yetcites [27] Mahfoud F Cremers B Janker J Link B Vonend O Ukena C Linz D Schmieder R Rump LC Kindermann I Sobotka PA Krum H Scheller B Schlaich M Laufs U Bohm M Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension Hypertension 2012 60 419 424 22733462 source
• Not checked yetcites [28] Ewen S Mahfoud F Linz D Poss J Cremers B Kindermann I Laufs U Ukena C Bohm M Effects of Renal Sympathetic Denervation on Exercise Blood Pressure, Heart Rate, and Capacity in Patients With Resistant Hypertension Hypertension 2014 63 839 845 24420550 source

In the paper

“Indeed, mice lacking the leptin receptor in the subfornical organ exhibited a blunted leptin-induced renal sympathetic excitation.”

What the sources say

• Not checked yetcites [42] Young CN Morgan DA Butler SD Mark AL Davisson RL The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects Hypertension 2013 61 737 744 23357182 PMC3832948 source

In the paper

“Disruption of leptin receptor signaling in POMC neurons abolished the ability of exogenous leptin administration to increase blood pressure (39;41) which provides additional support to the notion that leptin is a critical hormone in coupling hypertension and obesity (Figure 1).”

What the sources say

• Not checked yetcites [39] do Carmo JM da Silva AA Cai ZW Lin SY Dubinion JH Hall JE Control of Blood Pressure, Appetite, and Glucose by Leptin in Mice Lacking Leptin Receptors in Proopiomelanocortin Neurons Hypertension 2011 57 918 926 21422382 PMC3092393 source
• Not checked yetcites [41] Dubinion JH do Carmo JM Adi A Hamza S da Silva AA Hall JE Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin Hypertension 2013 61 1066 1074 23529161 PMC3678380 source

In the paper

“This indicates that brain action of insulin is also involved in coupling obesity and hypertension (Figure 1).”

In the paper

“Similarly, mice lacking leptin signaling in POMC neurons or in the arcuate nucleus of the hypothalamus, where most POMC neurons reside, through deletion of the leptin receptor itself (39;40) or components of its signaling pathway such as the signal transducer and activator of transcription-3 (41) are protected against obesity-associated hypertension.”

What the sources say

• Not checked yetcites [39] do Carmo JM da Silva AA Cai ZW Lin SY Dubinion JH Hall JE Control of Blood Pressure, Appetite, and Glucose by Leptin in Mice Lacking Leptin Receptors in Proopiomelanocortin Neurons Hypertension 2011 57 918 926 21422382 PMC3092393 source
• Not checked yetcites [40] Harlan SM Morgan DA Agassandian K Guo DF Cassell MD Sigmund CD Mark AL Rahmouni K Ablation of the Leptin Receptor in the Hypothalamic Arcuate Nucleus Abrogates Leptin-Induced Sympathetic Activation Circ Res 2011 108 808 812 21311043 PMC3072835 source
• Not checked yetcites [41] Dubinion JH do Carmo JM Adi A Hamza S da Silva AA Hall JE Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin Hypertension 2013 61 1066 1074 23529161 PMC3678380 source

In the paper

“Conversely, disruption of the white adipose tissue sensory afferents caused a rapid and long-lasting decrease in renal sympathetic tone and arterial pressure in obese rats, but not in controls.”

What the sources say

• Not checked yetcites [60] Xiong XQ Chen WW Han Y Zhou YB Zhang F Gao XY Zhu GQ Enhanced adipose afferent reflex contributes to sympathetic activation in diet-induced obesity hypertension Hypertension 2012 60 1280 1286 23033372 source

In the paper

“The efficacy of chronic treatment with Ang 1–7, a peptide that negatively modulate RAS activity, in alleviating obesity-associated impairment in endothelium-dependent vasodilation supports further the pathophysiological role of the RAS in obesity-related endothelial dysfunction (73).”

What the sources say

• Not checked yetcites [73] Beyer AM Guo DF Rahmouni K Prolonged treatment with angiotensin 1–7 improves endothelial function in diet-induced obesity J Hypertens 2013 31 4 730 738 23425706 PMC5684878 source

In the paper

“This analysis also showed enhanced levels in the subcutaneous adipose tissue of the mRNA derived from a particular allele of the angiotensinogen gene bearing the −20C variant in its promoter.”

What the sources say

• Not checked yetcites [59] Park S Lu KT Liu X Chatterjee TK Rudich SM Weintraub NL Kwitek AE Sigmund CD Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue Hypertension 2013 62 41 47 23648704 PMC3718031 source

In the paper

“It should be noted, however, that vascular defects such as endothelial dysfunction are not universally associated with obesity. This is based on a number of studies showing the development of obesity without concomitant presence of vascular abnormalities (65;72).”

What the sources say

• Not checked yetcites [65] Beyer AM Raffai G Weinberg B Fredrich K Lombard JH Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity Hypertension 2012 60 404 410 22710645 PMC3444144 source
• Not checked yetcites [72] Beyer AM Guo DF Sheffield VC Rahmouni K Contrasting vascular effects caused by loss of Bardet-Biedl syndrome genes Am J Physiol Heart Circ Physiol 2010 299 H1902 H1907 20852044 PMC3006278 source

In the paper

“The sodium retention associated with experimental obesity appears due to an increase in tubular reabsorption of sodium as indicated by the increased glomerular filtration rate and decreased fractional sodium excretion (22).”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source

In the paper

“Alterations in the vasculature including structural changes, endothelial dysfunction, enhanced contractile response and altered stiffness are hallmarks of obesity.”

In the paper

“Consistent with the notion that in obesity vascular alterations precede hypertension, Weisbrod et al. (11) demonstrated that diet-induced obese mice develop arterial stiffness and endothelial dysfunction prior to the onset of hypertension.”

What the sources say

• Not checked yetcites [11] Weisbrod RM Shiang T Al SL Fry JL Bajpai S Reinhart-King CA Lob HE Santhanam L Mitchell G Cohen RA Seta F Arterial stiffening precedes systolic hypertension in diet-induced obesity Hypertension 2013 62 1105 1110 24060894 PMC3951434 source

In the paper

“It should be noted, however, that ablating the renal nerves in obesity reduced plasma renin activity presumably through inhibition of renal renin production and/or release (22).”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source

In the paper

“This finding point to a pathological role of insulin resistance in the albuminuria associated with obesity although it is possible that such correction may reflect the normalization of arterial pressure.”

In the paper

“Importantly, obesity-associated vascular changes can be reversed by weight loss even after their establishment (11;69).”

What the sources say

• Not checked yetcites [11] Weisbrod RM Shiang T Al SL Fry JL Bajpai S Reinhart-King CA Lob HE Santhanam L Mitchell G Cohen RA Seta F Arterial stiffening precedes systolic hypertension in diet-induced obesity Hypertension 2013 62 1105 1110 24060894 PMC3951434 source
• Not checked yetcites [69] Lurbe E Torro I Garcia-Vicent C Alvarez J Fernandez-Fornoso JA Redon J Blood pressure and obesity exert independent influences on pulse wave velocity in youth Hypertension 2012 60 550 555 22733475 source

In the paper

“Capsaicin-mediated stimulation of afferent reflex originating from inguinal fat depot was found to increase efferent renal sympathetic discharge and blood pressure in rats.”

What the sources say

• Not checked yetcites [60] Xiong XQ Chen WW Han Y Zhou YB Zhang F Gao XY Zhu GQ Enhanced adipose afferent reflex contributes to sympathetic activation in diet-induced obesity hypertension Hypertension 2012 60 1280 1286 23033372 source

In the paper

“Multiple other mechanisms including sympathetic overdrive, inflammatory mediators, excessive reactive oxygen species production, decreased NO bioactivity may contribute to the deleterious effects of obesity on the vasculature (70;71;74;75).”

What the sources say

• Not checked yetcites [70] Cao J Peterson SJ Sodhi K Vanella L Barbagallo I Rodella LF Schwartzman ML Abraham NG Kappas A Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet Hypertension 2012 60 467 475 22753217 PMC3423899 source
• Not checked yetcites [71] Marshall NJ Liang L Bodkin J Dessapt-Baradez C Nandi M Collot-Teixeira S Smillie SJ Lalgi K Fernandes ES Gnudi L Brain SD A role for TRPV1 in influencing the onset of cardiovascular disease in obesity Hypertension 2013 61 246 252 23150506 source
• Not checked yetcites [74] Belin de Chantemele EJ Mintz JD Rainey WE Stepp DW Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice Hypertension 2011 58 271 279 21690486 PMC3141100 source
• Not checked yetcites [75] Leopold JA Cellular and molecular mechanisms of arterial stiffness associated with obesity Hypertension 2013 62 1003 1004 24060893 PMC3905983 source

In the paper

“Consistent with the notion that in obesity vascular alterations precede hypertension, Weisbrod et al. (11) demonstrated that diet-induced obese mice develop arterial stiffness and endothelial dysfunction prior to the onset of hypertension.”

What the sources say

• Not checked yetcites [11] Weisbrod RM Shiang T Al SL Fry JL Bajpai S Reinhart-King CA Lob HE Santhanam L Mitchell G Cohen RA Seta F Arterial stiffening precedes systolic hypertension in diet-induced obesity Hypertension 2013 62 1105 1110 24060894 PMC3951434 source

In the paper

“These intriguing results indicate that leptin-mediated enhancement in white adipose tissue sensory afferent activity as a major pathophysiological mechanism of hypertension and vasomotor sympathetic overdrive in obesity.”

In the paper

“Analysis of human adipose tissues obtained during surgery revealed a great variability in the total level of angiotensinogen gene expression among subjects (59).”

What the sources say

• Not checked yetcites [59] Park S Lu KT Liu X Chatterjee TK Rudich SM Weintraub NL Kwitek AE Sigmund CD Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue Hypertension 2013 62 41 47 23648704 PMC3718031 source

In the paper

“Longitudinal studies have shown that alterations in renal excretory function occur prior to the onset of obesity hypertension in animal models and humans (61;62) indicating that renal dysfunction may drive arterial pressure elevation in obesity.”

What the sources say

• Not checked yetcites [61] Grubbs V Lin F Vittinghoff E Shlipak MG Peralta CA Bansal N Jacobs DR Siscovick DS Lewis CE Bibbins-Domingo K Body Mass Index and Early Kidney Function Decline in Young Adults: A Longitudinal Analysis of the CARDIA (Coronary Artery Risk Development in Young Adults) Study Am J Kidney Dis 2014 63 590 597 24295611 PMC3969447 source
• Not checked yetcites [62] Kassab S Kato T Wilkins FC Chen R Hall JE Granger JP Renal Denervation Attenuates the Sodium Retention and Hypertension Associated with Obesity Hypertension 1995 25 893 897 7721450 source

In the paper

“However, despite its efficacy to control blood pressure selective ablation of the renal nerves failed to correct the glomerular hyperfiltration observed in obesity (22).”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source

In the paper

“Notably, these sympathetic and pressor responses elicited by adipose afferent reflex activation were enhanced in obese animals.”

What the sources say

• Not checked yetcites [60] Xiong XQ Chen WW Han Y Zhou YB Zhang F Gao XY Zhu GQ Enhanced adipose afferent reflex contributes to sympathetic activation in diet-induced obesity hypertension Hypertension 2012 60 1280 1286 23033372 source

In the paper

“This finding points to the RAS as a potential mechanism by which renal denervation improves blood pressure control in obesity.”

In the paper

“More striking is the finding that salt-sensitive (SS) rats fed high fat diet exhibit an improvement in endothelium-dependent vascular relaxation despite the significant weight gain and the presence of several cardiovascular risks including elevated blood pressure and reduced renal function (65).”

What the sources say

• Not checked yetcites [65] Beyer AM Raffai G Weinberg B Fredrich K Lombard JH Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity Hypertension 2012 60 404 410 22710645 PMC3444144 source

In the paper

“This is supported by the finding that systemic sympathetic inhibition eliminated the renal abnormalities in obese dogs (22).”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source

In the paper

“The type 2 scavenger receptor, CD36, and Na/K-ATPase have also emerged as key molecules in mediating the renal inflammation triggered by obesity in mice (68).”

What the sources say

• Not checked yetcites [68] Kennedy DJ Chen Y Huang W Viterna J Liu J Westfall K Tian J Bartlett DJ Tang WH Xie Z Shapiro JI Silverstein RL CD36 and Na/K-ATPase-alpha1 form a proinflammatory signaling loop in kidney Hypertension 2013 61 216 224 23172921 PMC3521864 source

In the paper

“Excessive sympathetic activity is a major cause of the abnormal sodium retention in obesity.”

What the sources say

• Not checked yetcites [22] Lohmeier TE Iliescu R Liu B Henegar JR Maric-Bilkan C Irwin ED Systemic and renal-specific sympathoinhibition in obesity hypertension Hypertension 2012 59 331 338 22184321 PMC3277854 source

In the paper

“This was associated with enriched binding to the −20C allele of a transcription factor, the upstream stimulatory factor 2, which is essential for angiotensinogen transcriptional regulation (59).”

What the sources say

• Not checked yetcites [59] Park S Lu KT Liu X Chatterjee TK Rudich SM Weintraub NL Kwitek AE Sigmund CD Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue Hypertension 2013 62 41 47 23648704 PMC3718031 source

In the paper

“Interestingly, sex appears to influence the development of renal changes in obesity.”

What the sources say

• Not checked yetcites [67] Bloor ID Sebert SP Mahajan RP Symonds ME The influence of sex on early stage markers of kidney dysfunction in response to juvenile obesity Hypertension 2012 60 991 997 22949537 source

In the paper

“Longitudinal studies have shown that alterations in renal excretory function occur prior to the onset of obesity hypertension in animal models and humans (61;62) indicating that renal dysfunction may drive arterial pressure elevation in obesity.”

What the sources say

• Not checked yetcites [61] Grubbs V Lin F Vittinghoff E Shlipak MG Peralta CA Bansal N Jacobs DR Siscovick DS Lewis CE Bibbins-Domingo K Body Mass Index and Early Kidney Function Decline in Young Adults: A Longitudinal Analysis of the CARDIA (Coronary Artery Risk Development in Young Adults) Study Am J Kidney Dis 2014 63 590 597 24295611 PMC3969447 source
• Not checked yetcites [62] Kassab S Kato T Wilkins FC Chen R Hall JE Granger JP Renal Denervation Attenuates the Sodium Retention and Hypertension Associated with Obesity Hypertension 1995 25 893 897 7721450 source

In the paper

“The suppressed RAS appears to account for the improvement in endothelial function in obese SS rats (65).”

What the sources say

• Not checked yetcites [65] Beyer AM Raffai G Weinberg B Fredrich K Lombard JH Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity Hypertension 2012 60 404 410 22710645 PMC3444144 source

In the paper

“Moreover, obese rats given a leptin receptor antagonist into the inguinal and retroperitoneal fat depots exhibited a very rapid decrease in renal sympathetic activity and arterial pressure that lasted for about 15 minutes (60).”

What the sources say

• Not checked yetcites [60] Xiong XQ Chen WW Han Y Zhou YB Zhang F Gao XY Zhu GQ Enhanced adipose afferent reflex contributes to sympathetic activation in diet-induced obesity hypertension Hypertension 2012 60 1280 1286 23033372 source

In the paper

“Moreover, targeting these K+ channels was found effective in reversing the decline in periadventitial regulation of arterial tone and peripheral resistance in hypertensive rats (56).”

What the sources say

• Not checked yetcites [56] Zavaritskaya O Zhuravleva N Schleifenbaum J Gloe T Devermann L Kluge R Mladenov M Frey M Gagov H Fesus G Gollasch M Schubert R Role of KCNQ channels in skeletal muscle arteries and periadventitial vascular dysfunction Hypertension 2013 61 151 159 23184384 source

In the paper

“For instance, mice lacking the Bardet-Biedl syndrome 2 gene do not display endothelial dysfunction despite the presence of obesity (72).”

What the sources say

• Not checked yetcites [72] Beyer AM Guo DF Sheffield VC Rahmouni K Contrasting vascular effects caused by loss of Bardet-Biedl syndrome genes Am J Physiol Heart Circ Physiol 2010 299 H1902 H1907 20852044 PMC3006278 source

In the paper

“The diversity in the processes implicated is consistent with the polygenic and multifactorial nature of obesity and its comorbidities.”

In the paper

“Given the evidence pointing to the significance of the neurogenic mechanisms in obesity-associated hypertension new strategies that disrupt these processes should be favored.”