Reviews: The Pathophysiology of Hypertension in Patients With Obesity

REVIEWS
The pathophysiology of hypertension

in patients with obesity
Vincent G. DeMarco, Annayya R. Aroor and James R. Sowers
Abstract | The combination of obesity and hypertension is associated with high morbidity and mortality
because it leads to cardiovascular and kidney disease. Potential mechanisms linking obesity to hypertension
include dietary factors, metabolic, endothelial and vascular dysfunction, neuroendocrine imbalances, sodium
retention, glomerular hyperfiltration, proteinuria, and maladaptive immune and inflammatory responses.
Visceral adipose tissue also becomes resistant to insulin and leptin and is the site of altered secretion
of molecules and hormones such as adiponectin, leptin, resistin, TNF and IL‑6, which exacerbate obesity-
associated cardiovascular disease. Accumulating evidence also suggests that the gut microbiome is important
for modulating these mechanisms. Uric acid and altered incretin or dipeptidyl peptidase 4 activity further
contribute to the development of hypertension in obesity. The pathophysiology of obesity-related hypertension
is especially relevant to premenopausal women with obesity and type 2 diabetes mellitus who are at high risk
of developing arterial stiffness and endothelial dysfunction. In this Review we discuss the relationship between
obesity and hypertension with special emphasis on potential mechanisms and therapeutic targeting that might
be used in a clinical setting.
DeMarco, V. G. et al. Nat. Rev. Endocrinol. advance online publication 15 April 2014; doi:10.1038/nrendo.2014.44
Introduction
Epidemiological data indicate that the current global In 1967, a prospective analysis of data from the
obesity epidemic began approximately 40 years ago; 1 Framingham Heart Study highlighted the relationship
however, some studies suggest that the rise in obesity between obesity and hypertension.12 Indeed, the high
rates started earlier, and that the progression of the epi- prevalence of hypertension among patients with obesity
demic has been somewhat irregular. 2–4 The causes of (>60%) accounts for 78% of incident hypertension in
the obesity epidemic are most frequently ascribed to men and 64% of incident hypertension in women.13–15
two factors: the combination of institutionally driven The prevalence of hypertension increases in relation to
decreases in physical activity (for example, reductions BMI in both men and women after adjusting for age.16,17
in school physical education classes and the sedentary Estimates indicate that the increased risk of develop-
nature of most modern vocations); and over-nutrition ing hypertension is 20–30% for every 5% increment in
resulting from modern food marketing practices and weight gain.18 Even before the Framingham Heart Study
technology (such as inappropriately large portion sizes data, researchers reported on the potential mechanisms
in restaurants and processed foods and the ready avail- of hypertension in patients with obesity by linking the
ability of inexpensive high-calorie fast food).4,5 However, cardiovascular and metabolic complications of obesity
evidence also suggests that additional factors might to adipose tissue that is distributed primarily at and
contribute to the obesity epidemic, including sleep above the waistline (that is, upper-body obesity).19 Con
debt, endocrine disruptors and intrauterine and inter temporaneous studies reported metabolic abnormalities
generational effects, and these have been extensively associated with upper-body obesity, including insulin
reviewed elsewhere.4,6 Obesity is a major public health resistance and hypertriglyceridaemia.20,21 This concept
burden in the USA and >300,000 deaths each year are was further refined in the 1980s when researchers demon
attributable to obesity or being overweight.7,8 In the USA, strated that an increase in the waist-to-hip ratio was
among the adult population of ~240 million individuals, associated with increased risk of hypertension.22–24 The
Internal Medicine, >65% are overweight and, of these, half have obesity;9 clustering of abdominal obesity, hypertension, insulin
University of Missouri, moreover, approximately 13 million US children are also resistance and hypertriglyceridaemia was, therefore, the
Columbia School of
Medicine, One Hospital
estimated to have obesity.10 Worldwide, in both devel- key to later development of the concepts of the metabolic
Drive, Columbia, oped and developing nations, one billion people are syndrome and cardiorenal syndrome (CRS).25,26 Clinical
MO 65212, USA either overweight or have obesity, making this disorder trials have, for the most part, demonstrated that weight
(V.G.D., A.R.A., J.R.S.).
a global epidemic.11 loss of ~10% of original body weight by calorie restriction
Correspondence to: and/or increased activity is an effective means to achieve
J.R.S.
sowersj@ Competing interests clinically meaningful reductions in blood pressure and
health.missouri.edu The authors declare no competing interests. mortality from cardiovascular disease (CVD).27,28
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION | 1

© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points hypertension by up to 25%.45,46 Moreover, maternal

and paternal obesity also seem to increase the risk of
■■ The incidence of hypertension is substantially increased in the population of
people with obesity and affected individuals have increased morbidity and
offspring to develop obesity and hypertension in early
mortality from cardiovascular disease (CVD) and chronic kidney disease adult life.32,47,48 Given the differences in cardiovascu
■■ Adipokine alterations, insulin resistance, sympathetic nervous system and lar physiology between sexes, women might require
renin–angiotensin–aldosterone system activation, obstructive sleep apnoea, female-specific and more aggressive therapeutic and
renal abnormalities, maladaptive immunity and gut microbiome changes all link lifestyle management for obesity and its cardiovascular
hypertension to obesity complications than men.41
■■ Hyperuricaemia associated with a high-fructose diet is emerging as a key factor
in the development of hypertension associated with diet-induced obesity
Dietary factors
■■ Dysregulation of the dipeptidyl peptidase 4–incretin system contributes to
the development of maladaptive immunity and associated hypertension
Fructose, fat and sodium
in obesity The current global obesity epidemic has primarily been
■■ Estrogen-mediated CVD protection is compromised in individuals with ascribed to excess consumption of energy-dense foods,
obesity, thereby underscoring the greater CVD risks associated with obesity in which are high in sugar, fat and sodium, in combina-
premenopausal women compared with those in age-matched men with obesity tion with an increasingly sedentary lifestyle.1 The intro-
■■ Adjunctive therapy with mineralocorticoid receptor antagonists and renal duction of high-fructose corn syrup (HFCS) in 1967
denervation is emerging as an additional therapeutic measure for management in the USA, and its dramatic increase in consumption
of obesity-related hypertension
compared with other carbohydrates between 1970 and
1990, has been related to obesity, CRS and diabetes mel-
Several other reviews have focused on specific factors litus.37,49,50 HFCS is more lipogenic than other sugars and
contributing to obesity-associated hypertension.29–37 increases the circulating levels of triglycerides, insulin,
In this Review, we present an integrated view of the glucose and LDL cholesterol,51 factors that increase the
pathophysiology of obesity-associated hypertension and risk of progression to the metabolic syndrome and CVD.
discuss the relationships between the multiple factors Increased HFCS consumption is also associated with
contributing to this condition. We also discuss factors that elevated uric acid synthesis (a property that is unique
contribute to obesity-associated hypertension, including among sugars51) and emerging evidence supports a role
incretin signalling, dysfunctional immunity and the gut for uric acid in the development of hypertension and
microbiome, as well as specific antihypertensive therapies CVD.37,52 However, the hypothesis that fructose and uric
especially relevant to patients with obesity. acid can induce hypertension is controversial. For exam
ple, in rodent studies, conflicting reports suggest that
Obesity and hypertension fructose consumption can lead to either no change53 or
Progression from a normotensive to hypertensive pheno an increase54,55 in blood pressure. These differences might
type results from a combination of genetic, environ be attributable to the methodology used to measure
mental, behavioural and dietary factors (Figure 1). blood pressure,53,56 if fructose is dissolved in water (like
The combination of obesity and hypertension has two in a sweetened beverage) or consumed in addition to
important consequences. Firstly, this combination is par high-fat or high-salt diets.53,56,57 Results reported in clini-
ticularly insidious in that the population with obesity and cal studies are equally controversial owing to differences
hypertension have high morbidity and mortality from between study design, treatment duration, variability of
CVD, including coronary heart disease, congestive heart nutrient composition or form of fructose added to the
failure, sudden cardiac death, chronic kidney disease diet (for example, fructose, HFCS, sucrose, or natural
(CKD), end-stage renal disease and stroke.29 Secondly, fruits).57 Investigators have presented consistent evidence
obesity increases the risk of treatment-resistant arterial supporting the observation that reducing sodium intake
hypertension, which therefore requires multiple medi- can lead to reductions in blood pressure.58,59 However,
cations and device therapy, such as renal sympathetic administering fructose with a high-salt diet leads to
denervation.7,38 Conversely, in population studies, future hypertension that persists even after removal of fruc
weight gain is significantly higher in patients with hyper- tose from the diet.54 Similarly, mice fed with a combina
tension than in normotensive individuals, indicating that tion of high-fructose and high-fat diet for 6 months
hypertension per se contributes to the increased risk of also develop hypertension.56 These results suggest a
obesity 12 and implying a further link between obesity synergistic deleterious effect owing to the interaction of
and hypertension. fructose with either salt or high fat content. Additional
Before menopause women are protected against CVD, well designed prospective studies are, therefore, needed
including hypertension, compared with age-matched to determine the effect of HFCS in the development of
men owing to the cardioprotective effect of estrogen;39 obesity-associated hypertension.50
howe ver, in the setting of obesity or type 2 diab etes
mellitus (T2DM) this protection is lost.40–43 Population Cardioprotective nutrients
studies indicate that women who are premenopausal The undesirable dietary changes in the USA during
but obese have a substantially higher risk of develop- the past 50 years might be further exacerbated by the
ing hypertension (43–56%) than age-matched men with imbalance in consumption of omega‑6 and omega‑3
obesity (20–27%).44 Weight loss of 5–10 kg in women fatty acids. Omega‑3 fatty acids must be obtained from
with obesity substantially lowers the risk of developing an individual’s diet. Humans evolved on diets that
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REVIEWS
Environmental factors (diet, sedentary or lifestyle), marine fish have received much attention by dieticians
genetic and epigenetic factors, maternal obesity and sex due to their high content of omega‑3 and more bal-
anced ratio of omega‑6 to omega‑3 fatty acids. In meta-
Hyperinsulinaemia, hyperuricaemia, DPP-4 analyses, fish oil supplements lower blood pressure in
patients with hypertension.61,62 However, the reports that
Afferent neural
Neuroimmune interactions fish oils can prevent CVD in general are inconclusive.63
Baroreceptor dysregulation
signalling
SNS output
Combination diets, notably the Dietary Approaches
Central RAAS activity, to Stop Hypertension (DASH) diet,64 which is rich in
SNS output
Efferent SNS nutrients from fruits, vegetables and has modest levels
signalling
Satiety, PNS output of sodium, omega‑3 and omega‑6 fatty acids, have
emerged as part of a balanced strategy for the manage-
ment of hypertension. Approaches such as the DASH
Visceral adipocyte dysfunction
T-cell alterations
diet include green leafy (for example, cabbages, spinach
Visceral adiposity, macrophage
and lettuces) and root (carrots and beets) vegetables that
infiltration, IL-6, TNF, resistin, are rich in inorganic nitrate.65 Beetroot juice, which also
leptin, DPP-4, angiotensinogen,
adosterone stimulator factor contains high levels of inorganic nitrate, can also lower
IL-10, adiponectin
blood pressure.66,67 The nitrate content of these foods is
likely to contribute to increased nitric oxide (NO) bio-
availability, which has multiple beneficial pleiotropic
Dysfunctional immunity effects in the vasculature such as vasodilation.68
M1 TH1 TH17 IL-6, TNF,
M1/M2 macrophage Gut microbiota, obesity and hypertension
M2 TREG IL-10, TREG /TH1,
Emerging evidence suggests that changes in the gut bac-
TREG /TH17 terial microbiome, associated with genetic and dietary
factors, can lead to metabolic disorders that result in
obesity, insulin resistance, T2DM and hypertension.69,70
In ob/ob71,72 and db/db73 mice, the number of caecal bac
teria from the phylum Bacteroidetes (so called ‘good
bacteria’) is reduced, which is accompanied by a pro-
portional increase in the number of bacteria from the
Renal dysfunction Vascular dysfunction phylum Firmicutes (so called ‘bad bacteria’). Bacterial-
M1/M2 macrophages,
M1/M2 macrophages derived lipopolysaccharides are thought to regulate hor-
TNF, IL-6, MCP-1, Oxidative stress, Cardiac dysfunction mones such as apelin in adipose tissue that alter glucose
aldosterone, Ang II, inflammation, Left ventricular hypertrophy
sodium reabsorption, perivascular fat,
homeostasis and inflammation.73 Mice fed a high-fat diet
M1/M2 macrophages,
tubulointerstitial fibrosis, endothelial
TNF, IL-6, MCP-1
have progressive increases in the number of Firmicutes
glomerular sclerosis, dysfunction, vascular
proteinuria stiffness, blood suggesting that the quality of the diet can modulate
IL-10, TREG /TH1,
IL-10, TREG /TH1,
pressure the gut microbiome.74 Changes in the gut microbiome
TREG /TH17, coronary
TREG /TH17 IL-10, NO availability flow, diastolic relaxation lead to abnormalities in pattern recognition receptor
function, immune and inflammatory responses, and
insulin sensitivity.75 These studies suggest that therapeu-
Figure 1 | Obesity contributes to the development of hypertension via the tic manipulation of the gut microbiome (for example,
interaction of dietary, genetic, epigenetic and environmental factors. Visceral by faecal transplantation or oral prebiotic or probiotic
adipocyte dysfunction leads directly to renal, cardiac and vascular dysfunction, preparations) might potentially suppress immune and
via an impaired immune or inflammatory response, and by affecting neuroimmune inflammatory responses and improve insulin sensitivity
interactions that alter SNS signalling. Cardiac and/or renal abnormalities can lead
—a novel approach that might be used to manage obesity
to vascular dysfunction and vice-versa. Obesity-related hypertension is associated
with structural and functional changes in the kidney, heart and vasculature. and hypertension in humans.76,77
Hyperuricaemia might also affect adipocyte function and vascular remodelling,
and cause renal abnormalities. Abbreviations: , increased; , decreased; Ang II, Mechanisms of hypertension in obesity
angiotensin II; DPP‑4, dipeptidyl peptidase 4; MCP‑1, monocyte chemoattractant The development of hypertension in patients with obesity
protein‑1; PNS, parasympathetic nervous system; RAAS, renin–angiotensin– is dependent on the interactions between dietary, gen
aldosterone system; SNS, sympathetic nervous system; TH, T helper cell; TREG, etic, epigenetic, and environmental factors (Figure 1).78,79
T regulatory cell.
Adipocyte dysfunction in patients with obesity contrib-
utes to vascular and systemic insulin resistance and the
contained fairly equal amounts of omega‑6 and omega‑3 dysfunction of the sympathetic nervous system (SNS) and
fatty acids. However, in the past 50 years the US diet has the renin–angiotensin–aldosterone system (RAAS).7,78
become deficient in omega‑3 fatty acid (ratio of omega‑6 Structural and functional changes in the kidney, includ-
to omega‑3 ~15:1) owing to increased consumption of ing activation of intrarenal angiotensin II (Ang II), are
plant-derived oils (soybean and corn oils) and red meat also important in the development of obesity-associated
from grain-fed animals, which are rich in omega‑6 but hypertension.80 For example, some investigators have
not omega‑3 fatty acids. 60 Consequently, cold water suggested that arterial hypertension in lean patients is

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mediated by an increase in peripheral vascular resist- insulin signalling in obesity can, therefore, contribute to
ance, whereas hypertension in individuals with obesity endothelial dysfunction and arterial stiffness.
is mediated, in part, by increased intravascular volume, In patients with obesity, metabolic changes in adipose
cardiac output,81 and proximal tubule sodium absorption tissue lead to altered secretion of bioactive molecules
in the kidney.82 However, crosstalk between components and hormones—collectively referred to as adipokines
of the intravascular RAAS, specifically Ang II and aldo —such as angiotensinogen, aldosterone stimulating
sterone, can also regulate vasoconstriction independently factor, dipeptidyl peptidase 4 (DPP‑4), leptin, resistin,
of renal control.83,84 Accumulating evidence also suggests TNF and IL‑6 (Figure 1). These factors can contribute
that uric acid might affect adipocyte function, and lead to to obesity-associated insulin resistance and hyperten-
vascular and renal injury.37,85 Moreover, incretin signalling sion.106 Impaired adiponectin secretion also promotes
is also an important modulator of insulin resistance and insulin resistance.78,107,108
immune function.86
The interplay between genetic and environmental Renal injury
factors (that is, epigenetic mechanisms) might also con Abnormal renal function also leads to hypertension in
tribute the pathophysiology of obesity-associated hyper patients who have obesity, as well as in animal models
tension.79,87 Epigenetic mechanisms include changes in of obesity (Figure 1). 109 Obesity increases tubular
DNA methylation, histone modifications and microRNA absorption of sodium and promotes a compensatory
(miRNA) regulation.88 For example, the miRNAs miR‑ shift in the pressure natriuresis curve towards higher
142-3p and miR‑140-5p are increased in patients with blood pressure in response to elevated plasma sodium
morbid obesity, and are biomarkers of the disease.89,90 levels.78,110 Moreover, these effects on sodium and pres-
Epigenetic factors are also relevant to the development sure natriuresis can be caused by an increase in adipose
of obesity-related hypertension,91,92 and might contribute tissue mass and extracellular matrix accumulation,
to in utero epigenetic programming, which has been which compress the renal medulla. Hyperinsulinaemia
used to explain the origins of fetal and infant diseases.93,94 and inappropriate RAAS and SNS activation also con-
Accumulating evidence suggests that environmental fac tribute to increased sodium resorption.78 Renal vascular
tors during early life might also program the development remodelling, characterized by inflammation, endothelial
of obesity and hypertension, but these aspects are beyond dysfunction and vascular smooth muscle proliferation,
the scope of this Review.29,32 is seen in humans and animals with hypertension.111
Tubulointerstitial inflammation owing to a systemic
Vascular injury immune and inflammatory response, elevated uric acid
Endothelial dysfunction and arterial stiffness are thought levels, tubulointestinal infiltration of immune cells, cir-
to be the earliest manifestations of vascular dysfunction in culating proinflammatory immune cells and enhanced
obesity and precede the development of prehypertension inflammation, oxidative stress and fibrosis collectively
and hypertension (Figure 1).95–98 Increased arterial stiff- contribute to renal damage.37,50,78,112
ness is seen in patients who are normotensive but have The kidney regulates plasma glucose levels by reabsor
obesity and who are predisposed to develop hyperten bing almost all of the glucose filtered by the glomeruli
sion; moreover, incident hypertension is more robustly (~162 g per day).113 Glucose reabsorption is primarily
predicted in patients who are in the highest quartile of localized to the S1 segment of the proximal convoluted
arterial stiffness.95–98 Changes in the extracellular matrix 99 tubule and functions via high-capacity, low-affinity
and vascular smooth muscle dysfunction100 contribute to sodium-glucose cotransporter‑2 (SGLT2).114 In humans
arterial stiffness; however, accumulating evidence sug- with diabetes mellitus,115 Zucker diabetic fatty rats,116
gests that endothelial dysfunction also contributes to and db/db mice117 SGLT2 expression is increased in the
vascular stiffness, which is in turn strongly associated proximal convoluted tubule, which correlates with glo
with insulin resistance.98,101 Impaired vascular reactiv- merular hyperfiltration leading to increased glucose
ity to insulin before the onset of hypertension is seen in reabs orption.117 This increased reabsorption leads to
spontaneously hypertensive rats,102 suggesting that insulin elevated plasma glucose levels and glucose toxicity, and
resistance is an early event in hypertension development. sodium reabsorption, which also contributes to sodium
In the vasculature two components of insulin signalling retention.118 In hypertensive rats, Ang II regulates the
exist: metabolic and growth factor signalling. Metabolic increase in SGLT2 expression via the angiotensin II type 1
signalling involves insulin receptor substrate‑1 (IRS‑1), receptor (AT1R), supporting a role for SGLT2-mediated
phosphoinositide 3‑kinase, protein kinase B (AKT), sodium reabsorption in the development of hyperten
and endothelial nitric oxide synthase (NOS); growth sion.119,120 Moreover, in vivo data suggest that insulin
factor signalling functions via the extracellular signal is an agonist for this effect of SGLT2 in humans and is
regulated kinases (ERK)1/2 and endothelin‑1 (ET‑1) important for postprandial glucose and sodium reabsorp-
pathways.84,103–105 In insulin resistant states, metabolism tion.121 Emerging evidence also indicates that inhibition
is impaired owing to serine phosphorylation of IRS‑1, of SGLT2, with molecules such as dapagliflozin, in animal
which leads to reduced NO bioavailability and impaired models or humans with T2DM induces a mild osmotic/
vascular relaxation.103 Conversely, in this state, upregula- natriuretic effect that promotes modest reductions in
tion of the ET‑1 pathway contributes to increased vas- blood pressure and body weight, which might reduce the
cular contraction.103 The imbalance in pathway-selective risk of a future cardiovascular event.122–124

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SNS overactivation CKD.137,139 The exact mechanisms for this non-dipping

Obesity is associated with activation of the SNS in pattern of blood pressure are unknown; however, insulin
diverse tissues—including the heart, kidneys, and skel- resistance, autonomic nervous system dysfunction,
etal muscle—and with baroreflex dysfunction, leading to increased SNS activity and increased inflammation can
altered blood pressure.33,34,125,126 Regardless of blood pres- all contribute to the phenomenon.137,140
sure, individuals who are obese have increased renal SNS OSA and hypertension are typically associated
activity compared with healthy individuals, indicated by comorbidities. 50–60% of individuals with OSA are
an elevation in renal norepinephrine levels.33 Interest hypertensive and half of individuals with hypertension
ingly, individuals who have obesity but are normotensive have OSA.141 Moreover, the frequency of the associa-
have suppressed cardiac SNS activity, whereas those who tion of these comorbidities is even higher in those with
have obesity and hypertension have elevated cardiac SNS treatment-resistant hypertension.142,143 OSA activates the
activity.33 Increases in both renal and cardiac SNS activ- SNS independently of obesity-related mechanisms144,145
ity might, therefore, be one mechanism that leads to the and, therefore, might be a major factor that promotes
development of hypertension in obesity. The importance treatment-resistant hypertension in those who have
of SNS activation in the kidney to obesity-related hyper- obesity. Renal sympathetic denervation has led to posi-
tension is highlighted by evidence that renal denervation tive improvements in blood pressure, OSA and glycaemic
can lower blood pressure and increase sodium excretion control in patients with obesity and treatment-resistant
in a canine model fed on a high-fat diet.127 However, hypertension.14,38,146 OSA is also highly prevalent among
other studies suggest that SNS activation alone might individuals with treatment-resistant hypertension and
not lead to the development of hypertension. Increased elevated aldosterone levels.146 SNS activation and aldo
α‑adrenergic-mediated vascular tone has been reported sterone production in response to non-classical adrenal
in overweight men, most of whom had hypertension;128 stimuli might contribute to the increased aldosterone
however, hypertension, rather than body weight, might levels seen in patients with obesity (Figure 2).146,147 Aldo
account for the increase in SNS activity reported in this sterone regulates blood pressure via mineralocorticoid
study. In individuals who have obesity but are normo- receptors in both the renal and vascular systems.148 Treat
tensive the observed increase in sympathetic outflow to ment with a continuous positive airway pressure assist
the forearm musculature does not lead to an increase device and mineralocorticoid receptor inhibitors to
in peripheral sympathetic vascular tone.129 The authors limit the deleterious effects of elevated aldosterone levels
speculated that a dissociation between SNS activity and can reduce the severity of OSA and normalize blood
peripheral vascular tone can protect a subset of indivi pressure (Figure 2).146
duals with obesity from developing hypertension, which
might explain the small population of individuals with RAAS
obesity but normal blood pressure.129 However, definitive In patients with obesity, inappropriate activation of RAAS
evidence that hypertension in individuals with obesity modulates insulin resistance, SNS activation, dysfunc-
is either initiated or maintained solely by a neurogenic tional immunity and abnormal renal sodium handling,
mechanism has yet to be determined.130 which collectively contribute to cardiovascular and renal
Several factors have been suggested to promote dysfunction (Figure 1).40,78,84,108 In addition to the conven-
obesity-associated hypertension by activating the SNS, tional circulating endocrine RAAS proteins, the heart,
including hyperinsulinaemia, hyperleptinaemia, RAAS kidney, vasculature, adipose tissue, immune cells and
activation (via Ang II), baroreflex dysfunction and brain express RAAS proteins as part of a tissue-specific
obstructive sleep apnoea (OSA) (Figure 1).131,132 However, local effect.98,149–152
evidence suggests that hyperinsulinaemia itself does not Ang II synthesis by intravascular and intrarenal RAAS
promote hypertension.133,134 Increased leptin secretion might directly regulate vascular stiffness, and endothelial
from dysfunctional adipose tissue is also an important and renal function.98,153 Ang II also modulates vascular
modulator of SNS activity.131 Disruption of signal trans- and renal function by inhibiting metabolic insulin signal
ducer and activator of transcription 3 (commonly known ling and enhancing ERK1/2 and ET‑1 signalling.84,104
as STAT3) signalling in the arcuate nucleus leads to resist- Expression of RAAS components and increased expres-
ance to the anorexic effects of leptin and might result in sion and secretion of angiotensinogen by adipose tissue
weight gain.135 Conversely, preservation of leptin sensiti in obesity states supports a role for local RAAS activa-
vity in the ventromedial and dorsomedial hypothalamus, tion in adipose tissue dysfunction.152 Moreover, increased
involving activation of PI3 kinase and melanocyte stimu- Ang II production by perivascular adipose tissue con-
lating hormone and its receptors, leads to enhanced renal tributes to impaired vascular function.154 This concept is
sympathetic outflow.131,132 Low adiponectin and increased further supported by studies in mice with an adipocyte-
apelin levels are linked to SNS activation, although their specific angiotensin knockout. When fed a high-fat diet,
role in SNS regulation is unclear.108,136 these mice have a lower blood pressure than wild-type
Progression to a chronic hypertensive state in indivi control mice on an identical diet.155
duals with obesity might be preceded by a loss of noc- Circulating aldosterone might also be involved in the
turnal blood pressure dipping in the absence of elevated development of hypertension in individuals with obe
daytime blood pressure.137,138 A non-dipping pattern of sity. Obesity can be accompanied by elevated plasma
circadian blood pressure increases the risk of CVD and aldosterone levels156 and soluble factors derived from

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Adipose insulin resistance is unchanged in these patients. 161,164

tissue Mineralocorticoid receptor antagonists might improve
insulin resistance in patients with hyperaldosteronism
Airway
in contrast to individuals with obesity in whom aldo
Weight loss
obstruction sterone levels are only moderately elevated.164 However,
cPAP Leptin insulin resistance in obesity can also develop via other
pathways, including through the effects of overnutrition
OSA and SNS overactivation, meaning that mineralocorti
Oxidized
fatty acids Angiotensinogen
coid receptor antagonists might not be appropriate in
(non-classical this context.40,165 In this regard, eplerenone, a drug with
pathway) SNS
activation higher binding specificity for the mineralocorticoid
receptor than spironolactone, improved flow-mediated
dilation in healthy individuals 55–79 years old.166 More
Kidney Renal over, impaired endothelial function was improved in
denervation
obese mice or exogenous-aldosterone-infused lean mice
with an endothelial-specific mineralocorticoid recep-
Renin
ARBs tor deletion. 167 A subset of individuals with obesity
and hypertension might also have insulin-resistance-
Adrenal Ang II related hyperaldosteronism, for which mineralocorticoid
receptor inhibitors might be useful to treat.168
Attenuation of Ang II‑induced vascular damage by
Mineralocorticoid
receptor antagonist
Aldosterone Vascular dysfunction mineralocorticoid receptor antagonists suggests a cross-
talk between the Ang II and aldosterone signalling path-
Sodium Hypertension
ways.84,169 For example, Ang II‑induced vascular smooth
retention muscle contraction and hypertension are reduced in
mice with a deletion of mineralocorticoid receptor speci
Figure 2 | Possible mechanisms of obesity-associated hypertension and therapeutic
fic to smooth muscle cells.148 This study also suggests
strategies. Adipose tissue releases leptin, angiotensinogen and oxidized fatty acids
to stimulate adrenal release of aldosterone via activation of the classic RAAS, as mineralocorticoid receptor-regulated blood pressure is
well as a non-classical pathway mediated by oxidized fatty acids. Leptin stimulates independent of hypertension induced by renal mecha-
the central SNS which in turn leads to renin release from the kidney. Activation of nisms. Both the direct beneficial effects of mineralo
RAAS in other tissues contributes to renal and vascular dysfunction. Increased corticoid receptor antagonists, and their role in reducing
adipose tissue can lead to OSA, which can be treated by therapeutic weight loss or Ang II‑induced pathology support the adjunctive use
application of cPAP. OSA leads to activation of the SNS which activates RAAS in the of mineralocorticoid receptor antagonists to manage
kidney. Increased aldosterone can be reduced with mineralocorticoid receptor resistant hypertension in obesity.29,38
antagonists. Abbreviations: , increased; , decreased; ARBs, angiotensin type 1
receptor blockers; cPAP continuous positive airway pressure; OSA, obstructive
Immune and inflammatory mechanisms
sleep apnoea; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic
Accumulating evidence suggests that in patients with
nervous system.
obesity, dysfunctional innate and adaptive immune and
inflammatory responses contribute to vascular dysfunc-
adip ose tissue stimulate adrenal aldosterone secretion and the pathogenesis of hypertension. However, the
tion. 157–159 Endot helial dysfunction 160 and enhanced mechanisms and mediators of this relationship are still
vasc ular smooth muscle reactivity have both been not well understood. Immune-mediated injury in obesity
implicated in the modulation of vascular remodelling and hypertension can occur in the vasculature, central
by aldosterone.98 Patients with primary hyperaldostero nervous system, kidney and adipose tissue, including
nism can be insulin-resistant, and aldosterone levels perivascular tissue (Figure 1).112,170,171
have been correlated with BMI and insulin resistance
in patients with obesity who are normotensive.161 The Innate immunity
precise role of aldosterone-induced vascular insulin Macrophage infiltration into adipose tissue is associ-
resistance has not been fully elucidated; however, sup- ated with systemic insulin resistance.172 Distinct macro
pression of local inflammation and vascular stiffness phage phenotypes elicit either a proinflammatory
by the mineralocorticoid antagonist spironolactone in (M1 macrophages) or an anti-inflammatory response
rodent models of hypertension and insulin resistance has (M2 macrophages).172 Lipid-filled foam cells are a type of
been reported.98,162 Aldosterone activates nicotinamide activated M1 macrophage that secrete proinflammatory
adenine dinucleotide phosphate-oxidase (NADPH), cytokines within the vascular wall.173 Proi nflamma
which promotes oxidative stress and decreases NO bio tory cytokines secreted by macrophages, such as TNF
availability.163 Aldosterone also increases endothelial and IL‑6, contribute to insulin resistance by activating
stiffness by modulating epithelial sodium channel expres- kinases that phosphoryl ate serine residues of IRS‑1
sion on the endothelial cell surface and NO release. 163 and IRS‑2 and lead to suppression of metabolic insulin
Spironolactone can lower blood pressure in patients with signalling and promotion of growth factor signalling in
obesity with elevated plasma aldosterone levels, although the vasculature.104

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Adaptive immunity and IL‑6 production, and an increase in IL‑10 secre-

Accumulating evidence suggest that T‑cell activation and tion.177 Similarly, adoptive transfer of TREG cells prevented
dysregulation of T‑cell polarization can affect the patho- aldosterone-induced vascular damage in vascular and
physiology of hypertension. T helper (TH) 1 cells mediate renal tissues of young C57BL6 mice.184
the proinflammatory response and oxidative stress, and RAAS-stimulated activation of the peripheral immune
promote infiltration of M1 macrophages into adipose system—via the central nervous system—might also
and vascular tissues.171 TH17 cells secrete IL‑17, which lead to immune-mediated hypertension in patients with
contributes to vascular injury in hypertension.174 CD8+ obesity.185,186 Spleen and lymph nodes are extensively
cells that are cytotoxic to the kidney and vasculature innervated by the SNS and norepinephrine also modu-
in hypertension also secrete IL‑17.112 T regulatory cells lates T‑cell activation.187,188 In rats, intracerebroventricular
(TREG) are a unique subpopulation of T cells40 that sup- administration of Ang II modulates lymphocyte prolif-
press proinflammatory T‑cell responses and promote eration and spleen cytokine secretion, and sympathetic
polarization of M2 macrophages, which in turn leads to denervation in the spleen can abolish these effects of
an anti-inflammatory response. Insulin resistance and Ang II.189 These studies suggest that the modulation
impaired vascular reactivity are associated with deple- of blood pressure occurs via both peripheral and central
tion of TREG cells and insulin sensitivity can be restored by immunomodulation in addition to the haemodynamic
TREG-cell transfer and/or induction in rodents.175 TREG cells effects of RAAS.
can also protect against insulin resistance and hyperten-
sion via secretion of anti-inflammatory cytokines such as Dietary fructose and uric acid
IL‑10, which can limit impaired insulin signalling caused A high-fructose diet can lead to hyperuricaemia owing
by proinflammatory cytokines.176 Moreover, IL‑10 can to decreased renal clearance, increased uric acid pro-
inhibit NADPH-oxidase-mediated oxidative stress.177 duction by adipose tissue and increased hepatic produc-
Finally, in patients with T2DM, an increase in proinflam- tion via the induction of fructokinase.37 Interestingly,
matory T‑cell ratio (that is, elevated levels of TH17 cells serum uric acid is independently associated with a non-
and a decrease in levels of TREG cells might contribute to dipping circadian pattern of blood pressure in patients
vascular dysfunction thereby leading to hypertension.178 with hypertension,190 and 24-h ambulatory diastolic and
daytime systolic blood pressure can be decreased by
Inflammasome reducing serum uric acid levels with allopurinol.191 How
Activation of the inflammasome by IL‑1β might contrib- ever, these findings need to be confirmed by large-scale
ute to insulin resistance,179 which is a response observed epidemiological and interventional studies.
after pathogen exposure or danger-associated signal acti- Adipocyte dysfunction, maladaptive immune and
vation.180,181 In obesity states, palmitate and ceramide lipid inflammatory response, inappropriate activation of
levels are elevated, which activates inflammasomes.180 RAAS and enhanced oxidative stress all contribute to
When fed a high-fat diet, mice deficient in central inflam- uric-acid-mediated induction of cardiovascular and renal
masome molecules fail to become insulin resistant, which injury.57,192 Uric acid increased expression of monocyte
is accompanied by suppression of immune and inflamma- chemoattractant protein‑1, macrophage infiltration and
tory responses.180,181 Mice fed a high-fructose diet become adipose tissue proinflammatory responses in a murine
obese and develop hyperuricaemia, which is associated model of CRS.193 Uric acid can also contribute to an
with inflammasome activation, suggesting that uric acid inflammasome response in obesity induced by a high-
also contributes to an inflammasome response in obesity fructose diet.192 Uric acid increases AT1R levels in the
induced by a high-fructose diet.182 vasculature, thereby contributing to Ang II-mediated
endothelial dysfunction and vascular inflammation.40
RAAS in the immune system Uric acid can also lead to ischaemic renal injury owing
The role of RAAS-mediated immune cell activation to excess collagen deposition, increased macrophage
in hypertensive states is supported by experiments in infiltration and expression of osteopontin, 194 ele-
Rag1–/– mice, which have an absolute deficiency of T vated juxtaglomerular renin production and reduced
and B lymphocytes.183 Adoptive transfer of T cells (but not NO levels in the macula densa.194 Ingestion of fructose
B cells) can restore normal blood pressure, endothelial can also increase salt and water resorption in the small
dysfunction, vascular remodelling and reactive oxygen intestine and kidney. Moreover, in rats, a high-fructose
species production.183 Moreover, in rats, Ang II triggers diet can induce synthesis of ET‑1 leading to hyper
the recruitment of TH1 cells to renal and cardiovascular tension, which can be attenuated by administration of an
tissues, which is prevented by inhibitors of AT1R.40,112,171 ET‑1 inhibitor.57,195
Adoptive transfer of TREG cells before Ang II infusion
can attenuate blood pressure increases and improve Incretins and DPP‑4
vascular stiffness and impaired vasodilatory responses Glucagon like peptide‑1 (GLP‑1) and glucose-dependent
in young C57BL6 mice.171 This improvement was asso- insulinotropic peptide are gut-derived hormones that
ciated with attenuation of infiltration of inflammatory enhance glucose-stimulated insulin secretion and sup-
monocytes, macrophages, and TH1 cells, suppression press glucagon release, thereby modulating postprandial
of Ang II‑induced NADPH oxidase activity, reactive and long-term glucose homeostasis.196 These incretins
oxygen species production, interferon γ (IFN)‑γ, TNF, are rapidly degraded by the exopeptidase DPP‑4, which

REVIEWS
circulates in the plasma and limits the half-life of these AT1R expression when NO synthase is inhibited and
substrate hormones to ~2 min.196,197 DPP‑4 secretion under high-salt conditions,222 which suggests that pre-
from adipose tissue and inhibition of insulin-mediated venting estrogen suppression of Ang II signalling might
glucose uptake in adipose and muscle cells by DPP‑4 sug- decrease cardiovascular risk in women who have obe
gests that this exopeptidase has direct effects on insulin sity. In the Framingham study, aldosterone levels were
resistance (Figure 1).198 In the past 10 years, DPP‑4- higher in women than in men, and were positively asso-
resistant GLP‑1 analogues (exenatide and liraglutide) ciated with markers of cardiac remodelling, such as left
and DPP‑4 inhibitors (sitagliptin, vildagliptin, saxiglip- ventricular wall thickness in women but not in men.210
tin, linagliptin and alogliptin) have been approved in These findings suggest that crosstalk between estrogen
the USA for use in patients with T2DM to lower HbA1c and mineralocorticoid receptors might contribute to
levels. Augmentation of GLP‑1 levels using these drugs altered immune and inflammatory responses, endothe
can improve cardiovascular outcomes in patients with lial dysfunction and arterial stiffness relating to obesity
T2DM,196,197 suggesting that their effect extends beyond and hypertension in women.
glycaemic control. Liraglutide and DPP‑4 inhibitors
can lower blood pressure in animal models of obesity Therapeutics
and hypertension and in humans with T2DM. 29,199,200 Lifestyle modifications, including calorie restriction and
Linagliptin also has potent vasodilatory effects in ex vivo exercise, are effective in limiting the effect of obesity on
vascular ring preparations.201 DPP‑4 substrates other hypertension (Figure 2). However, many patients find
than GLP‑1, such as stromal cell derived factor 1α and weight loss programs difficult to maintain and high
the natriuretic peptides,202 might also contribute to the dropout rates occur during the initial years of such
beneficial effect of DPP‑4 inhibitors in the vascula- programs.223 Pharmacologic interventions are, there
ture. Natriuretic peptide levels are low in patients with fore, useful when patients who have obesity are unable
obesity 203 and, therefore, DPP-4 inhibitors might be used to comply with their weight reduction program or
to extend the bioavailability of these proteins. when weight reduction measures alone cannot reduce
DPP‑4 is also widely expressed in the kidney and CD4+ hypertension (Figure 2).
and CD8+ immune cells.196,204 DPP‑4 inhibitors can reduce Targeting RAAS can potentially improve multiple
the accumulation of M1 macrophages and increase levels pathophysiological components of obesity-associated
of M2 macrophages in adipose tissue or atherosclerotic hypertension, including increasing GLP‑1 levels and
lesions.205,206 Moreover, GLP‑1 can enhance TREG-cell modulating SGLT2 or SNS overactivation. 29,38,223 The
function.207 DPP‑4 inhibitors might, therefore, be useful angiotensin receptor inhibitor losartan can reduce serum
to treat immune-mediated mechanisms of hypertension uric acid levels, but a similar effect has not been seen
in obesity. with other such blockers.224 DPP‑4 inhibitors and GLP‑1
analogues might also be used to manage hypertension
Estrogen as an add-on therapy in patients with T2DM.29 Owing
In premenopausal women, estrogens can lower the risk to the complex pathophysiology of treatment-resistant
of CVD; however, this cardioprotective effect is lost in hypertension, the correct management of hypertension
premenopausal women who have obesity and diabetes in patients who have obesity is of major concern to clini-
mellitus. 1,208–210 Differences in sympathetic–adrenal cians.225 Aldosterone antagonists and control of inappro-
nervous system regulation between men and women priate SNS activation by renal denervation are emerging as
suggest that premenopausal women might have better new modalities for the management of treatment-resistant
control of stimuli that activate the SNS than men and hypertension (Figure 2).7,40,226
are consequently protected from development of arterial
hypertension, which correlates with results seen in lean Conclusions
hypertensive rats.211–213 In these female patients, arterial Hypertension related to obesity can occur via multiple
stiffness is substantially higher than in age-matched mechanisms: insulin resistance; adipokine alterations;
men, which might explain why obesity limits the cardio inappropriate SNS and RAAS activation; structural and
vascular protection of estradiol in premenopausal women functional abnormalities in the kidney, heart and vascula-
who have obesity.214–216 Estrogen receptor‑α and GPR‑30 ture; and maladaptive immunity. Hyperuricaemia associ-
can also increase TREG-cell function,217 and insulin sensi ated with a high-fructose diet also contributes to vascular
tivity is modulated by signalling mediated by estrogen dysfunction, renal injury and immune activation. DPP‑4-
receptor α in macrophages.218 Whether these immune mediated incretin signalling can affect vascular func-
functions of TREG cells and macrophages are modulated tion, immune responses and natriuresis in obesity states.
in premenopausal women who have obesity remains to Estrogen-mediated insulin sensitivity in premenopausal
be determined. women who do not have obesity is compromised when
Estrogen modulates Ang II signalling differently they develop obesity. Alteration in the gut microbiome
under normal and high-salt diets. For example, estradiol in obesity is another factor that contributes to insulin
suppresses Ang II signalling by reducing AT1R expres- resistance and dysfunctional immunity. Treatment-
sion,98,219 whereas GPR‑30 increases the expression of resistant hypertension is more common in individuals
angiotensin converting enzyme (ACE) 2, decreasing with obesity than in those who do not have obesity, espe-
AT1R expression.220,221 By contrast, estradiol can increase cially in patients with OSA, and is a major challenge in the

REVIEWS
management of hypertension. Adjunctive therapy with Review criteria

mineralocorticoid receptor antagonists and renal dener-
MEDLINE and PubMed databases were searched for full-
vation are emerging as therapeutic measures to control
text English-language articles published between 1950
treatment-resistant hypertension. Therapeutic strategies and 2014 with the following terms: “obesity”, “resistant
targeting obesity-associated hypertension are needed hypertension”, “insulin resistance”, “obstructive sleep
—mineralocorticoid receptor antagonists are especially apnea”, “SNS activation”, “high fructose corn syrup”,
promising in this context.7,29 More studies focused on the “uric acid”, “endothelial dysfunction”, “DPP‑4”, “tissue
clinical utility of treating hypertension in children with RAAS”, “aldosterone”, “adipose dysfunction”, “gut
obesity are also necessary. Despite the positive therapeu- microbiome”, both alone and in combination. The
tic developments, obesity-related treatment-resistant reference lists of identified articles were also consulted
for other relevant papers.
hypertension remains a major issue in health care.
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The pathophysiology of hypertension

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Key points hypertension by up to 25%.45,46 Moreover, maternal

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SNS overactivation CKD.137,139 The exact mechanisms for this non-dipping

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Adipose insulin resistance is unchanged in these patients. 161,164

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Adaptive immunity and IL‑6 production, and an increase in IL‑10 secre-

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management of hyper­tension. Adjunctive therapy with Review criteria

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