Mechanisms of Obesityrelated Hypertension

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Mechanisms of Obesity-related Hypertension 

•  V.  Lamounier-Zepter 1, 2, S.  R.  Bornstein 1,
  M.  Ehrhart-Bornstein 21 Department of
  Endocrinology, University Medical Center,
  Heinrich Heine University, Düsseldorf, Germany2
  German Diabetes Center, Düsseldorf, Germany
• 93-8-18 ???

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Abstract

• Obesity has become an epidemic problem in western
  societies, contributing to metabolic diseases,
  hypertension and cardiovascular disease.
• Although the importance of obesity as a cause of
  hypertension is well established, the molecular
  basis of the relationship between obesity and
  increased blood pressure remains poorly
  understood.
• This brief review examines the association
  between obesity and hypertension along with the
  mechanisms proposed to explain this association,
  while presenting evidence of a direct causal
  effect of adipose tissue in the development of
  hypertension through the involvement of the
  adrenal cortex.

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Introduction

• The prevalence of overweight and obesity has
  increased dramatically world wide .
• According to recent reports from the National
  Health and Nutrition Examination Survey (NHANES),
  almost two-thirds (64 ) of the adult population
  in the United States is overweight, and
  approximately 31 is obese with a body mass
  index (BMI) of more than 30 .
• In Europe, more than 50 of the population
  between 35 and 65 years of age is either
  overweight or obese .
• This tendency constitutes one of the major health
  problems since obesity has been associated with
  severe disorders such as hypertension, type 2
  diabetes, coronary artery disease, respiratory
  complications (obstructive sleep apnea) and
  increased mortality from certain types of cancer
  .

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Obesity and Hypertension

• Obesity, especially the visceral type of obesity,
  is strongly associated with arterial
  hypertension.
• This association has been well-documented in
  different racial, ethnic and socioeconomic
  population groups and is not confined to
  industrialized countries .
• In some populations, an almost linear relation
  between BMI and systolic/diastolic blood pressure
  has been observed .
• Moreover, the Framingham Heart Study suggests
  that around 78 of the risk for hypertension in
  men and 65 in women can be directly related to
  excess body weight.

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• These epidemiological studies have also been
  supported by clinical and experimental studies.
• The therapeutic value of weight loss for reducing
  arterial pressure have been consistently shown by
  clinical studies, and experimental studies with
  animals have also shown that diet-induced excess
  weight gain almost invariably raises blood
  pressure .
• All of these studies together indicate obesity as
  a major risk factor for the development of
  hypertension.

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Pathophysiology of Obesity-related Hypertension

• Although the importance of obesity as a cause of
  hypertension is well established, the molecular
  basis of the relationship between obesity and
  increased blood pressure remains poorly
  understood.
• The central mechanism for the obesity-related
  hypertension seems to be an increased renal
  tubular sodium and water reabsorption.
• Factors that may contribute to altered sodium
  handling mainly include the activation of the
  sympathetic nervous system and the
  renin-angiotensin-aldosterone system (Fig. 1).

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• In addition, a recent finding indicates that
  peroxisome proliferator-activated receptor gamma
  (PPAR?) activation leads to sodium reabsorption
  in the cortical collecting duct .
• Since PPAR? activation plays a critical role in
  adipocyte differentiation and lipid metabolism,
  involvement of this transcription factors
  regulation in the bodys reaction to exuberant
  food supply at different levels may be
  hypothesized.

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Sympathetic Nervous System Activation

• Several studies have shown an increased
  sympathetic activity in association with obesity.
• This was observed by measurements of the
  catecholamine levels and through direct
  recordings of muscle sympathetic nerve activity
  by using microneurography .
• The increase in sympathetic activity does not
  seem to be global, but restricted to the kidney.
• Thus, a selective renal sympathetic activation
  would lead to increased sodium reabsorption and
  hypertension in obesity.
• The mechanisms proposed as responsible for the
  sympathetic hyperactivity mainly include central
  stimulation by leptin and hyperinsulinemia.

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Leptin

• Leptin, an adipocyte-derived protein, acts
  centrally on the hypothalamus, decreasing
  appetite and increasing energy expenditure
  through sympathetic stimulation.
• Apart from its well-studied role in the body
  weight regulation, increasing amounts of data are
  emerging on its role as a neuroendocrine hormone.
  
• Although acute leptin infusion has vasorelaxant
  effects, the chronic infusion of leptin induces
  significant increase in blood pressure.
• The long-term pressor effect of leptin can be
  blocked by a- and ß-adrenergic antagonists.

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• Furthermore, transgenic mice overexpressing
  leptin develop elevation of blood pressure due to
  sympathetic activation.
• Thus, elevated plasma leptin concentrations in
  obesity may lead to sympathetic hyperactivity and
  consequently to hypertension.
• However, since a resistance to the effects of
  leptin on satiety seems to occur in obese
  subjects, it is possible that leptin resistance
  would also involve its effects on sympathetic
  activation.

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Insulin

• Insulin resistance is a common feature of
  obesity.
• Based in the observations that short-term insulin
  infusion may induce increased sympathetic
  activity and sodium retention, it has been
  postulated that hyperinsulinemia as a consequence
  of insulin resistance would mediate the increase
  in arterial pressure in obesity .
• However, neither chronic venous insulin infusion
  nor infusion into cerebral circulation has been
  shown to cause increased arterial pressure .

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Renin-Angiotensin-Aldosterone System

• Several reports suggest that the
  renin-angiotensin-aldosterone system (RAAS) is
  activated in obesity.
• A positive correlation between BMI and diverse
  components of the RAAS has been observed by
  different investigators.
• Thus, the abnormal activation of RAAS in obesity
  would raise the blood pressure through enhanced
  vascular tone by angiotensin II or through the
  effects of aldosterone on renal sodium retention.

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• Aldosterone is the most potent mineralocorticoid
  secreted by the adrenal cortex promoting sodium
  retention and elevation of arterial pressure.
• Diverse clinical studies have observed elevated
  plasma aldosterone levels in obese patients with
  arterial hypertension, especially those with
  visceral obesity.
• Follow-up on these patients showed a decrease in
  plasma aldosterone with weight loss associated
  with a significant decrease in blood pressure.
• Consequently, increased serum aldosterone levels
  have been linked to the development of obesity
  hypertension.

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• The importance of aldosterone in the development
  of obesity-related hypertension has also been
  supported by the finding that blocking
  aldosterone activity significantly attenuated the
  rise in arterial pressure associated with
  diet-induced obesity in dogs .
• So, it is not surprising that high sodium intake
  is significantly associated with increased
  cardiovascular disease risk in obese compared to
  non-obese subjects according to a large
  prospective study.

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• However, the mechanisms that link obesity with
  increased aldosterone secretion remains unclear.
• Different mechanisms have been discussed such as
  a genetic predisposition, the involvement of
  adipose renin-angiotensin system, adipose
  receptors for atrial natriuretic peptide (ANP) or
  fatty acids transformed through hepatic
  oxidation.
• We have recently shown a direct stimulatory
  effect of adipocyte secretory products on
  aldosterone secretion.

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• Adipose tissue is an important production site of
  angiotensinogen (AGT) and angiotensin II (Ang
  II).
• The local role of adipose AGT and Ang II in
  adipocyte development is well-established, but
  the functional importance of the adipose
  renin-angiotensin system on obesity-hypertension
  is still unclear.
• A systemic role of adipose AGT in the blood
  pressure regulation is mainly supported by an
  experimental study on transgenic mice showing
  that adipocyte-derived AGT can be released into
  circulation.

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• Furthermore, the authors found increased systolic
  blood pressure associated with increased plasma
  AGT levels in mice overexpressing adipose AGT.
• In obese humans, however, the role of adipose
  renin-angiotensin system in the development of
  hypertension remains to be defined.

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• The role of genetic factors in the stimulation of
  RAAS in obesity is still unclear.
• Some studies have observed an association between
  the AGT gene polymorphism, obesity and
  hypertension.
• In addition, an association between variations in
  the human insulin gene, and plasma renin
  activity, urinary sodium, potassium and
  aldosterone has been observed.
• However, environmental factors appear to be much
  more important than genetic factors in
  influencing the RAAS system in obesity.
• Some investigators have observed that the
  increase in aldosterone levels in obesity seems
  to be independent of plasma renin activity.

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• Thus, a renin-angiotensin-independent stimulus
  should be responsible for the increased
  aldosterone production observed in obese
  subjects.
• A mechanism of this type has been suggested by
  Goodfriend et al., who observed that linoleic
  acid oxidation products stimulate aldosterone
  secretion in rat adrenal cells
• .
• Therefore, they postulated that in obesity
  increased plasma levels of fatty acids might lead
  to increased aldosterone secretion stimuli after
  oxidation by the liver .
• However, we recently demonstrated that isolated
  human adipocytes secrete potent mineralocorticoid
  releasing factors that directly stimulate
  aldosterone secretion .

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• Human adipose tissue secretes a wide variety of
  endocrinologically active factors, and its
  involvement in the bodys metabolism and
  homeostasis has been revealed.
• Based on these findings, we tested the hypothesis
  that adipocyte secretory products directly
  stimulate adrenocortical aldosterone secretion.
• Indeed, our data indicate that human adipocytes
  secrete potent mineralocorticoid-releasing
  factors.
• Fat cell-derived secretagogues stimulated
  adrenocortical steroidogenesis with the most
  prominent effect on aldosterone release (Fig.
  2).

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• This effect was independent of adipocyte
  angiotensin II or the adipokinins leptin,
  adiponectin, interleukin-6, or tumor necrosis
  factor-a, and involves at least two factors that
  interact in their stimulation of aldosterone
  release.
• These findings suggest a hitherto unknown direct
  involvement of adipose tissue in the regulation
  of adrenocortical function and especially
  mineralocorticoid secretion.
• Further studies will be needed to characterize
  the adipose mineralocorticoid releasing factors.

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• How do adipocyte secretory products reach the
  adrenal cortex?
• Many adipocyte secretory products influence
  adipocyte metabolism in an autocrine/paracrine
  manner.
• However, several factors are released into the
  circulation and can be measured in the plasma.
• Thus, mineralocorticoid releasing factors
  secreted from subcutaneous or visceral fat into
  the circulation will reach the adrenal and
  stimulate adrenocortical steroidogenesis in an
  endocrine manner.

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• However, fat cells are frequently present within
  the adrenal and in direct contact to the
  steroid-producing cells.
• This close cellular proximity forms the
  prerequisite for direct paracrine interactions
  and a possible stimulation of steroidogenesis by
  adipocyte secretory products.
• Recently, our group published the case of an
  intraadrenal myelolipoma associated with
  ACTH-independent Cushings syndrome with highly
  intermingled myelolipomatous and adrenocortical
  tumor cells with ample direct cell-cell contact.

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• It is conceivable that paracrine influences of
  secretory products from the myelolipoma cells
  were responsible for the enhanced cortisol
  secretion in this patient.
• We therefore propose that adipocyte-derived
  mineralocorticoid-releasing factors may directly
  stimulate aldosterone secretion by endocrine or
  paracrine means, making them responsible for
  hyperaldosteronism and therefore hypertension in
  obesity (Fig. 3).

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• In conclusion, the complex mechanisms involved in
  the pathophysiology of obesity-related
  hypertension are still not completely understood.
• However, aldosterone seems to play a significant
  role in the development of obesity hypertension.
• Therefore, an antihypertensive treatment with
  aldosterone antagonists would be beneficial for
  obese hypertensive subjects.
• Further studies are needed to verify the
  effectiveness of aldosterone antagonists compared
  with other antihypertensive drugs in reducing
  morbidity and mortality in obese patients.

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• Thanks for your attention