Natriuretic peptides and obesity.
An approach to an interest topic.
Yaniel Castro Torres, Anamary Fleites Pérez.
Universidad de Ciencias Médicas Dr. Serafín Ruiz de Zárate Ruiz.
Luz Caballero #161 e/Hospital y Alejandro Oms.
Santa Clara. Villa Clara. Cuba.
Recibido 19-NOV-2012 – ACEPTADO después de revisión el 15-ENERO-2013.
The authors declare not having conflicts of interest.
Natriuretic peptides are cardiac hormones that have some very well-known functions such as increasing diuresis, natriuresis and vasodilation. Since recent years there are several observations that show a reverse relation among these peptides with obesity and other metabolic disorders. Many investigations have allowed to determine the specific way by which natriuretic peptides induce lipolysis. This discovery has been very useful to increase our knowledge about this topic; which could explain the strong relation among cardiovascular diseases and obesity. New perspectives of treatment will be developed with the administration of these hormones to the overweight or obese patients, with a better prognosis and life quality of them.
|Key words:Natriuretic peptides. Obesity. Lipolysis. Overweight. Metabolic disorders.
Rev Fed Arg Cardiol. 2013; 42(1): 7-14
Currently, obesity represents one of the main health care problems in the world. It is an important risk factor for the development of cardiovascular, cerebrovascular diseases and type 2 diabetes mellitus. According to data from the World Health Organization, in year 2008 the number of obese people older than 20 years reached a figure of 500 millions. The world prevalence of this disorder almost doubled between 1980 and 2008, in that last year almost 10% of men and 14% of women at world level were obese . It is estimated that the prevalence of patients with overweight or obese in the USA is 68% (72% in men and 64% in women) .
In the 1980s, it was posed for the first time that the heart could have an endocrine function, regulating the activity of other body organs . More recently, the existence of low levels of natriuretic peptides (NPs) (classically, its function was known in the regulation of diuresis, salt excretion and blood pressure) has been related to the presence of obesity. In this regard, there have been advancements in the understanding of the pathophysiologic mechanisms involved, although to this moment a consensus has not been established as to their use as a therapy for this entity. The knowledge of these elements, presupposes a new way of approaching a disorder that constitutes a true scourge for humanity, so the constant updating in relation to this issue is extremely important for the medical community, with especial emphasis for those that treat directly obese people or that have a predisposition to suffer this disorder.
Structure and metabolism of NPs
NPs are a family of polypeptide hormones that have an important role in the regulation of the homeostasis of water, salt and blood pressure. The atrial natriuretic peptide (ANP), the brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are the most widely known and studied . The first member of this family, the ANP, was discovered by Bold et al. These investigators found that the administration of atrial tissue by infusion in a group of rats, determined in them an increase in natriuresis and diuresis. Later by isolation and purification mechanisms, the identification of this compound was achieved in the atria . Some years later, another member of the group was isolated in the brain of pigs, so it was called BNP ; it would later be discovered that it was also secreted by the cardiac ventricular cells of humans . A third compound called CNP has been found in the central nervous system, as well as in endothelial cells and chondrocytes .
The three keep a very similar structure, consisting of a ring of 17 amino acids joined by disulfide bonds. The active form of ANPs in human beings is a peptide of 28 amino acids, while that of BNPs and CNPs is of 32 and 22 amino acids respectively. ANP is synthesized in the atria and stored in granules present in the cardiac cells, the initial compound is known as pro-ANP and has 126 amino acids , it is transformed to its active form by the action of the corin [10,11]. BNP is also produced in the heart, specifically in the ventricles. Its initial form is pro-BNP that contains a structure of 134 amino acids . This is regulated by the transcription factor GATA-4 , and its production as with ANP, is determined by an increase in the pressure of the cardiac chambers . Unlike the two previous ones, CNP is secreted by the vascular endothelium, and it has the function of regulating the tone and growth of it . The genes that encode the ANP and BNP are located in chromosome 1, in the 1p36.3 locus, while the gene of the CNP is in chromosome 2 .
Both the ANP and BNP are released in the heart with the purpose of regulating the volume or pressure overload existing in its chambers, and in turn, regulate a series of physiological processes in the body. Its natriuretic, diuretic, and vasodilator activity is known. Currently, it was possible to determine some compounds that are capable of increasing the production/secretion of such peptides, besides the increase in tension of the cardiac chambers already mentioned. Within these we have endothelin-1, angiotensin II, glucocorticoids, thyroid hormones, growth factors and especially some cytokines as interleukin-1 and interleukin-6 [17-35] (Table 1). Although it is posed that ANP is essentially synthesized and secreted in the atria, and BNP in the ventricles , it is known that both can be synthesized, stored and released by both chambers in pathological conditions [36,37].
Table 1. Main factors stimulating or inhibiting the production/secretion of NPs.
PNs: Natriuretic peptides.
Receptors of NPs
To this moment, three subtypes of receptors are known for these compounds, known as receptors of NPs, and each of them presents a different genotypic expression in each of the organs in which they have been found, such as the heart, kidneys, suprarenal glands, lungs, thymus, brain, gastrointestinal tract and systemic vasculature [38-41]. Type A and B receptors are structurally similar. They present three ligands; the extracellular one, the transmembrane one, and the intracellular one. Both receptors present approximately 44% of homology in the extracellular ligand and act through guanylate cyclase. The essential location of the type A receptor is in the kidney and the suprarenal glands, and it presents a great affinity to ANP and BNP [38,42]. The type-B receptor has a great affinity to CNP and its fundamental location is in the brain and fibroblasts [43,44]. While the type-C receptor has had no enzymatic activity acknowledged yet, it has been identified in tissues like the kidney and the adipose tissue [42,45]. The last receptor acts first, as a purifying receptor, and along with neprilysin (neutral endopeptidase) it regulates the values of NPs in circulation .
Mechanisms that explain its action on the adipose tissue
The demonstration made by several investigators on the expression of the NPs receptors in the adipose tissue, suggests a possible metabolic action of the latter (Figure 1). This observation has been corroborated by several studies that have shown a lipolytic effect of these compounds. Such effect occurs independently from the action of the catecholamines, which until a while ago were acknowledged as the main factor involved in lipolysis. The lipolytic effect of NPs is as strong as isoproterenol and the other α-adrenergic medications. Such intensity is different between the different peptides, and it has been suggested in the following way: ANP>BNP>>CNP .
Figure 1. Metabolism and biological actions of NPs on adipose tissue.
A and B type NPs act on the receptor of A-type NPs located in adipose cells tissue. This union favors the formation of cGMP from GMP. cGMP activates protein kinase, which starts two processes: first it activates intracellular lipase, which degrades triacylglycerides into free fatty acids and glycerol; second, it activates the p38 MAPK enzyme, which determines the expression of genes of brown adipose tissue.
PNS: Natriuretic peptides; AG: Fatty acids; GC: Glycerol; GMPc: Cyclic guanosine monophosphate; GTP: Guanosine triphosphate; LI: Intracellular lipase; PNA: A-type natriuretic peptide; PNB: B-type natriuretic peptide; PK-dep GMPc: cGMP-dependent protein kinase; TAG: Triacylglycerides.
Catecholamines induce lipolysis by the activation of cyclic adenosine monophosphate (cAMP), while in the case of ANP and BNP they do it through guanylate cyclase. The NPs, after acting on cell receptors, cause an increase in the cyclic guanosine monophosphate (cGMP) within the cells. cGMP subsequently activates protein kinase G. This in turn, phosphorylates the intracellular lipase, which leads to an increase in the degradation of triacylglycerol . The 8-bromo-cGMP, an analogue of cGMP has the same lipolytic effect as NPs. On the other hand, the use of H-89, an inhibitor of the protein kinase A (another enzyme closely related to the onset of lipolysis by other mechanisms) did not affect the lipolysis mediated by NP . This allows us to reaffirm that the action of NPs is exclusively mediated by the action of cGMP and protein kinase G.
Recently, Bordichia et al, found that the protein kinase G activated by NPs may activate the p38 MAPK enzyme, which favors the expression of the genes of the brown adipose tissue . Until recently, it was only known that this mechanism could be triggered by the action of catecholamines. As it is known, brown adipose tissues promotes the use of energy and thermogenesis, moving the metabolic balance of the body toward the consumption of the excess of calories. This represents an additional beneficial element to the action of the NPs, which could be used in future investigations.
The mentioned lipolytic effects of these cardiac hormones could be linked to other mechanisms. Adiponectin is a peptide of 244 amino acids described for the first time in year 1995 and that to the present time, has shown to be an important regulator of metabolism [50-53]. It occurs essentially in the adipose tissue, although not exclusively .
Several studies have found that this is decreased in patients with obesity and other metabolic disorders. Tsukamoto et al, clarified aspects on this topic when they proved that the action of ANP and BNP increases the production and secretion of adiponectin . This is a discovery that will allow a better understanding of this topic, which will favor the design of subsequent studies in this field.
NPs and obesity
The relation between obesity and NPs has been approached by numerous investigations [56-66] (Table 2). This is a topic that has received several approaches and that currently presents multiple ways to approach it.
Table 2. Studies that show an inverse relation between NPs and obesity.
CA: Abdominal circumference; FG: Glomerular filtration; IC: Heart failure; IMC: Body mass index;
PNA: A-type natriuretic peptide; PNB: B-type natriuretic peptide.
In these investigations, patients with multiple associated conditions were included; however, the relation proposed above was a common denominator. In some cases with greater or lesser significance, which could be influenced by several factors like co-morbidity, level of physical activity and calorie consumption. As it will later be presented here, the two last factors have modified the levels of NPs in several studies.
It is possible to see that not only the deficit of NPs was related to obesity, but also to other metabolic disorders, as metabolic syndrome and resistance to insulin. In many cases these entities are combined, additionally relating to cardiac pathologies as heart failure and hypertension, which undoubtedly worsen the prognosis of patients. This makes us think that the activity of these peptides could be an essential element in the genesis of such association, representing a key element in their evolution. So modifying their production, secretion, plasma concentrations and action on the tissues, would bring great benefits for these people.
During physical exercise, an increase in the serum levels of NPs has been proven, and these have been related to an increase in the degradation of adipose tissue lipids [67-69]. This increase in the lipolysis has also been observed in the simultaneous block of α adrenergic receptors, which reaffirms the independence already analyzed previously, in the action mechanisms of NPs and catecholamines as lipolytic agents . This increase in the levels of these peptides while making exercises would be an additional element that would allow understanding the physiological mechanisms involved in the increase of the degradation of lipids, as well as in controlling some diseases such as hypertension, when a regular physical activity is practiced.
The activity of NPs in several studies has been modified by calorie consumption. It has been observed that the excessive consumption of these is an element that influences negatively on their activity. A study made in lab rats showed that the levels of ANP and BNP were decreased in the group of obese rats that received hypocaloric diets for 3 weeks after the follow-up . In another investigation, a group of obese women that underwent a diet low in calories, presented an increase in lipolysis after ANP infusion . These findings makes us think that the administration of NPs and its subsequent action on the adipose tissue may be fostered when a low-calorie diet is followed, being an additional element that should be taken into account when analyzing the beneficial effects of the reduction of calorie consumption in patients with overweight or obese.
The inverse relation between NPs levels, obesity and the increase in blood pressure figures has also been shown in several investigations [56,73]. If we take into account the decrease in NPs values in obese and overweight patients, and the relation they have in the regulation of blood pressure essentially through the increase in diuresis, natriuresis and inhibition of renin-angiotensin-aldosterone system activity, then it is possible to understand such relation. A mechanism could be the existence of a decreased natriuresis in obese patients , which would favor their salt retention and their development of hypertension. There is another element in relation to this issue, and it is the difference in tissue expression of NPs receptors in obese patients with hypertension. It is posed that the levels of ANP and A type receptors in adipocytes of obese patients with hypertension, is significantly lower than in normotensive patients . However, other studies suggest that there is not only alterations in the concentrations of these peptides and in the expression of its receptors, but also the activity of ANP in normotensive obese individuals is lower than in those with normal weight .
The aspects approached previously in relation to the low concentrations of NPs and the appearance of obesity and other metabolic disorders, may represent a key point for the development of new strategies of intervention for this type of patients. The lipolytic effects of these hormones shown in vitro have been confirmed in vivo, after the administration of ANP by a mechanism of microdialysis through subcutaneous implants . Some years ago, a group of investigators found that the IV administration of therapeutic doses of ANP promoted an increase in lipolysis and this was independent from the activation of the sympathetic nervous system . In another study, the administration of ANP by infusion, reaching serum levels similar to those observed in the cases of heart failure also caused a quick oxidation and movement of the lipids in the adipose tissue .
However, there are aspects that should be taken into account, such as that related to the decrease in sensibility of NPs receptors after the existence of high levels of these in plasma. This phenomenon could be attributed to a decrease in the activity of guanylate cyclase or the receptors of NPs themselves . The use of these hormones as lipolytic agents in previous studies, has shown positive and encouraging results. Their use as a single treatment or combined with other drugs, still has to be widely evaluated in future investigations, becoming more accurate in terms of effectiveness and security with larger samples of patients.
New elements are added to this topic, in relation to the genetic expression of brown adipose tissue after the action of NPs. Bordichia et al , after the administration of ANP in lab rats and human adipose cells, observed that the transcription of genes related to the expression of brown adipose tissue increased. Moreover, they showed that this mechanism was developed by the activation of two kinases, which to the present were not taken into account in the metabolism of the lipids mediated by the action of NPs, although its relation to catecholamines was indeed known. This creates new therapeutic expectations acting through this via, from the benefits this tissue has on body metabolism.
Some papers have been published on the increase in the figures of blood pressure observed in lab rats, with deficits of corin . Corin, as it was previously presented here, is the enzyme in charge of converting pro-ANP into its active form. So the lack of it would decrease the formation of such peptide, with negative consequences for blood pressure. But what is significant is that not only the regulation of blood pressure would be affected, but also the lipolytic effect already approached of these hormones would be affected too. These observations have not just been made in lab animals, but also the presence of a polymorphism has been found in the gene that encodes this enzyme in African patients with hypertension and left ventricular hypertrophy [81,82].
The results shown by several investigators on the inverse relation between adiponectin and the presence of obesity and other metabolic disorders is a scenario that could provide wide results. The problem is related to previous observations that show an increase in the production and secretion of such peptide, after the action of the NPs on the adipose tissue .
There is currently, another important basis of investigation related to the synthesis of new NPs by the addition, substitution or deletion of one amino acid(s) of its structure . Thus a specific effect would be achieved, with a significant reduction of undesirable effects. It is a new field of experimentation that still requires a lot of advancements before it is possible to extend its use globally. If this idea extends, not just obese patients would be benefitted, but also all those that present diseases in which NPs deficit plays a determinant role.
NPs cause an increase in the degradation of lipids by a mechanism different than that of catecholamines. This observation has been corroborated by numerous investigations that have found an inverse relation between NPs and the presence of obesity. The use of these hormones as a therapeutic means is a focus of investigation at world level, because of the useful aspects it may provide for a great number of patients, although more studies in this field are required to define new managements.
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Publicación: Marzo 2013