Adrenomedullin gene is located on chromosome 11 and contains 3 intron and 4 exon domains. Transcriptionally activated TATA, CAAT, GC boxes and, nuclear factor-interleukin 6 (NF-IL-6) and activator protein-2 (AP-2) domains are found at the 5’ end of this gene. The AP-2 region activates the protein kinase C (PKC)-cAMP cascade 20, whereas the NF-IL-6 region is the site where acute phase proteins, which are particularly effective in inflammation, bind. The binding of many cytokines involved in the inflammation to the NF-IL-6 region stimulates human ADM synthesis of 52 amino acids and subsequently accelerates blood flow in the area of inflammation 121.

ADM is included in calcitonin/CGRP/amylin family as it has a slight resemblance in sequence to calcitonin gene-related peptide (CGRP) 1. mRNA responsible for ADM synthesis encodes information for the synthesis of a preprohormone known as preproadrenomedullin with 185-amino acid. Later, 21 amino acid signal peptide is cleaved from preproadrenomedullin (1-185) and the 164 amino acid peptide proadrenomedullin (proADM) (22-185) is formed 2223. Proadrenomedullin has three vasoactive peptides: ADM, proadrenomedullin N-terminal 20 peptide (PAMP) and adrenotensin. In addition, it has an inactive domain known as MR-proADM. Afterwards PAMP 2223242526272829303132333435363738394041, mid-regional proadrenomedullin (MR-proADM) 454647484950515253545556575859606162636465666768697071727374757677787980818283848586878889909192, ADM 9596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146 and adrenotensin (153-185) are detached from proADM. ADM, detached from proADM precursor, is an immature and inactive molecule of 53 amino acids bound to glycine called “ADM-glycine”. Glycine is then removed by amidation and 52 amino acid active form is obtained. This active form is called “ADM-mature” 2425 (Figure 1).

Tissues with highest ADM mRNA levels are reported to be adrenal medulla, heart, lungs and kidneys 22. Besides these, it was found to be synthesized in gastrointestinal, endocrine and central nervous system, reproductive system cells, vascular smooth muscle and endothelial cells 26. It has also been detected in body fluids like blood, urine, saliva, cerebrospinal fluid, sweat, amniotic fluid and breast milk 3426. As it is found in almost all tissues and body fluids, it brought out the thought that ADM has multiple biological functions. That is why there are many ongoing studies about ADM currently.

Production and metabolism of ADM is very fast with a half-life of 20 minutes 27. It is carried in circulation with a specific protein called adrenomedullin binding protein-1 (AMBP-1) 28. Another interesting feature of ADM is that it does not have circadian rhythm and plasma levels are not affected by age and gender 29. Plasma ADM levels also were found to be not affected by food or water intake and to be stable all day 30.

Although it is defended that ADM is not stored and secreted continuously 3132, there are several studies known to report that ADM is stored in tissues of the pancreas and adrenal medulla 33. The major form of ADM in circulation is immature or inactive ADM-glycine form 25. Metalloproteinases and aminopeptidases are shown to be effective in ADM catabolism 34.

ADM synthesis and release are under the control of many factors. Particularly cytokines (such as IL-1α, IL-1β, TNF-α and TNF-β), liposaccharides 35 and endotoxins 36 strongly stimulate the synthesis of ADM. This, in turn shows that ADM has a strong relationship with inflammation and sepsis. Steroids hormones like glucocorticoids, peptide hormones like thyroxine 37, mediators like AT II 38, endotelin-1 39 and bradykinin 40, atrial natriuretic peptide (ANP) 41 and arginine vasopressin (AVP) 42 stimulate ADM synthesis. Besides these, higher altitudes, hypoxia 43 and pregnancy 44 are known to elevate plasma ADM levels.

ADM is a member of calcitonin peptide family, which also includes calcitonin, calcitonin-gene related peptide (CGRP) and amylin 1. Its functions in the body are mediated by CGRP and adrenomedullin receptors. These receptors are receptors, which are called calcitonin receptor-like receptor (CLR), which are seven transmembrane folding and a kind of G protein 45. In order for CLR proteins to function, they need proteins (RAMPs) with three types that alter receptor activity. CLR/RAMP1 complex serves as CGRP receptor, while CLR/RAMP2 complex serves as ADM1 receptor and CLR/RAMP3 complex serves as ADM2 receptor 464748 (Figure 2).

ADM performs its effect mostly by activation of protein kinase A (PKA) by increasing intracellular cAMP levels 49. ADM also increases intracellular Ca⁺⁺ independent from cAMP and activates endothelial NO synthase (eNOS) which induces NO release and causes vasodilatation 50. It has also been shown to induce NO synthesis by inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells 51. Vasodilatory effect of ADM is known to be caused by NO release 52. ADM also increases NO-activated guanosine 3′, 5′- cyclic monophosphate (cGMP) levels and causes protein kinase G (PKG) activation (NO/cGMP/PKG signal pathway) 53. Besides these pathways, it also uses different signal pathways like mitogen-activated protein kinase (MAPK) 54, K⁺-ATP channel activation 55, c-fos expression 56 and phosphatidylinositol-3-kinase/akt dependent pathway 57.

ADM receptors have been widely distributed throughout the central nervous system. ADM receptors have been detected in many areas such as cerebral cortex, cerebellum, pons, medulla oblongata, thalamus and hypothalamus 98. The fact that ADM levels in the cerebrospinal fluid are lower than the plasma levels indicate that the secretion of ADM from the cerebrospinal fluid occurs independently of plasma 44. It has been reported that ADM increases the blood flow by vasodilatation in the cerebral circulation and increases the production of cAMP/PKA pathway and NO in the vascular smooth muscle cell, especially in large-scale cerebral vessels, causing vasodilatation 6452.

In the case of hypoxic ischemia and hypoglycemia, it has been observed that ADM gene expression is increased in central cortex neurons, endothelium and perivascular glial cells 99. Cortisol, NO and ADM levels were higher in chronic schizophrenia than control group 100. Increased ADM mRNA expression was detected in ischemic cortex in rats with stroke formed by occlusion of the middle cerebral artery 101. ADM infusion after hypertrophic rupture of the middle cerebral artery has been shown to increase regional blood flow and collateral circulation, thus reducing ischemic brain damage 102. As a result, it is understood that ADM has important effects in post-ischemia reperfusion.

ADM has been shown to inhibit ACTH secretion from rat anterior pituitary cells in a dose-dependent manner, reducing CRH-induced ACTH production and performing all of these with a mechanism independent of cAMP 103. ADM levels were found to be quite high and significantly decreased after surgical treatment in patients with Cushing's disease due to pituitary adenoma 104.

ADM has been reported to inhibit the salt appetite in rats by controlling oxytocin (OT) release in the hypothalamus. ADM has been shown to change water intake, salt appetite and food intake when given directly to the brain. It has also been reported that central ADM stimulates OT release by affecting CNS and inhibits more Na consumption 105106. The effect of ADM via a neurotransmitter OT suggests that many processes related to OT can be regulated via ADM. It was found that OT stimulates uterine muscle contraction, facilitates delivery and helps protect the brain from hypoxia, regulates the menstrual cycle and ejaculation of men, decreases the repetitive behaviors in diseases such as autism, prevents the proliferation of breast cancer and other tumor cells, stimulates angiogenesis while reducing inflammation, provides cardiac repair in ischemia-reperfusion injury and it also has apoptosis-inhibitory effects in the heart 107108109110111112. We believe that at least some of these effects of OT may be under the influence of ADM.

CNS-induced ADM is considered as a physiological regulator of thirst. It is suggested that brain-derived ADM increases vasopressin secretion and therefore acts as a physiological regulator of fluid homeostasis 113. ADM is synthesized and released in both adrenal cortex and adrenal medulla. ADM and its receptors have been found to be intense in the adrenal cortex, especially in the area of the zona glomerulose 114. ADM has been shown to inhibit aldosterone production but has no effect on plasma renin activity and plasma corticosterone (or K⁺) levels 115. However, in another study, an increase in plasma renin activity was observed after ADM infusion to sheeps and cortisol decreased. This study also showed a decrease in ACTH levels. The decrease in cortisol levels was thought to be due to a decrease in ACTH, not a direct effect on the adrenal cortex 116. In addition, it was observed that synthetic ADM application increased the adrenal blood flow in rats and this has led to the use of ADM for therapeutic purposes 117.

ADM is found in the myometrium and endometrium layer of the ovary and uterus of women 118119. ADM levels were high in the follicular phase of the menstrual cycle and low in the luteal phase 120. It has been suggested that ADM produced by granulosa cells may play a role in the development of corpus luteum 121. ADM has been found to play an important role in the growth of placenta and fetus and prevention of uterine contraction by providing blood flow to uterus (blood supply to the placenta) and implantation of the embryo 122123124125126. ADM is thought to be present in the blood, placenta and amniotic fluid during normal pregnancy due to the important tasks it undertakes in all these stages 44127.

ADM was detected in testis, epididymis and prostate in male genital tract 128129130. The expression of ADM gene is shown in the sertoli and leydig cells in the testis 131132. It has been suggested that ADM affects sperm maturation and movement, inhibits contraction in prostate and stimulates prostatic blood flow 128133134135. ADM has also been reported to cause vasodilatation via NO/cGMP in cavernous vascular endothelial cells 57.

ADM has complex effects on inflammation. It has been reported that plasma ADM levels are increased in the local and systemic inflammation and are synthesized in mucosal surfaces and contributes to anti-microbial protection 136. It controls the leukocyte migration and differentiation, while increasing the blood flow in the inflammation zone. It also reduces endothelial permeability and inhibits exudate formation 137. In addition, the fact that it may have local effects suggest that it can be used with topical drugs. Therefore, we consider that it can be used in the treatment of edema.

ADM has been found to play a regulatory and stabilizer role among proinflammatory and anti-inflammatory cytokines. Proinflammatory markers, TNF-α and IL-1β, have been seen as potent stimulators of ADM release 13822. ADM also stimulates proinflammatory cytokine release, such as IL-6 and IL-10 while IL-10 also shows anti-inflammatory effect by suppressing TNF-α and IL-1β release 16139. ADM is transported in the plasma by binding to the complement factor H, known as adrenomedullin binding protein-1 (AMBP-1). In this way, ADM plays an active role in the regulation of the complement system. It also increases the cleavage of C3b through factor I and it affects the complement regulator function of factor H 28. Since ADM levels were significantly elevated in sepsis and septic shock (especially in endotoxic shock), ADM was thought to be secreted as a preservative against sepsis 140141. As a result, ADM regulates the immune system by functioning through both cellular and secretory (cytokines and complement) system. We think that ADM has significant potential as an agent that can be used in the treatment of septic shock due to its anti-inflammatory effects.

Immunoreactive ADM has been detected in various tissues including plasma, as well as kidney, pancreas and intestine 142. It is reported that ADM may act as autocrine or paracrine way in these tissues where it is released as a vasoactive hormone in the circulation 71143. Subcutaneous ADM was found to have anti-ulcer effect in rats with reserpine-induced gastric mucosal damage. Probable cause of this effect is possibly associated with accelerative effect of ADM on blood flow in the gastric mucosa and partially anti-gastric secretory activity by increasing the release of NO 144. Rossowski et al. previously reported that ADM strongly inhibits gastric acid secretion 145. All these findings suggest that ADM may be an anti-ulcer agent.

ADM and PAMP are able to regulate many physiological and pathological conditions such as intestinal hormones. It has also been reported that it has a regulatory role in small intestine and colon peristaltism. It is also argued that ADM and PAMP regulate the intestinal mucosa and help the mucosal host defense system. In addition, it is also thought that ADM and PAMP deficiency may be effective in the development and progression of intestinal diseases with its effect on microbiota composition 146. However, the use of ADM as an antimicrobial agent requires more investigations that are precise.

In a study investigating the effect of thyroid hormones on ADM, ADM levels were higher in hyperthyroid rats and lower in hypothyroid rats compared to control group 8. Higher ADM and PAMP levels with higher thyroid hormones were detected in cultured vascular smooth muscle cells (VSMC) and thyroid storm due to Graves' disease 14737148149. Therefore, thyroid hormones are thought to regulate the production of ADM in vivo.

Due to significant effects on oxygen consumption and metabolic rate, thyroid hormones are essential for normal operation of almost all tissues. For this reason, the relationship between thyroid hormones and ADM is also a matter of curiosity. It has been reported that thyroid hormones increase the oxygen capacity of blood by increasing erythropoietin (EPO) production and increase tissue perfusion by vasodilation via accelerating ADM synthesis 15037. In addition, it was stated that direct ADM synthesis could be stimulated via thyroid hormones in case of hypoxia 151. Therefore, it is considered that important part of ADM's effect on energy metabolism is carried out by thyroid hormones.

Fat-rich diet increases ADM secretion 152, ADM stimulates lipolysis in brown adipose tissue 153 and adipose tissue adipocyte differentiation 154. Due to these effects, it is important to use it in combating obesity.

There are views that ADM is stored in pancreas secretory granules. ADM has been shown to inhibit insulin secretion by inhibiting β cells in the pancreas 33. It was also emphasized that high ADM levels in DM patients may be caused by hyperglycemia-induced ADM expression 155. On the other hand, it has been suggested that ADM levels are not affected by plasma glucose concentrations 156. Circulating ADM concentrations have been reported to be higher in pregnant women with gestational DM, and have been reported to suppress insulin secretion in pancreatic β-cells in vitro 157.

Obesity, resulting from the expansion of adipose tissues, is characterized by impaired insulin sensitivity of target organs and triggers type 2 diabetes, and also closely related to the proinflammatory (due to its effect on TNF-α) and immune systems 158159160161. We think that the relationship between ADM and proinflammatory and inflammatory regulation is the key mechanism in the relationship between obesity and ADM. However, the role of adaptive immune response in the inflammation of adipose tissue remains unclear.

In a study aiming to indicate the role of adipose tissue inflammation on the pathogenesis of insulin resistance (IR), a short-term high-fat diet was found to increase the number of CD4 (+) T cells in adipose tissues. This increase in the number of CD4 (+) T cells may contribute to the local inflammatory response in the early inflammation phase of adipose tissue and this may have an important role in insulin resistance. Major histocompatibility complex class II (MHCII) dependent antigen presentation for activation of CD4 (+) T cells has been suggested to induce early inflammation and IR in adipose tissue. MHCII inhibition is reported to decrease IR 162163.

In a study with transgenic mice, ADM 2 treatment was determined to fix the high fat diet induced early insulin resistance in the fat tissue. It is assumed that this is mainly achieved by inhibiting adipocyte MHCII-dependent antigen presentation and CD4 (+) T-cell activation 163. This finding has been found to be of interest as featured as a peptide with anti-insulin resistance effect.

In a study investigating ADM regulation in obesity and its localization in human adipose tissue, it is considered as a new member of the adipokine family due to being produced from stromal cells of human adipose tissue, including macrophages and synthesized in individuals with metabolic syndrome, especially in the omental region 161.

All of these indicate that ADM may have an important role in energy use and metabolism and obesity-induced insulin resistance as well as its relationship with thyroid hormones. However, since this issue needs clear evidence, there are many things to be investigated.

a) have significant potential as an agent for the treatment of septic shock due to its anti-inflammatory effects, b) have a possibility of taking an active role in the breakdown of insulin resistance in obesity, c) may accelerate tissue perfusion by means of thyroid hormones, d) play a regulatory and stabilizing role among proinflammatory and anti-inflammatory cytokines, e) possibly contribute to the implantation of the embryo by providing the blood supply to the uterus and placenta, f) may have bronchodilator activity especially in acute asthma attacks, g) exhibits diuretic and natriuretic effect by increasing renal blood flow and glomerular filtration by vasodilatation with a NO-dependent mechanism in the arterioles, h) effect on plasma renin activity, i) have significant effects in post-ischemia reperfusion at CNS, j) alters thirst, salt appetite and food intake by stimulating OT synthesis k) lowering blood pressure while increasing blood flow, l) protects against atherosclerosis by having anti-apoptotic effect on endothelial cells and anti-proliferative/ anti-migrate effects on vascular smooth muscle cells in ischemic heart disease m) contributes to intestinal mucosal microbiota and provides antimicrobial host defense system, and finally n) stimulates angiogenesis and regenerates the damaged endothelial layer. This multifunctional feature of ADM brings it into the forefront for the purpose of treatment and leads to perform increasing amount of researches in recent years.