Endothelin-1 in the Pathophysiology of Obesity and Insulin Resistance

Abstract

The association between plasma endothelin-1 (ET-1) and obesity has been documented for decades, yet the contribution of ET-1 to risk factors associated with obesity are not fully understood. In 1994, one of first papers to document this association also noted a positive correlation between plasma insulin and ET-1, suggesting a potential contribution of ET-1 to the development of insulin resistance. Both endogenous receptors for ET-1, ET_A and ET_B, are present in all insulin sensitive tissues including adipose, liver, and muscle, and ET-1 actions within these tissues suggest that ET-1 may be playing a role in the pathogenesis of insulin resistance. Further, antagonists for ET-1 receptors are clinically approved making these sites attractive therapeutic targets. This review focuses on known mechanisms through which ET-1 affects plasma lipid profiles and insulin signaling in these metabolically important tissues and also identifies gaps in our understanding of ET-1 in obesity related pathophysiology.

Introduction-Obesity and Insulin Resistance

According to the World Health Organization, the prevalence of individuals suffering from obesity has risen to over 39% worldwide. Associated with the rising incidence of obesity is a dramatic increase in patients battling diabetes mellitus type 2 (T2DM), making up over 10% of the United States adult population and rising.¹ The course of T2DM begins as insulin resistance and a compensatory increase in insulin release to maintain plasma glucose levels within a normal range. Over time, the pancreas is unable to keep up with insulin demand. Secreted insulin levels begin to decline, and the pathology of insulin resistance becomes clinically evident.^2-4 In a physiological state, low blood glucose results in decreased insulin release and activation of fasting state processes. These include increased glycogenolysis and gluconeogenesis by the liver to increase blood glucose, skeletal muscle switching to glycogen stores and then free fatty acids as a major fuel source and increased lipolysis via hormone sensitive lipase (HSL) activity in adipocytes.^5-8 In states of insulin resistance (IR), glycogenolysis and gluconeogenesis remain active even in the postprandial state, resulting in elevated glucose levels and eventual pathology.^5,6,8 Skeletal muscle takes up plasma glucose in an insulin-dependent process and accounts for about 80% of glucose uptake in response to insulin infusion.⁹ In a physiologic state, activation of insulin receptor tyrosine kinase results in intracellularly sequestered Glucose Transporter 4 (GLUT4) translocation to the cell surface.^10,11 This results in the major clearance mechanism of extracellular glucose as skeletal muscle utilizes its glycolytic pathways for energy.¹⁰ In states of insulin resistance, skeletal muscle is less able to incorporate GLUT4 receptors into the sarcolemma and, therefore, less able to clear glucose.¹¹ In human adipocytes, insulin acts to increase lipoprotein lipase activity to promote clearance of free fatty acids and decrease HSL activity to prevent lipolysis.^2,12 Therefore, the state of insulin resistance results in an imbalanced release of free fatty acids rather than storage, increasing plasma levels of triglycerides and free fatty acids. In combination with the increased glucose production by the liver and decreased glucose incorporation into skeletal muscle, the pathophysiology of insulin resistance results in a hyperglycemic, hyperlipidemic state, a clinically evident pathology seen in many individuals suffering from obesity (Figure 1).^1,13

Figure 1:

Mechanisms by which obesity promotes insulin resistance. Excess adipose in obesity reduces circulating adiponectin. Lower adiponectin, an insulin sensitizing adipokine, reduces the effect of insulin to inhibit glycogenolysis and gluconeogenesis by the liver and muscle. Insulin resistance also causes loss if insulin mediated glucose uptake by muscle via Glucose Transporter 4 (GLUT4) leading to elevated plasma glucose. In adipocytes, loss of insulin signaling pathways causes increased lipolysis by increasing lipoprotein lipase (LPL) activity and decreasing hormone sensitive lipase (HSL), thereby promoting hyperlipidemia.

It is known that chronic states of elevated insulin levels lead to resistance; however, this elevation in the obese state is not entirely explained by chronically elevated plasma glucose levels.^2,14 Obesity is associated with tissue hypoxia and inflammation, including but not limited to adipose and skeletal muscle tissues.^14,15 Several studies in isolated human adipocytes show a decrease in adiponectin release secondary to exposure to hypoxic growth conditions.¹⁵ Adiponectin is known to protect against insulin resistance by increasing hepatocyte glycogenesis and decreasing gluconeogenic and glycogenolytic processes, resulting in decreased plasma glucose and improved glucose tolerance.¹⁶ Adipocyte hypoxia in the obese state, therefore, results in reductions in adiponectin levels, poorer glucose control, and eventual resistance to insulin.

Obesity and Endothelin-1

Recent studies indicate a positive correlation between obesity and plasma endothelin-1 (ET-1) levels.¹⁷ ET-1 is a vasoactive peptide primarily produced and released by endothelial cells. In fact, half of circulating ET-1 is thought to be derived from vascular endothelial cells, with recent evidence indicating synthesis by adipocytes.^18,19 ET-1 is the predominant and most potent of the endothelins. Two other endothelin paralogs, ET-2 and ET-3, are encoded on separate genes and are far less studied in terms of their physiology due to the relatively low abundance; however all three human endothelin paralogs have a conserved 21-amino acid structure and produce pressor effects in vitro on porcine de-endothelized arterial walls and in rodent models²⁰.^21,22 This review will focus on the pathophysiology of ET-1 in obesity.

Active ET-1 is a 21-amino acid hormone that is the result of extensive post transcriptional processing, including intracellular cleavage.²³ Immature ET-1 is translated as a 200-amino acid pre-pro-endothelin that is cleaved to big ET-1, an inactive ET-1 precursor.²³ Further modification occurs through endothelin converting enzymes (ECEs) located on the cellular plasma membrane. Once cleaved by ECEs, mature ET-1 is released mostly toward the interstitial space, but also to a lesser extent into the circulation.²⁴ Receptors are located on a variety of tissues, including endothelium, vascular smooth muscle cells, adipocytes and hepatocytes.^23,25 Constitutive secretion of ET-1 helps to maintain basal vascular tone and metabolic function in healthy individuals.¹⁸ However, increased levels of plasma ET-1 have been observed in pathophysiological states including obesity and insulin resistance.²

ET-1, Its Receptors and Signal Transduction

Two mammalian ET-1 receptors exist, ET_A and ET_B, both of which are G_q receptors located on multiple tissue types. The cellular events following ET-1 binding to its receptors are best studied and modeled in vascular endothelium and smooth muscle. Upon binding to either ET receptor, the αq subunit of the G protein coupled receptor exchanges guanosine diphosphate (GDP) for guanosine triphosphate (GTP), thereby activating phospholipase C (PLC) within the cell membrane.^26,27 Activated PLC cleaves membrane phospholipids to generate membrane-bound diacylglycerol (DAG) and soluble inositol-1,4,5- triphosphate (IP3).²⁷ In the context of smooth muscle cells, IP3 causes release of Ca²⁺ from cellular sarcoplasmic reticulum to initiate calcium-dependent sarcomere contraction, but it also frees up calcium for signaling cascades in other cell types (Figure 2).^26,27 DAG complexes with intracellular Ca²⁺ to activate protein kinase C (PKC), which is important in phosphorylation cascades that induce smooth muscle contraction, as well as in activation of the MAP kinase pathways (Figure 2).²⁷ Of the MAP kinases, activity of extracellular regulators kinases (ERK) 1 and 2 have specifically been shown to increase upon stimulation by ET-1. ERK 1/2 controls cellular proliferation through transcriptional regulation in fibroblasts, cardiomyocytes, and adipocytes.^28,29 Pro-inflammatory effects have also been seen in states of increased ERK activity secondary to ET-1 activation.²⁷ ET-1 stimulation has been linked to increased tumor necrosis factor expression by macrophages and higher transcription rates of interleukin-6, NF kappaB and monocyte chemotactic protein-1.^30,31 While it is known that G_q receptor activation results in activation of the IP3/DAG pathway and subsequent increases in intracellular calcium and inflammatory marker expression, a detailed pathway specific for ET-1 binding of ET_A/B has yet to be identified in all tissues.

Figure 2:

Classical signaling pathways associated with endothelin receptor binding.

The effects of ET-1 within a specific tissue type depend on the receptor type activated; this has become increasing apparent within adipose tissue. Recent studies have shown that activation of ET_A in mouse 3T3-L1 fibroblasts, which have been differentiated into adipocytes, stimulates lipolysis in vitro. Activation of ET_B functions largely to inhibit the effects of insulin’s antilipolytic actions.^29,32 This variation in response to ET-1 is still being investigated, with simplified cascades beginning to be mapped. While a detailed pathway has yet to be described in all tissues, ET_B activation and its downstream effects have been well described in vascular endothelium (Figure 2). Activation of the G-coupled receptor results in the release of prostaglandins (specifically PGI₂) and nitric oxide (NO) that cause vascular smooth muscle relaxation.²⁴ Activation of the G_q linked PLC pathway results in an increase in intracellular calcium and its binding to calmodulin (CaM). CA²⁺/CaM complex then activates endothelial nitric oxide synthase (eNOS) and cyclooxygenases (specifically COX-2) that produce NO and PGI_2, respectively.²⁴ An additional phosphoinositide-3-kinase (PI3K)/Protein Kinase B (Akt)/eNOS pathway has also been described as a downstream effect of ET_B activation, again resulting in NO production and release. NO and PGI₂ act through well described mechanisms, including the protein kinase G and A pathways, to decrease intracellular Ca²⁺ in vascular smooth muscle (VSM), resulting in vasodilation.^24,33 While this pathway has been well studied in the endothelium and VSM, pathways in other tissues, including adipocytes and hepatocytes, have yet to be elucidated. However, as more is understood about the impact of ET-1 in obesity and obesity related illness, a greater understanding of the effects of ET-1 at the liver and adipocyte level is necessary.

ET-1 in Obesity: Clinical Implications

Patients suffering from obesity have increased plasma levels of ET-1 compared to lean counterparts. This has been observed in both adults and adolescents.^34,35 It is unclear if elevated plasma ET-1 in patients with obesity is due to overproduction or reduced clearance, because ET-1 is typically secreted toward the interstitial space within tissues. The ET-1 that makes it into the circulation is cleared mainly by ET_B receptors in the lung.³⁶ Nonetheless, it is widely accepted that ET-1 production is elevated, especially within adipose tissue. Adipose from patients with obesity releases 2-3 times more ET-1 than adipose from lean individuals, although it is unclear whether this ET-1 is derived from adipocytes or vascular endothelial cells.¹⁹ Following vertical sleeve gastrectomy (VSG), reductions in plasma ET-1 levels by about 20% occur in conjunction with reduced adiposity and weight loss, suggesting that elevated plasma ET-1 is the result of increased adiposity.³⁷ In addition, higher pre-surgery ET-1 correlated with reduced body weight following VSG suggesting that ET-1 may contribute to or predict weight loss outcomes following VSG.³⁷ It has also been hypothesized that increased ET-1 may contribute to the lipid derangements and insulin resistance seen in many patients with obesity by interacting with receptor subtypes ET_A and ET_B. ^32,37

ET-1 is released in response to a number of stimuli including acute and chronic stress,³⁸ hyperosmolality,³⁹ high sodium intake,³⁹ and hypoxia.⁴⁰ Obesity is a disease of chronic tissue hypoxia,⁴¹ a known stimulus for ET-1 production from endothelial cells through activation of hypoxia inducible factor alpha (HIF-1α).⁴² Thus, hypoxia may be the major factor driving ET-1 production and increased plasma levels in patients with obesity. Therefore, it is thought that tissue hypoxia increases ET-1 production by either endothelial cells or adipocytes leading to increased tissue and plasma levels of ET-1.

ET-1 in Insulin resistance

A positive correlation has been made between plasma ET-1 levels and insulin resistance in humans.^29,37 The effects of this elevation in ET-1 in combination with resistance to insulin and decreased glucose uptake varies depending on tissue type and which receptor subtype is activated. Several lines of evidence suggest that ET-1 may contribute to the development of IR, although no clinical trials have tested this hypothesis. Both receptors are expressed on insulin sensitive tissues including skeletal muscle, liver, and adipose tissue. In addition, exogenous infusion of ET-1 into humans causes IR.⁴³ In a separate study, ET-1 infusion caused whole body IR in Wistar Kyoto rats, measured by hyperinsulinemia-euglycemic clamp.⁴⁴ Our lab has recently demonstrated that a rat model lacking functional ET_B receptors has reduced fasting blood glucose and improved insulin and glucose tolerance compared to wild type littermates.⁴⁵ These data suggest an important role for ET-1 in promoting IR, especially in disease states in which ET-1 is known to be elevated, such as obesity; however, mechanisms associated with ET-1 induced IR are still not fully understood. Over the next few paragraphs, we will review known actions of ET-1 in insulin sensitive tissues and discuss potential mechanisms by which ET-1 may promote IR in these tissues.

Adipose and ET-1

Both ET_A and ET_B receptors are expressed in adipose tissue, which also can produce ET-1.³² At the adipocyte level, stimulation of the ET_B receptors results in inhibition of the antilipolytic effects of insulin, thereby promoting lipolysis during the fed state.¹⁹ Similarly, stimulation of ET_A directly results in lipolysis, which may contribute to increased plasma free fatty acids and triglycerides in individuals with obesity.^29,32 While a clear mechanism has not been established, it is thought that increased lipolysis is due to phosphorylation of HSL secondary to either ERK-1/2 activity or PKC activation of adenylyl cyclase.^27,46 Insulin resistance and decreased plasma clearance of lipids by adipocytes also seem to be related to ET_A stimulation. Data from 3T3-L1 adipocytes indicates that exposure to ET-1 resulted in a short-term increase in adiponectin release via Gq/IP3/Ca²⁺⁺ pathway, but a long-term reduction in mRNA levels and overall decrease in secretion of adiponectin.⁴⁷ This reduction in adiponectin synthesis was effectively reversed by selectively inhibiting ET_A, but not ET_B, receptors via pretreatment with receptor selective antagonists.⁴⁷ To further study this model, pretreatment with MAPK/ERK inhibiters effectively blunted the effects of ET-1 to reduce adiponectin in a similar manner as ET_A blockade, implying that MAPK/ERK kinase mediated activation of ERK is necessary to reduce expression and secretion of adiponectin.⁴⁷ Taken together, this study suggests that ET_A stimulation by ET-1 results in ERK1/2 activation and subsequent reduction in adiponectin expression and secretion.⁴⁷ Other studies on 3T3-L1 adipocytes have shown that activation of the ERK pathway decreases Peroxisome Proliferator-Activated Receptor Gamma (PPAR-gamma) transcripts and final protein product.⁴⁸ As a known regulator of adiponectin expression and production, this reduction in PPAR-gamma levels may well be at play in reduced adiponectin secretion in the context of ET-1 stimulation in adipocytes;⁴⁹ however, further studies must be performed to investigate this link. A reduction in adiponectin production by adipocytes may be one potential mechanism by which ET-1 promotes insulin resistance (Figure 3). Numerous studies have shown that adiponectin is vital in sensitization of muscle and liver to insulin and promoting adipocyte differentiation and clearance of plasma triglycerides.^50-52 Adiponectin acts to decrease glucose production in the liver by promoting the AMP-activated protein kinases pathway and increasing fatty acid oxidation in skeletal muscle.⁵³ Therefore, adiponectin plays a vital role in maintaining insulin sensitivity. Reductions in adiponectin levels are directly linked to insulin resistance and hypertriglyceridemia, while pharmacologic increase in adiponectin levels via PPAR-gamma agonists are well characterized to improve metabolic profiles.^54,55

Figure 3:

Hypothetical scheme by which ET-1 promotes insulin resistance in the obese state.

Overall, ET-1 stimulation at the adipocyte level promotes lipolytic processes and insulin resistance through a variety of pathways, resulting in increased plasma free fatty acids, glycerol, and glucose.²⁹ In contrast, insulin acts to increase lipoprotein lipase activity to promote clearance of free fatty acids and decrease HSL activity to prevent lipolysis.^6,12 Furthermore, adipocytes take up glucose in an insulin-dependent process by increasing membrane bound GLUT4, an insulin sensitive glucose transporter.²² This glucose is necessary for the formation of glycerol and the subsequent conversion of free fatty acids into its storage form of triacylglycerol.^13,56 In addition, ET-1 increases adipocyte hyperplasia after 4 weeks of infusion.⁵⁷ Therefore, elevated plasma ET-1 and states of low insulin or insulin resistance both function to increase levels of plasma free fatty acids by increasing adipocyte lipolysis and decreasing the storage of free lipids. Jurrissen et. al. recently reported that treatment with the dual ET-1 receptor antagonist Bosentan, improved glucose tolerance in Low Density Lipoprotein (LDL) knockout mice, although there was no difference in circulating lipids in Bosentan treated mice.⁵⁸ More studies using models that more closely relate to human obesity along with the use of specific ET-1 receptor antagonists will be useful to determine the contribution of ET-1 to pathophysiology related to the obese state. Evidence suggests that the effect of ET-1 on adipocyte function contributes to IR and comorbidities associated with IR (Figure 3).

Interactions between ET-1 and leptin signaling on adipocytes have been well established in both in vitro and in vivo models. In 3T3-L1 adipocyte-like cells and Ob-Luc adipocytes, ET-1 stimulates leptin production via ET_A receptor signaling. It was further shown that ET-1 positively interacts with insulin in stimulating leptin gene expression by adipocytes.⁵⁹ On the other hand, leptin also stimulates ET-1 production in human umbilical vein endothelial cells (HUVECs) through a putative mechanism that may involve the transcription factor Activator Protein-1 (AP-1).⁶⁰ In cultured neonatal rat cardiomyocytes, leptin was shown to elevate ET-1 and reactive oxygen species (ROS) levels resulting in cellular hypertrophy. The increase in cardiomyocyte ROS levels treated with both leptin and ET-1 was blunted by a selective ET_A receptor antagonist, atrasentan.⁶¹ A study in humans utilizing plethysmography, found that under physiological conditions, intravenous leptin administration stimulates both ET-1 and NO activity in the human circulation. This effect of leptin stimulating ET-1 and NO was absent in hyperleptinemic patients suffering from metabolic syndrome who are unresponsive to additional leptin administration.⁶² Mice fed a high fat diet have elevated serum ET-1, myocardial tissue ET-1, leptin and leptin-receptor mRNA. However, this was not seen in leptin-deficient obese (ob/ob) mice.⁶³ Finally, ET-1 has a known role in the regulation of leptin production associated with gastric mucosal response to injury. This gastric-specific stimulatory effect of ET-1 on leptin production occurs via ET_A receptor activation.⁶⁴ Therefore, there are a number of interactions between ET-1 and leptin that occur through a variety of tissue specific mechanisms.

ET-1 in Liver

Although ET-1 and both receptor subtypes are expressed in hepatocytes, little is known about their role in physiology and pathophysiology.⁶⁵ Exogenously infused ET-1 accumulates abundantly in hepatocytes and hepatic parenchymal cells where it has been shown to stimulate glycogenolysis in cultured hepatocytes via phosphoinositide activation.⁶⁶ In the isolated perfused liver, infusion of ET-1 causes an increase in glucose output. Both stimulation of glycogenolysis and subsequent increases in glucose output by the liver are mediated by activation of the ET_B receptor. These data suggest that elevated ET-1, particularly in insulin resistant states, may be inhibiting the ability of insulin to suppress glucose output by the liver and increase glycogen storage; although in vivo experiments to test this are lacking.

ET-1 indirectly acts on the liver through altering plasma levels of adiponectin and changing systemic metabolic processes.⁵³ Adiponectin stimulation results in activation of the AMP-kinase pathway, which exerts numerous effects in a variety of tissues.⁵³ At the level of the hepatocyte, adiponectin and its downstream mediators phosphorylate acetyl-CoA carboxylase and downregulate expression of intermediates in the gluconeogenesis pathway, thereby decreasing production and release of glucose from the liver.^53,67 ET-1 also acts on the liver indirectly by altering blood lipid and glucose levels via its downstream effects in other tissues.^29,32 Free fatty acids can be directly used for energy by skeletal muscle and heart muscle tissues and are the preferential fuel in apparent low insulin/low glucose states.⁶⁸ The liver also converts these fatty acids into ketones to be used as an energy source by a wider variety of body tissues in the fasting state.⁶⁹ Furthermore, odd chain fatty acids and glycerol can be converted into glucose by the liver and released into the blood stream. Odd chain fatty acids can enter the TCA cycle as succinyl-CoA and glycerol can be converted through various steps into dihydroxyacetone phosphate (DHAP) to enter the glycolysis pathway.^26,27 In situations of low blood glucose or insulin resistance, the liver can use both as substrates for gluconeogenesis with subsequent release of free glucose into the blood stream for use by other tissues, such as skeletal muscle.^5,10

ET-1 in Muscle

Skeletal muscle is able to take up plasma glucose in an insulin-dependent process and is one of the major clearance mechanisms of plasma glucose following insulin release by increasing GLUT4 receptor availability on the cell surface.⁹ States of insulin resistance, as well as poor blood flow and tissue hypoxia, decrease glucose clearance by decreasing exposure to the GLUT4 receptor. ^5,10,11,13 ET-1 directly inhibits glucose uptake in cultured skeletal muscle cells, and reduces insulin stimulated Akt phosphorylation and glucose uptake. ET-1 also reduced forearm blood glucose in both healthy and patients diagnosed with type 2 diabetes.⁷⁰ In addition, ET-1 decreased insulin stimulated glucose uptake in soleus skeletal muscle cells from WKY rats.⁴⁴ Chronic treatment of WKY rats with ET-1 induced IR associated with a reduction in skeletal muscle glucose uptake.⁴⁴ Therefore, ET-1 has a direct effect on skeletal muscle to reduce insulin mediated glucose uptake.

In addition to the potential direct effects of ET-1 on muscle, ET-1 may have indirect effects to alter insulin signaling in skeletal muscle through changes in muscle blood flow.⁷¹ Reductions in skeletal muscle blood flow are associated with IR in individuals suffering from obesity as well as other pathophysiological conditions such as preeclampsia,⁷² although this mechanism is still highly debated. ET-1 has potent effects on muscle blood flow through stimulation of both receptors (Figure 2). ET_A receptors are localized mainly on vascular smooth muscle cells lead to a potent and long-lasting vasoconstriction by activating Ca²⁺ channels to increase intracellular Ca²⁺.⁷³ On the other hand, ET_B receptor activation on endothelial cells leads to short lived vasodilation. This is evident from studies in rats in which IV infusion of the ET_B agonist Sarafotoxin 6c reduces blood pressure acutely; however, after 10 minutes, the vasodilatory response is outweighed by a longer lasting constriction.²² This constriction is thought to be due to activation of ET_B receptors on adrenergic cells leading to release of norepinephrine, because the constriction, measured by changes in arterial pressure, can be abolished with an alpha adrenergic blocker, and exacerbated by blockaded of beta adrenergic receptors.²² Therefore, ET-1 promotes reductions in blood flow through activation of ET_A receptors on vascular smooth muscle and ET_B receptors on vascular nerve terminals. Furthermore, blockade of ET-1 receptors with Bosentan unmasked a vasodilatory property of insulin in rat aortas suggesting ET-1 inhibits insulin mediated vasorelaxtion.⁷⁴

ET-1 antagonist in clinical trials

Since the discovery of ET-1, a number of antagonists have been produced. These include antagonists that are selective for either ET_A or ET_B receptors and dual antagonists that discriminate less against a single receptor. ET_B receptor antagonism will never be viable, as treatment with selective ET_B antagonists causes severe salt-sensitive hypertension in rodent models;⁷⁵ however, co-treatment with ET_A antagonist abolishes the hypertension.⁷⁶ Clinically, selective ET_A antagonists and dual ET-1 receptor antagonists have been widely tested in several pathophysiological states including heart failure, hypertension, diabetic nephropathy, and others (Figure 4). Bosentan and Macitentan, both dual ET-1 receptor antagonists, are approved for use in patients with pulmonary hypertension because they have been shown to improve six-minute walking distance and time to worsening.^77,78 Very few of these trials have reported parameters associated with obesity. To date, there is only one clinical trial that has been conducted that reported metabolic parameters following treatment with an ET-1 antagonist (Bosentan). In a small trial, Bosentan did not improve plasma cholesterol or triglycerides in patients with type II diabetes; however reported means were both below reference.⁷⁹ Apart from this trial, there have not been sufficient studies on the effects of endothelin receptor antagonists on pathophysiology related to obesity. The only other clinical trials undertaken that come close are The Study of Diabetic Nephropathy with Atrasentan (SONAR) and Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan (RADAR) in which primary end points were related to kidney function in patients diagnosed with diabetic nephropathy, both concluding that blockade of ET_A receptors delays the onset of nephropathy in patients with diabetes.⁸⁰

Figure 4:

Diseases for which endothelin receptor antagonists were tested. Lists were generated by searching the drug names listed within ClinicalTrials.gov. Green font indicates a disease in which endothelin antagonists have been approved for treatment.

Given the vast data suggesting a contributory role for ET-1 in the pathophysiology of risk factors associated with obesity, reporting of these risk factors, including plasma lipids and markers of insulin resistance, are almost non-existent. In fact, the RADAR trial was the first to report plasma lipids decreased in patients with diabetes following treatment with the ET_A receptor antagonist atrasentan. Consistent with preclinical data, atrasentan reduced plasma LDL and triglycerides, which returned to normal upon cessation of the treatment.⁸¹ This was recently repeated by Farrah et. al. in predialysis patients diagnosed with chronic kidney disease. In this cohort, sitaxentan, a selective ET_A antagonist significantly reduced circulating total cholesterol, LDL, and triglycerides, while increasing high density lipoprotein (HDL).⁸² These suggest that ET-1 antagonist may be beneficial in treating cardiovascular risk factors observed in patients with obesity.

Conclusions and the future of ET-1 research in obesity

The pathophysiology related to elevated ET-1 in patients with obesity is not understood completely. ET-1 is thought to contribute to hypertension in patients with obesity, but as pointed out in this review, most likely plays a role in plasma lipid derangements and insulin resistance associated with obesity. While this is evident through antagonist studies, the specific tissue and cellular mechanisms by which ET-1 promotes insulin resistance and alters plasma lipids is not known. Understanding these mechanisms may provide a potential therapeutic target to improve disease risk factors associated with obesity.