Adipose endothelin signaling—An unusual suspect linking obesity to insulin resistance

Endothelins are peptide hormones best known for their function in the regulation of vessel tone. They are mainly secreted by endothelial cells, but expression has been reported for many other tissues including liver, muscle, adipose tissues, and the brain.1 The main of the three endothelin isoforms, endothelin-1 (ET-1), is the most potent natural vasoconstrictor known so far and has been implicated in a broad range of cardiovascular diseases. Interestingly, increased ET-1 levels are also reported in obese and diabetic patients, and ET-1 signaling through one of its two receptors, endothelin receptor beta (ETB), has been implicated in the regulation of insulin action and glucose homeostasis. In this issue, Rivera-Gonzalez and co-workers studied the metabolic function of ET-1/ETB signaling in a mouse model of diet-induced obesity.2 Their data suggest that ET-1-induced ETB signaling in adipose tissues inhibits the expression and release of the adipokine hormone adiponectin. This, in turn, is a well-known sensitizer of insulin signaling and glucose import and metabolization in tissues, such as adipose, muscle, and liver.3 The new data offer an intriguing mechanistic explanation for the metabolic function of ET-1 signaling: obesity-induced upregulation of ET-1 expression leads to ETB-mediated downregulation of adiponectin release from adipocytes. Diminished adiponectin levels in the circulation, in turn, would desensitize insulin signaling and glucose disposal in target tissues promoting hyperglycemia and the development of insulin resistance (Figure 1). The authors of this study provide several lines of evidence supporting their conclusions. First, they studied metabolic responses to ET-1 treatment in primary adipocytes upon genetic or pharmacological inhibition of ETB signaling. They show that ET-1 downregulates expression of the master metabolic transcriptional regulator, peroxisome proliferator-activated receptor gamma (Pparγ), and adiponectin (Adipoq). Second, they generated mice that specifically carry a knockout of or overexpress ETB in adipose tissue. By adipose tissue RNA-sequencing, they show that genes associated with metabolic pathways like insulin and adipokine signaling are upregulated in ETB knockout animals under high-fat-diet conditions. These include insulin receptor 1 (Irs-1), the insulin-dependent glucose transporter GLUT4 (Slc2a4), and adiponectin (Adipoq). Effects on other adipokines such as leptin and adipsin were also observed suggesting a pro-obesogenic action of ET-1 in adipose tissue. These effects were more pronounced in—hormonally more active—visceral compared to subcutaneous adipose depots. Finally, knockout of ETB improved insulin sensitivity and glucose handling in obese animals, while ETB overexpression had little effect. Obesity is a widespread and complex systemic disorder with an enormous impact on well-being and life expectancy. It also has an enormous impact on public health systems worldwide. While the hallmark of obesity itself, the excessive accumulation of white adipose tissue, has only moderate pathological effects, a vast array of associated complications such as type-2 diabetes and arteriosclerosis can dramatically affect life quality and duration.4 Metabolic hormones with central effects, such as leptin, glucagon-like peptide 1, and adiponectin, have been the focus of intense studies aiming at counteracting the development of obesity and its sequelae. GLP-1 receptor agonists, for example, have recently gained much attention as potent inhibitors of appetite and stimulators of pancreatic insulin responses.5 Adiponectin has been shown to suppress appetite and stimulate insulin sensitivity and glucose utilization. Unlike leptin, it is suppressed in obesity and, thus, may counteract insulin resistance and type-2 diabetes development.3 Higher ET-1 levels are found in obese and diabetic patients.6 This may result from increased inflammatory signaling in endothelial cells but could also derive from upregulation of ET-1 expression in adipocytes, for example, through hypoxic events. The findings from this paper suggest that white adipose tissue may be the main site of action of ET-1/ETB signaling in obesity. Local upregulation of ET-1 may downregulate adipokines which, in turn, affect adipocyte insulin signaling. At the same time, loss of adiponectin will affect glucose handling in muscle and liver, thus disrupting systemic glucose homeostasis and tissue function. Through adiponectin action on smooth muscle systems such mechanism could further link the metabolic and cardiovascular effects of ET-1.7 ETB receptor antagonists are available, and it would be interesting to test these drugs for their preventive potential in obesity or type-2 diabetes. While providing intriguing mechanistic insights into ET-1 action in adipose tissues, this study has limitations. First of all, systemic effects of adipose ETB knockout on body weight and adiposity in mice were not detected. While this could be due to the specific choice of diet (high fat instead of a more diabetic option like a cafeteria diet) or the moderate intervention period of 8 weeks, it could also mean that other sites of ET-1 action like muscle or brain should be considered. It also remains to be shown if ET-1/ETB/adiponectin/insulin signaling occurs exclusively in adipose tissues or if systemic effects of adiponectin are involved. Finally, the proposed role of hypoxia signaling in this context deserves more attention, as ETB knockout failed to affect Hif regulation (at least at mRNA levels) in adipocytes. In summary, Rivera-Gonzalez and co-workers provide compelling evidence that ET-1 signaling might be an attractive alternative target linking insulin resistance and cardiovascular dysfunction as two important complications of obesity. It will, thus, be of interest to assess ETB signaling in clinical settings. Henrik Oster: conceptualization, validation, writing. The author has nothing to reports. No funding was received for the work included in this editorial. The author declares no conflict of interest. No patient consent was required for the work included in this editorial. No material from other sources is included in this editorial. This editorial is not based on a clinical trial.