Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. We hypothesized that high ET-1 levels cause dyslipidemia, inflammation, and insulin resistance within the adipose tissue of obese mice. To test this hypothesis, male C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle, atrasentan (ETA receptor antagonist, 10mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100mg/kg/day). Atrasentan and bosentan lowered circulating non-esterified free fatty acids and triglycerides seen in HFD mice, while atrasentan-treated mice had significantly lower liver triglycerides compared to non-treated HFD mice. ET-1 receptor blockade significantly improved insulin tolerance compared to insulin resistant HFD mice and lowered expression of genes in epididymal white adipose tissue (eWAT) associated with insulin resistance and inflammation. Flow cytometric analyses of eWAT indicated that HFD mice had significantly higher percentages of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan or bosentan.  Atrasentan treatment also abolished the decrease in eosinophils seen in HFD mice. Taken together, these data indicate that ETA and ETA/ETB receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglycerides, and also attenuates the proinflammatory immune profile in eWAT of mice fed a HFD. These data suggest a potential use for ETA and ETA/ETB receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE is contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100mg/kg/day) for four weeks. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, HOMA-IR, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.

Endothelin‐1 (ET‐1) is elevated in patients who are overweight and suffer from obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. Obesity is associated with dyslipidemia and insulin resistance, which may in part be mediated adipocyte hypertrophy and dysfunction leading to a reduction in circulating insulin sensitizing adipokines. Pharmacological blockade of ETB receptors improves insulin sensitivity in mice fed a high fat diet for 8 weeks, which is associated with increased Peroxisome proliferator‐activated receptor gamma (pparg) levels in visceral adipose and increased circulating adiponectin, suggesting a role for ETB receptor activation on adipocytes in pathophysiology related to obesity. We hypothesized that elevated ET‐1 in obesity promotes insulin resistance by reducing adipose pparg leading to a reduction in the secretion of adipokines, such as adiponectin. To test this hypothesis, adipocyte‐specific ETB receptor knockout mice (adETBKO) were generated by crossing adiponectin Cre mice with ETB floxed mice. AdETBKO or wild type (WT) littermates were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks. WT HFD fed mice had significantly higher body weight and fat mass compared to WT NMD, although there was no difference between WT HFD and adETBKO HFD mice. KEGG pathway analysis of differentially expressed genes determined by RNA‐Sequencing of gonadal adipose indicated that compared to WT HFD fed mice, adETBKO HFD mice have an attenuation of over 500 genes enriched within insulin signaling and fatty acid metabolism pathways including adiponectin, insulin receptor substrate 1, Glucose transporter 4, fatty acid synthase, and adipolin. In addition, adETBKO HFD mice had significantly improved glucose tolerance (4510±395 vs 6610±582 AUC, p<0.05)and insulin tolerance (‐6867±517 vs ‐2927±584 AUC, p<0.05)compared to insulin resistant HFD fed mice. Plasma adiponectin was reduced by 2‐fold in WT HFD compared to WT NMD mice (6.82±0.253 vs 10.8±0.624 ug/ml, p<0.05), and this was attenuated in adETBKO HFD fed mice (6.82±0.253 vs 9.90±0.352 ug/ml, p<0.05). Plasma insulin and leptin levels were significantly increased in WT HFD mice, an effect that was attenuated in adETBKO HFD mice (1.59±0.276 vs 0.809±0.064 ng/ml insulin, p<0.05, 22.6±1.08 vs 16.4±1.52 ng/ml leptin, p<0.05). Blood chemistry analysis showed that adETBKO HFD mice had significantly improved ALT (15.5±1.26 vs 46.5±6.16 U/L, p<0.05), HDL (98.3±3.68 vs 84.6±1.76 mg/dl, p<0.05), LDL (19.6±0.945 vs 29.2±2.63 mg/dl, p<0.05) and NEFA (0.377±0.035 vs 0.751±0.076 mEq/L, p<0.05) levels compared to WT HFD mice. These data indicate that loss of the ETB receptor in adipocytes improves peripheral glucose homeostasis, dyslipidemia and the metabolic/cholesterol profile in mice fed a HFD. Coupled with the transcriptomic profile of visceral adipose tissue in adETBKO HFD mice, which reflects a more insulin sensitive phenotype, these data suggest a role for the adipocyte ETB receptor in the development of insulin resi...