Endothelin‐1 Suppresses Long‐Chain Fatty Acid Uptake and Glucose Uptake Via Distinct Mechanisms in 3T3‐L1 Adipocytes

Abstract

Endothelin‐1 (ET‐1) has been demonstrated to induce insulin resistance (IR) and lipolysis, raising the possibility that ET‐1 may also contribute to the elevated fatty acid levels in IR‐associated comorbidities. We attempted to evaluate whether ET‐1 also affects the long‐chain fatty acid (LCFA) utilization in 3T3‐L1 adipocytes. The effects of chronic ET‐1 exposure on basal and insulin‐stimulated LCFA uptake, and LCFA uptake kinetics were examined in 3T3‐L1 adipocytes. Chronic exposure to ET‐1 induced IR and suppressed basal and insulin‐stimulated LCFA uptake. Given that insulin acutely stimulates LCFA uptake, there was dramatically similar trend of dose‐response curves for ET‐1‐suppressed LCFA uptake, and also similar corresponding IC50 values, between basal and insulin‐stimulated states, reflecting that ET‐1 predominantly suppresses basal LCFA uptake. Results of LCFA kinetics, western blots, and CD36 inhibition using sulfosuccinimidyl oleate (SSO) revealed that suppression of LCFA uptake by ET‐1 is associated with downregulation of CD36. ET type A receptor (ETAR) antagonist BQ‐610 reversed the IR induction and the ET‐1‐suppressed LCFA uptake. Exogenous replenishment of phosphatidylinositol (PI) 4, 5‐bisphosphate (PIP2) prevented IR induction, but not the suppression of LCFA uptake by ET‐1. Pharmacological inhibition of the activation of mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) completely blocked the ET‐1‐suppressed LCFA uptake. Serving as an inducer of IR, ET‐1 also chronically suppresses LCFA uptake via PIP2‐independent and ERK‐dependent pathway. The interplay between impaired glucose disposal and diminished LCFA utilization, induced by ET‐1, could worsen the dysregulation of adipose metabolism and energy homeostasis in insulin‐resistant states.

The Risk of Heart Failure and Cardiometabolic Complications in Obesity May Be Masked by an Apparent Healthy Status of Normal Blood Glucose

“…For example, ANP reduces fibrosis by inhibiting TGF- β 1 and fibronectin [41], while ET-1 acts in conjunction with TGF- β 1 to stimulate the synthesis of fibronectin [58]. Similarly, ANP suppresses inflammation to reduce insulin resistance [59], while ET-1 stimulates inflammatory/oxidative insults causing insulin resistance [60]. On the other hand, ANP stimulates the production of adiponectin [61], a protein with insulin-sensitizing and anti-inflammatory effects [52].…”

Chronic endothelin‐1 infusion causes adipocyte hyperplasia in rats

“…According to above findings, it is possible that chronic ET‐1 infusion may stimulate adipocyte lipolytic activity and consequently cause decreased adipocyte size and increased plasma fatty acid level in rats. Conversely, our colleagues have demonstrated that treatment with ET‐1 suppressed fatty acid uptake in 3T3‐L1 adipocytes . This finding suggests that ET‐1 may affect adipocyte lipogenesis through inhibiting fatty acid uptake.…”

ADP-ribosylation factor 6 regulates endothelin-1-induced lipolysis in adipocytes

“…Chronic ET-1 exposure induces IR through PIP 2 depletion but suppresses LCFA uptake independent of the PIP 2 levels [7]. However, the inhibition of ERK activation prevents ET-1 suppression of LCFA uptake, indicating that ET-1 suppresses LCFA through the ERK dependent pathway [7]. In conclusion, the findings here suggest ET-1 activation of ET A R leads to activation of ARF6, which subsequently activates ERK1/2.…”

“…Ligand binding to GPCR initiates subsequent signalling, which is terminated by receptor internalisation and desensitisation [35]. Chronic ET-1 exposure induces IR through PIP 2 depletion but suppresses LCFA uptake independent of the PIP 2 levels [7]. However, the inhibition of ERK activation prevents ET-1 suppression of LCFA uptake, indicating that ET-1 suppresses LCFA through the ERK dependent pathway [7].…”

“…4,5-bisphosphate (PIP 2 ) and suppresses insulin-stimulated long chain fatty acid (LCFA) uptake in adipocytes [5][6][7]. Plasma ET-1 concentrations are raised in obese, IR and type 2 diabetic (T2D) patients [8,9].…”