2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes

Abstract

Several studies have linked impaired glucose uptake and insulin resistance (IR) to functional impairment of the heart. Recently, endocannabinoids have been implicated in cardiovascular disease. However, the mechanisms involving endocannabinoid signaling, glucose uptake, and IR in cardiomyocytes are understudied. Here we report that the endocannabinoid 2-arachidonoylglycerol (2-AG), via stimulation of cannabinoid type 1 (CB1) receptor and Ca/calmodulin-dependent protein kinase β, activates AMP-activated kinase (AMPK), leading to increased glucose uptake. Interestingly, we have observed that the mRNA expression of CB1 and CB2 receptors was decreased in diabetic mice, indicating reduced endocannabinoid signaling in the diabetic heart. We further establish that TNFα induces IR in cardiomyocytes. Treatment with 2-AG suppresses TNFα-induced proinflammatory markers and improves IR and glucose uptake. Conversely, pharmacological inhibition or knockdown of AMPK attenuates the anti-inflammatory effect and reversal of IR elicited by 2-AG. Additionally, in human embryonic stem cell-derived cardiomyocytes challenged with TNFα or FFA, we demonstrate that 2-AG improves insulin sensitivity and glucose uptake. In conclusion, 2-AG abates inflammatory responses, increases glucose uptake, and overcomes IR in an AMPK-dependent manner in cardiomyocytes.

Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models

“…In human iPSC-derived CMs subjected to lipid overload Akt(S473)-phosphorylation is decreased to the same extent as the IR-antagonist, indicating a state of poor insulin sensitivity or insulin resistance. These unpublished findings are corroborated by two recent studies in which high FA conditions were demonstrated to reduce Akt phosphorylation and glucose uptake in iPSC-derived CM [62, 72]. Interestingly, in one of these studies, similar results were obtained for induction of insulin resistance by the inflammatory mediator TNF-alpha which could be an alternative strategy for modeling diabetic cardiomyopathy, relating a disease model to the clinical findings of increased presence of pro-inflammatory mediators in patients with T2DM [72, 73].…”

A comparison of the mitochondrial proteome and lipidome in the mouse and long-lived Pipistrelle bats

“…Ceramide (32:1), N-acylethanolamines (18:2 and 22:6) and a docosanoid species were identified within the top six lipid species, each more abundant in the bat mitochondrial fractions. We noticed that lipid species known to be metabolic precursors of lipid mediators of inflammatory processes, particularly the N-acylethanolamines, DPA, DHA and AA are found to be highly abundant in bat mitochondria when compared with young or older mouse mitochondrial lipids [34,35]. This finding may support the idea of a central function for these lipids in the longer maintenance of healthy mitochondria.…”

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

“…Its levels in WKY and SHAM were 220 and 75 times higher than the concentration of the best-known endocannabinoid AEA, respectively. This is an important observation in the light of recent publications that 2-AG in vivo worsens heart function after acute myocardial infarction [47], increases the severity of the cerebral blood flow deficit [55] or promotes atherogenesis [56] on the one hand but ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes on the other [57]. Unfortunately, there are only limited data regarding the cardiovascular effects of endocannabinoids other than 2-AG and AEA.…”