2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes.
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 Ca2+/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.
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands d.chanda@maastrichtuniversity.nl.
Dipanjan
0000-0003-0685-187X
D
Chanda
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Yvonne
Y
Oligschlaeger
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Ilvy
I
Geraets
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Yilin
Y
Liu
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Xiaoqing
X
Zhu
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Jieyi
J
Li
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Miranda
M
Nabben
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Will
W
Coumans
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Joost J F P
JJFP
Luiken
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Jan F C
JFC
Glatz
From the Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands.
Dietbert
D
Neumann
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001095:Arachidonic Acids / Q000737:chemistry*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology; D063388:Endocannabinoids / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D005989:Glycerides / Q000737:chemistry*; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D063388:Endocannabinoids; D051275:Glucose Transporter Type 4; D005989:Glycerides; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; C495693:Slc2a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C094503:glyceryl 2-arachidonate; D006003:Glycogen; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D005947:Glucose
AMP-activated kinase (AMPK); cell signaling; endocannabinoid; glucose transporter type 4 (GLUT4); glucose uptake; inflammation; insulin resistance