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Abstract
BackgroundAdiponectin exerts several beneficial cardiovascular effects, however their specific molecular mechanisms require additional understanding. This study investigated the mechanisms of adiponectin action in the heart during high fat diet (HFD) feeding or in palmitate (PA) treated H9c2 cardiomyoblasts.Methods6-week-old male adiponectin knock out (Ad-KO) mice were fed chow or 60% HFD for 6 weeks then received saline or recombinant adiponectin (3μg/g body weight) for an additional 2 weeks. After acute insulin stimulation (4 U/kg), tissue and serum samples were collected for analysis. H9c2 cardiomyocytes were treated ±0.1 mM PA, the adiponectin receptor agonist AdipoRon, or the antioxidant MnTBAP then assays to analyze reactive oxygen species (ROS) production and cell death were conducted. To specifically determine the mechanistic role of S1P, gain and loss of function studies were conducted with adding S1P to cells or the inhibitors THI and SKI-II, respectively.ResultsHFD feeding induced cardiac insulin resistance in Ad-KO mice, which was reversed following replenishment of normal circulating adiponectin levels. In addition, myocardial total triglyceride was elevated by HFD and lipidomic analysis showed increased levels of ceramides and sphingosine-1-phosphate (S1P), with only the latter being corrected by adiponectin administration. Similarly, treatment of H9C2 cardiomyoblasts with PA led to a significant increase of intracellular S1P but not in conditioned media whereas AdipoRon significantly increased S1P production and secretion from cells. AdipoRon or the antioxidant MnTBAP significantly reduced PA-induced cell death. Gain and loss of function studies suggested S1P secretion and autocrine receptor activation mediated the effect of AdipoRon to attenuate PA-induced ROS production and cell death.ConclusionOur data establish adiponectin signaling-mediated increase in S1P secretion as a mechanism via which HFD or PA induced cardiomyocyte lipotoxicity, leading to insulin resistance and cell death, is attenuated.
Highlights
Adiponectin exerts several beneficial cardiovascular effects, their specific molecular mechanisms require additional understanding
Studies identified two Ad receptor adapter proteins adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) and 2 (APPL2) which regulate the downstream activation of effectors such as AMP-activated protein kinase (AMPK) [13], leading to increased glucose uptake and lipid uptake and oxidation
Polyclonal phosphospecific antibodies to Akt (T308&S473), total Akt, pAMPK Thr172, AMPK, GAPDH and horseradish peroxidase (HRP)-conjugated anti-rabbit-IgG were from Cell Signaling Technology (Beverly, MA), while polyclonal phospho-specific antibodies to Adiponectin receptor 1 (AdipoR1) and Adiponectin receptor 2 (AdipoR2) were a kind gift from Dr’s Tony Clementz and Jan Oscarsson (Astra Zeneca, Sweden), and Adaptor protein (APPL1), Adaptor protein (APPL2) antibodies from Antibody Immunoassay Services (Hong Kong)
Summary
Adiponectin exerts several beneficial cardiovascular effects, their specific molecular mechanisms require additional understanding. Lipotoxicity is a consequence of a high-fat diet (HFD), resulting in elevated circulating free fatty acids and can lead to insulin resistance and metabolic dysfunction [6]. Metabolic changes include less mitochondrial oxidative metabolism, elevated glycolysis, as well as uncoupling between glycolysis and glucose oxidation These result in metabolic inefficiency leading to cardiac contractile dysfunction. Insulin resistance is well characterized as a major contributor to cardiac dysfunction via metabolic and other cellular consequences [8]. Metabolic modulation, such as via insulin sensitization, remains a priority target for new therapeutics [9]. Cardiomyocyte apoptosis is another important consequence of lipotoxicity which contributes to the development of heart failure [10, 11]
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