Abstract
ObjectiveTo investigate the role of Acylation Stimulating Protein (ASP) receptor C5L2 in skeletal muscle fatty acid accumulation and metabolism as well as insulin sensitivity in both mice and human models of diet-induced insulin resistance.Design and MethodsMale wildtype (WT) and C5L2 knockout (KO) mice were fed a low (LFD) or a high (HFD) fat diet for 10 weeks. Intramyocellular lipid (IMCL) accumulation (by oil red O staining) and beta-oxidation HADH enzyme activity were determined in skeletal muscle. Mitochondria were isolated from hindleg muscles for high-resolution respirometry. Muscle C5L2 protein content was also determined in obese type 2 diabetics and age- and BMI matched men.ResultsIMCL levels were increased by six-fold in C5L2KO-HFD compared to WT-HFD mice (p<0.05) and plasma insulin levels were markedly increased in C5L2KO-HFD mice (twofold, p<0.05). Muscle HADH activity was elevated in C5L2KO-LFD mice (+75%, p<0.001 vs. WT-LFD) and C5L2KO-HFD displayed increased mitochondrial fatty acid oxidative capacity compared to WT-HFD mice (+23%, p<0.05). In human subjects, C5L2 protein content was reduced (−48%, p<0.01) in type 2 diabetic patients when compared to obese controls. Further, exercise training increased C5L2 (+45%, p = 0.0019) and ASP (+80%, p<0.001) in obese insulin-resistant men.ConclusionThe results suggest that insulin sensitivity may be permissive for coupling of C5L2 levels to lipid storage and utilization.
Highlights
Acylation Stimulating Protein (ASP; aka C3adesArg) is an adipocyte-derived hormone that promotes triglyceride synthesis in adipose tissue [1]
Intramyocellular lipid (IMCL) levels were increased by six-fold in C5L2 knockout (C5L2KO)-high-fat diet (HFD) compared to WT-HFD mice (p,0.05) and plasma insulin levels were markedly increased in C5L2KO-HFD mice
Muscle HADH activity was elevated in C5L2KO-low-fat diet (LFD) mice (+75%, p,0.001 vs. WT-LFD) and C5L2KO-HFD displayed increased mitochondrial fatty acid oxidative capacity compared to WT-HFD mice (+23%, p,0.05)
Summary
Acylation Stimulating Protein (ASP; aka C3adesArg) is an adipocyte-derived hormone that promotes triglyceride synthesis in adipose tissue [1]. Fasting ASP levels in humans are predictive of postprandial triglyceride clearance [3]. Fasting plasma ASP is elevated in obesity and insulin resistant states [4,5]. Based on a physiological role of ASP in humans on enhancing postprandial triglyceride clearance in white adipose tissue (WAT) [3], elevated ASP levels in pathological states (obesity, diabetes) are of interest [6]. It has been proposed that these elevated levels of ASP could further help to stimulate or could be explained as ASP resistance [3,7]
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