title: Reduced adipose tissue triglyceride synthesis and increased muscle fatty acid oxidation in C5L2 knockout mice.
abstract: Activation of C5L2, a G-protein-coupled receptor, by acylation-stimulating protein/complement C3adesArg (ASP/C3adesArg) has been shown to stimulate triglyceride (TG) synthesis in both mature adipocytes and preadipocytes. ASP is an adipocyte-derived hormone that acts by increasing diacylglycerol acyltransferase activity and glucose transport. ASP-deficient mice (C3KO, precursor protein) are lean, display delayed postprandial TG clearance, increased food intake, and increased energy expenditure. The present study shows that C5L2KO mice on a low fat diet are hyperphagic (~60% increase in total food intake) yet maintain the same body weight and adipose tissue mass as wild-type (WT) controls. However, on a high fat diet, average adipocyte size and adipose tissue TG/DNA content were significantly reduced and postprandial TG clearance was delayed in C5L2KO. Adipose tissue TG synthesis (WT: 47.2 +/- 5.6 versus C5L2KO: 7.8 +/- 1.8 pmol/microg protein, P < 0.001), TG lipolysis (WT: 227.6 +/- 36.4 versus C5L2KO: 45.8 +/- 5.0 nmol/microg protein, P < 0.001), and fatty acid re-esterification (WT: 85.3 +/- 2.4% versus C5L2KO: 59.5 +/- 6.8%, P < 0.001) were significantly reduced in C5L2KO mice. Indirect calorimetry measurements revealed C5L2KO mice have unchanged oxygen consumption levels yet reduced respiratory quotient value, suggesting preferential fatty acid utilization over carbohydrate. In agreement, fatty acid oxidation was elevated in heart and skeletal muscle tissue in C5L2KO mice and skeletal muscle levels of uncoupling protein 3 (425.5 +/- 86.3%, P < 0.0001), CD36 (277.6 +/- 49.5%, P < 0.05), cytochrome c (252.6 +/- 33.9%, P < 0.05), and phospho-acetyl CoA carboxylase (118.4 +/- 9.3%, P < 0.05) were significantly increased in C5L2KO mice versus WT (100%). The study shows that in response to reduced TG storage in white adipose tissue, C5L2KO mice have developed a compensatory mechanism of increased muscle fat oxidation.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Christian
authors.initials: C
authors.lastname: Roy
authors.forename: Esther
authors.initials: E
authors.lastname: Moonen-Kornips
authors.forename: Huiling
authors.initials: H
authors.lastname: Lu
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002153:Calorimetry, Indirect; D045304:Cytochromes c / Q000378:metabolism; D004032:Diet; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D007473:Ion Channels / Q000378:metabolism; D050155:Lipogenesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010101:Oxygen Consumption; D019518:Postprandial Period; D011494:Protein Kinases / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis*; D000071247:Uncoupling Protein 3
chemical_list: D015415:Biomarkers; C000594938:C5ar2 protein, mouse; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D014280:Triglycerides; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D045304:Cytochromes c; D011494:Protein Kinases