Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo.
Acylation-stimulating protein (ASP), a lipogenic hormone, stimulates triglyceride (TG) synthesis and glucose transport upon activation of C5L2, a G protein-coupled receptor. ASP-deficient mice have reduced adipose tissue mass due to increased energy expenditure despite increased food intake. The objective of this study was to evaluate the blocking of ASP-C5L2 interaction via neutralizing antibodies (anti-ASP and anti-C5L2-L1 against C5L2 extracellular loop 1). In vitro, anti-ASP and anti-C5L2-L1 blocked ASP binding to C5L2 and efficiently inhibited ASP stimulation of TG synthesis and glucose transport. In vivo, neither anti-ASP nor anti-C5L2-L1 altered body weight, adipose tissue mass, food intake, or hormone levels (insulin, leptin, and adiponectin), but they did induce a significant delay in TG clearance [P < 0.0001, 2-way repeated-measures (RM) ANOVA] and NEFA clearance (P < 0.0001, 2-way RM ANOVA) after a fat load. After treatment with either anti-ASP or anti-C5L2-L1 antibody there was no change in adipose tissue AMPK activity, but neutralizing antibodies decreased perirenal TG mass (-38.4% anti-ASP, -18.8% anti-C5L2, P < 0.01-0.001) and perirenal LPL activity (-75.6% anti-ASP, -72.5% anti-C5L2, P < 0.05). In liver, anti-C5L2-L1 decreased TG mass (-42.8%, P < 0.05), whereas anti-ASP increased AMPK activity (+34.6%, P < 0.001). In the muscle, anti-C5L2-L1 significantly increased TG mass (+128.0%, P < 0.05), LPL activity (+226.1%, P < 0.001), and AMPK activity (+71.1%, P < 0.01). In addition, anti-ASP increased LPL activity (+164.4, P < 0.05) and AMPK activity (+53.9%, P < 0.05) in muscle. ASP/C5L2-neutralizing antibodies effectively block ASP-C5L2 interaction, altering lipid distribution and energy utilization.
Cui
Wei
W
Department of Experimental Medicine, McGill University, Montreal, Canada.
Paglialunga
Sabina
S
Kalant
David
D
Lu
Huiling
H
Roy
Christian
C
Laplante
Mathieu
M
Deshaies
Yves
Y
Cianflone
Katherine
K
D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D015926:Complement C3a / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism; D036361:Peptide Hormones / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D000906:Antibodies; D001786:Blood Glucose; C417003:C5aR2 protein, human; C000594938:C5ar2 protein, mouse; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D009097:Multienzyme Complexes; D036361:Peptide Hormones; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D014280:Triglycerides; C044541:complement C3a, des-Arg-(77)-; D015926:Complement C3a; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase; D005947:Glucose