Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo

Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1482-91. doi: 10.1152/ajpendo.00565.2006. Epub 2007 Aug 21.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • AMP-Activated Protein Kinases
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Antibodies / metabolism
  • Antibodies / pharmacology*
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • CHO Cells
  • Cell Line
  • Complement C3a / immunology*
  • Complement C3a / metabolism
  • Complement C3a / pharmacology
  • Cricetinae
  • Cricetulus
  • Dietary Fats / pharmacology
  • Eating / drug effects
  • Fatty Acids, Nonesterified / blood
  • Glucose / metabolism
  • Lipid Metabolism / drug effects*
  • Lipoprotein Lipase / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Multienzyme Complexes / metabolism
  • Peptide Hormones / blood
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine / immunology*
  • Receptors, Chemokine / metabolism
  • Triglycerides / blood
  • Triglycerides / metabolism*

Substances

  • Antibodies
  • Blood Glucose
  • C5aR2 protein, human
  • C5ar2 protein, mouse
  • Dietary Fats
  • Fatty Acids, Nonesterified
  • Multienzyme Complexes
  • Peptide Hormones
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine
  • Triglycerides
  • complement C3a, des-Arg-(77)-
  • Complement C3a
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Lipoprotein Lipase
  • Glucose