title: Shift in metabolic fuel in acylation-stimulating protein-deficient mice following a high-fat diet.
abstract: ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (-39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (-25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (-31%, P = 0.005), hexokinase (-43%, P = 0.007), phosphofructokinase (-51%, P < 0.0001), and GAPDH (-15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (-48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.
authors.affiliation: Centre de Recherche Hôpital Laval, Y-2186, Chemin Ste-Foy, QC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Roy
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fisette
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Esther
authors.initials: E
authors.lastname: Moonen-Kornips
authors.forename: Josée
authors.initials: J
authors.lastname: St-Onge
authors.forename: Matthjis K
authors.initials: MK
authors.lastname: Hesselink
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
authors.forename: Denis R
authors.initials: DR
authors.lastname: Joanisse
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D055372:AMP-Activated Protein Kinases; D002001:Adipose Tissue, Brown / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D003176:Complement C3 / Q000172:deficiency* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D025221:Phosphofructokinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012119:Respiration
chemical_list: D003176:Complement C3; D004041:Dietary Fats; D009097:Multienzyme Complexes; D006003:Glycogen; D015094:3-Hydroxyacyl CoA Dehydrogenases; C458480:Hsd17b10 protein, mouse; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D024981:Glycogen Phosphorylase; D025221:Phosphofructokinases; D006593:Hexokinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose