Acylation-stimulating Protein (ASP)/Complement C3adesArg Deficiency Results in Increased Energy Expenditure in Mice

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(–/–) ASP-deficient mice had elevated oxygen consumption (VO2) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 ± 2.4 m whereas KO mice moved 30.1 ± 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT –68%, WAT –29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice. Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(–/–) ASP-deficient mice had elevated oxygen consumption (VO2) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 ± 2.4 m whereas KO mice moved 30.1 ± 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT –68%, WAT –29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice. Acylation-stimulating protein (ASP) 1The abbreviations used are: ASPacylation-stimulating proteinBATbrown adipose tissueWATwhite adipose tissueFAfatty acidTGtriglycerideKOknock-outANOVAanalysis of varianceWTwild typeUCPuncoupling proteinNEFAnon-esterified fatty acidDGATdiacylglycerol acyltransferaseRQrespiratory quotientAUCarea under curveVO2oxygen consumptionNSnot significant. is an adipocyte-derived protein that has potent anabolic effects on human adipose tissue where it increases glucose uptake and non-esterified fatty acid (NEFA) storage (1Cianflone K. Maslowska M. Sniderman A.D. Semin. Cell Dev. Biol. 1999; 10: 31-41Crossref PubMed Scopus (110) Google Scholar, 2Yasruel Z. Cianflone K. Sniderman A.D. Rosenbloom M. Walsh M. Rodriguez M.A. Lipids. 1991; 26: 495-499Crossref PubMed Scopus (118) Google Scholar) via translocation of glucose transporters (GLUT1, GLUT3, and GLUT4) from intracellular sites to the cell surface (3Tao Y. Cianflone K. Sniderman A.D. Colby-Germinario S.P. Germinario R.J. Biochim. Biophys. Acta. 1997; 1344: 221-229Crossref PubMed Scopus (82) Google Scholar, 4Germinario R. Sniderman A.D. Manuel S. Pratt S. Baldo A. Cianflone K. Metabolism. 1993; 42: 574-580Abstract Full Text PDF PubMed Scopus (139) Google Scholar) and activation of diacylglycerol acyltransferase (DGAT) (2Yasruel Z. Cianflone K. Sniderman A.D. Rosenbloom M. Walsh M. Rodriguez M.A. Lipids. 1991; 26: 495-499Crossref PubMed Scopus (118) Google Scholar). These effects appear to be mediated through specific cell surface binding (5Kalant D. Zhang Z.J. Cianflone K. Sniderman A.D. Clin. Investig. Med. 1995; 18 (B10 (abstr.))Google Scholar, 6Murray I. Parker R.A. Kirchgessner T.G. Tran J. Zhang Z.J. Westerlund J. Cianflone K. J. Lipid Res. 1997; 38: 2492-2501Abstract Full Text PDF PubMed Google Scholar) resulting in activation of a signal pathway that includes protein kinase C (7Baldo A. Sniderman A.D. St. Luce S. Zhang X.J. Cianflone K. J. Lipid Res. 1995; 36: 1415-1426Abstract Full Text PDF PubMed Google Scholar). In addition, ASP has been shown to inhibit hormone-sensitive lipase in adipocytes, independently and additively to insulin (8Van Harmelen V. Reynisdottir S. Cianflone K. Degerman E. Hoffstedt J. Nilsell K. Sniderman A. Arner P. J. Biol. Chem. 1999; 274: 18243-18251Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). There is a differentiation-dependent increase in ASP binding and ASP response in human adipocytes (1Cianflone K. Maslowska M. Sniderman A.D. Semin. Cell Dev. Biol. 1999; 10: 31-41Crossref PubMed Scopus (110) Google Scholar). The major site of action of ASP is adipocytes, as determined by competitive binding, stimulation of triglyceride synthesis, enhanced glucose transport, and transporter translocation (5Kalant D. Zhang Z.J. Cianflone K. Sniderman A.D. Clin. Investig. Med. 1995; 18 (B10 (abstr.))Google Scholar). acylation-stimulating protein brown adipose tissue white adipose tissue fatty acid triglyceride knock-out analysis of variance wild type uncoupling protein non-esterified fatty acid diacylglycerol acyltransferase respiratory quotient area under curve oxygen consumption not significant. ASP is identical to C3adesArg, a cleavage product of complement C3. Cleavage of complement C3 is mediated through the alternate complement pathway via the interaction of C3, factor B, and adipsin that generates C3a. Rapid cleavage of the C-terminal arginine of C3a by carboxypeptidase N generates ASP (9Hugli T. Curr. Top. Microbiol. Immunol. 1990; 153: 181-208PubMed Google Scholar). Adipocytes are one of the few cells capable of producing all three factors (factor B, adipsin, and C3) that are required for the production of ASP (10Cianflone K. Roncari D.A.K. Maslowska M. Baldo A. Forden J. Sniderman A.D. Biochemistry. 1994; 33: 9489-9495Crossref PubMed Scopus (139) Google Scholar). ASP production increases consequent to adipocyte differentiation (11Cianflone K. Maslowska M. Eur. J. Clin. Invest. 1995; 25: 817-825Crossref PubMed Scopus (87) Google Scholar) and plasma ASP levels are elevated in obesity (12Cianflone K. Sniderman A.D. Kalant D. Marliss E.B. Gougeon R. Int. J. Obesity. 1995; 19: 604-609Google Scholar, 13Maslowska M. Vu H. Phelis S. Sniderman A.D. Rhode B.M. Blank D. Cianflone K. Euro. J. Clin. Inv. 1999; 29: 679-686Crossref PubMed Scopus (129) Google Scholar). In vitro chylomicrons stimulate ASP production by adipocytes (14Maslowska M. Scantlebury T. Germinario R. Cianflone K. J. Lipid Res. 1997; 38: 21-31Abstract Full Text PDF Google Scholar, 15Scantlebury T. Maslowska M. Cianflone K. J. Biol. Chem. 1998; 273: 20903-20909Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In vivo arterial-venous gradients across a subcutaneous adipose tissue bed in humans demonstrate direct postprandial production of ASP (16Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. J. Lipid Res. 1998; 39: 884-891Abstract Full Text Full Text PDF PubMed Google Scholar). The postprandial increase in ASP is adipose tissue specific and is not observed in the general circulation (17Charlesworth J.A. Peake P.W. Campbell L.V. Pussell B.A. O'Grady S. Tzilopoulos T. Int. J. Obesity Rel. Metab. Dis. 1998; 22: 1096-1102Crossref PubMed Scopus (38) Google Scholar). Altogether, these data suggest that ASP and lipid storage are metabolically intertwined. ASP acts as an adipocyte autocrine factor and we propose that it plays a central role in the metabolism of adipose tissue by increasing the efficiency of triglyceride synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance (18Cianflone K. Xia Z Chen L.Y. Biochim. Biophys. Acta. 2003; 1609: 127-143Crossref PubMed Scopus (315) Google Scholar). As ASP is derived through cleavage of complement C3, C3 knock-out mice (C3–/–) are necessarily deficient in ASP. We have previously demonstrated that genetic deficiency of ASP leads to reduced body fat and decreased leptin levels (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, male mice have triglyceride clearance (16Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. J. Lipid Res. 1998; 39: 884-891Abstract Full Text Full Text PDF PubMed Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) this has not been demonstrated in all R.A. J. E. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). with knock-out mice demonstrated a to of triglyceride synthesis and demonstrated that these effects of ASP of ASP-deficient mice (C3–/–) have decreased body and and they have a increased in This the are ASP-deficient mice they more We that by energy and postprandial fat during resting and active phases of the diurnal and of genetic of the mice used in this was C3 knock-out (C3–/–) mice genetic as as wild-type mice, from to a genetic (C3–/–) mice demonstrate a in triglyceride the (C3–/–) mice the reduced leptin and in both (18Cianflone K. Xia Z Chen L.Y. Biochim. Biophys. Acta. 2003; 1609: 127-143Crossref PubMed Scopus (315) Google Scholar). in a 12 and on mice the by the and by the The mice by with as previously for C3 the mice at of (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). and a fat of by a This and fat The mice and the was three to analysis was with of and and activity was the from The of an and a all and via for and for of the from the and the through the and The with and in the and to the for 18 to the data The includes an and and data and analysis and an of with of by of the was by a S. A. A. J. P. 1997; PubMed Scopus Google Scholar) to as previously (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, A. D. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. E. R. K. A. M. K. Biophys. Res. 1997; PubMed Scopus Google Scholar, J. K. H. K. T. Y. H. Y. Y. K. 1997; PubMed Scopus Google Scholar). ASP was at the time of fat administration. ASP was and as previously (7Baldo A. Sniderman A.D. St. Luce S. Zhang X.J. Cianflone K. J. Lipid Res. 1995; 36: 1415-1426Abstract Full Text PDF PubMed Google Scholar, A. Sniderman A.D. S. Maslowska M. A. S. Cianflone K. J. Clin. Investig. 1993; PubMed Scopus Google Scholar). intraperitoneal of ASP in of fatty acid have demonstrated that of the in had no of postprandial clearance in the mice with the mice (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). was at the time for muscle tissue was as of body on data in mice S. H. R. S. A. 1997; PubMed Scopus Google Scholar). was the for and from mice intragastric fat administration. was by and at non-esterified fatty and glucose and leptin by mice with a of of of of and of to body by The following muscle brown adipose tissue adipose adipose adipose adipose and The and in at for to lipid and from fatty acid oxidation with of the following of was and the was at for to a phase The lipids in the and in for by as previously to fatty and lipids by J. PubMed Scopus Google Scholar). The phase oxidation was mRNA of wild-type and KO mice for and in at The used for and 18 was used as was from the tissue from the was and in and The resulting was to of and with of in and to The was for at by of and by The all from The was by on in at with and was by the that with as a of specific results are as ± by as in the and was at p < where not significant. We have previously that C3(–/–) ASP-deficient mice (KO) have reduced body adipose tissue and plasma leptin but more energy with WT mice (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). This was of the present where KO mice had a reduced body and increased levels WT ± KO ± p < analysis demonstrated in fat in KO as with WT male ± KO male ± p < and WT female ± KO female ± p < = In addition, we have previously demonstrated that ASP-deficient C3(–/–) mice have increased insulin as reflected by decreased on insulin and glucose levels (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google the mice are an Z. Sniderman A.D. Cianflone K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ASP-deficient mice demonstrate enhanced clearance of glucose following an oral fat and an oral glucose (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). In the present study, the KO mice demonstrated in insulin to glucose and where the WT ± KO ± of WT ± KO ± insulin and WT ± KO ± for WT and KO mice for the with intragastric fat administration on male mice. In this we the body of the KO and WT mice to a resulting from a difference in adipose tissue and body the KO mice on and for from on to on for data from the are to The mice to and was and the was and As shown in in wild-type mice male and oxygen consumption as was in the active phase and in phase and the KO mice this female mice had oxygen consumption the male mice WT and and this was in where the mice in a male and female KO mice had in the active phase with wild-type mice active phase p = p = The as area under the curve as p = p = The KO males had phase as area under the curve of (p < during the phase was not different the KO and WT (VO2) and in ASP-deficient C3 and wild-type male and female active phase was from phase was from ± ± ± ± ± ± ± ± not ± ± ± ± ± ± ± ± The active phase was from The phase was from not significant. in a KO female mice a p < 0.05) increase in active phase with WT but there no in active phase KO and WT male mice. The diurnal of the was in the female KO and WT mice, the KO males had a increase in of during the active phase with WT males the of body not the over a of and body WT male ± KO male ± WT female ± and KO female ± = mice in of body male mice wild-type mice, KO mice and KO mice that intraperitoneal of ASP at the time as the intragastric fat for the was as to not be different ± KO ± the KO mice an a fat of was to the mice, and was over and the mice at the fat to in the KO mice for body to WT mice, KO mice had clearance WT ± KO ± p < KO with ASP ± p < KO and and clearance WT ± KO ± p < KO with ASP ± p < the fat ASP at the time of fat administration = normalized both and clearance There was no difference in the of in and in the three of not We have previously that ASP deficiency not fat (19Murray I. Havel Sniderman A.D. Cianflone K. PubMed Scopus Google Scholar, I. Sniderman A.D. Havel Cianflone K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). incorporation was in adipose adipose adipose and adipose tissue in all three of mice are as body muscle was as of body to previously data S. H. R. S. A. 1997; PubMed Scopus Google Scholar). both WT and KO mice, of the was present in the of and the male KO mice, there was a increase (p < 0.05) in muscle ± KO ± KO with ASP ± and a increase in liver ± KO ± KO with ASP ± with but a decrease (p < 0.05) in in ± KO ± KO with ASP ± p < 0.05) of ASP in KO mice normalized tissue uptake in these three there was no difference in in white adipose tissue in for all three not We the into lipid and As shown in in both and WAT there in incorporation into the lipid (p < normalized to the WT by ASP administration WT ± KO ± KO with ASP ± WT ± KO ± KO with ± This decrease in incorporation was reflected in a decrease in the WT ± KO ± p < KO with ASP ± KO p < WT ± KO ± p < KO with ± that there was into triglyceride in KO in these the in these there was no in the phase fatty acid oxidation not different results in muscle and As shown in in KO mice, with WT mice, there was increase in in the phase fatty acid oxidation WT ± KO ± KO with ASP ± WT ± KO ± KO with ASP ± p < both in muscle and liver resulting in a increase in the liver and a increase in both p < the there was no difference in the lipid was there a difference in the in in liver in WT ± KO ± and KO ASP ± p = and in WT ± KO ± and KO ASP ± p = ASP at the time as the intragastric fat administration in male KO mice in a decrease in liver (p < 0.05) and a decrease in muscle (p < 0.05) oxidation with no difference in lipid These data suggest that in male KO mice the fat was with WT mice, with into muscle and oxidation in liver and muscle appear to be increased The in in fatty oxidation to in be with in plasma difference in plasma was in male KO WT mice ± ± p = mRNA expression normalized to was in and As shown in and expression was decreased in and These to the leptin in KO mice (19Murray I. 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In of these of adipose tissue the site of increased energy but be mediated through increased uncoupling increased to on the mechanisms for the increased metabolism through in vitro in as muscle and In ASP is an factor in The of ASP production results in increased energy in both male and female mice. and female KO mice different mechanisms to with the not in adipose tissue resulting from of both a insulin