Acylation-stimulating Protein (ASP) Deficiency Induces Obesity Resistance and Increased Energy Expenditure in ob/obMice

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. ASP administration results in more rapid postprandial lipid clearance. In mice, C3 (the precursor to ASP) knockout results in ASP deficiency and leads to reduced body fat and leptin levels. The protective potential of ASP deficiency against obesity and involvement of the leptin pathway were examined in ob/ob C3(−/−) double knockout mice (2KO). Compared with age-matched ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance; associated with decreased body weight (4–17 weeks age: male: −13.7%, female: −20.6%, p < 0.0001) and HOMA (homeostasis model assessment) index (−37.7%), suggesting increased insulin sensitivity. By contrast, food intake in 2KO mice was +9.1% higher overob/ob mice (p < 0.001, 2KO 5.1 ± 0.2 g/day, ob/ob 4.5 ± 0.2 g/day, wild type 2.6 ± 0.1 g/day). The hyperphagia/leanness was balanced by a 28.5% increase in energy expenditure (oxygen consumption: 2KO, 131 ± 8.9 ml/h; ob/ob, 102 ± 4.5 ml/h; p< 0.01; wild type, 144 ± 8.9 ml/h). These results suggest that the ASP regulation of energy storage may influence energy expenditure and dynamic metabolic balance. Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. ASP administration results in more rapid postprandial lipid clearance. In mice, C3 (the precursor to ASP) knockout results in ASP deficiency and leads to reduced body fat and leptin levels. The protective potential of ASP deficiency against obesity and involvement of the leptin pathway were examined in ob/ob C3(−/−) double knockout mice (2KO). Compared with age-matched ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance; associated with decreased body weight (4–17 weeks age: male: −13.7%, female: −20.6%, p < 0.0001) and HOMA (homeostasis model assessment) index (−37.7%), suggesting increased insulin sensitivity. By contrast, food intake in 2KO mice was +9.1% higher overob/ob mice (p < 0.001, 2KO 5.1 ± 0.2 g/day, ob/ob 4.5 ± 0.2 g/day, wild type 2.6 ± 0.1 g/day). The hyperphagia/leanness was balanced by a 28.5% increase in energy expenditure (oxygen consumption: 2KO, 131 ± 8.9 ml/h; ob/ob, 102 ± 4.5 ml/h; p< 0.01; wild type, 144 ± 8.9 ml/h). These results suggest that the ASP regulation of energy storage may influence energy expenditure and dynamic metabolic balance. Acylation-stimulating protein (ASP) 1The abbreviations used for: ASP, acylation-stimulating protein; HOMA, homeostasis model assessment; BMR, basal metabolic rate; RQ, respiratory quotient; NEFA, postprandial non-esterified fatty acid; 2KO, double knockout mice; ANOVA, analysis of variance. is an adipocyte-derived protein that has potent anabolic effects on human adipose tissue for both 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). This occurs via translocation of glucose transporters (GLUT1, GLUT3, and GLUT4) from intracellular sites to the cell surface (3Tao Y.Z. 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 an increase in diacylglycerol acyltransferase (DGAT) activity (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 (6Kalant D. Zhang Z.J. Cianflone K. Sniderman A.D. Clin. Invest. Med. 1995; 18: B10Google Scholar, 7Murray 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 signaling pathway that includes protein kinase C (8Baldo A. Sniderman A.D. Yazruel Z. 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 (9Van Harmelen V. Reynisdottir S. Cianflone K. Degerman E. Hoffstedt J. Nilsell K. Sniderman A.D. 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 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 (6Kalant D. Zhang Z.J. Cianflone K. Sniderman A.D. Clin. Invest. Med. 1995; 18: B10Google Scholar). 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 (10Hugli T.E. 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 (11Cianflone K. Roncari D.A.K. Maslowska M. Baldo A. Forden J. Sniderman A.D. Biochemistry. 1994; 33: 9489-9495Crossref PubMed Scopus (138) Google Scholar). ASP production increases consequent to adipocyte differentiation (13Cianflone K. Maslowska M. Eur. J. Clin. Invest. 1995; 25: 817-825Crossref PubMed Scopus (87) Google Scholar), and plasma ASP levels are elevated in obesity (14Cianflone K. Sniderman A.D. Kalant D. Marliss E.B. Gougeon R. Int. J. Obes. 1995; 19: 604-609Google Scholar, 15Maslowska M. Vu H. Phelis S. Sniderman A.D. Rhodes B. Blank D. Cianflone K. Eur. J. Clin. Invest. 1999; 29: 679-686Crossref PubMed Scopus (129) Google Scholar). Chylomicronsin vitro stimulate ASP production by adipocytes (16Maslowska M. Scantlebury T. Germinario R. Cianflone K. J. Lipid Res. 1997; 38: 21-31Abstract Full Text PDF Google Scholar, 17Scantlebury T. Maslowska M. Cianflone K. J. Biol. Chem. 1998; 273: 20903-20909Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar).In vivo arterial-venous gradients across a subcutaneous adipose tissue bed in humans demonstrate direct postprandial production of ASP (18Saleh 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 (19Charlesworth J.A. Peake P.W. Campbell L.V. Pussell B.A. O'Grady S. Tzilopoulos T. Int. J. Obes. 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 (20Cianflone K. J. Endocrinol. 1997; 155: 203-206Crossref PubMed Scopus (26) Google Scholar). As ASP is derived through cleavage of complement C3, C3 knockout mice are necessarily deficient in ASP. We have previously demonstrated that genetic deficiency of ASP leads to reduced body fat and decreased leptin levels (21Murray I. Havel P.J. Sniderman A.D. Cianflone K. Endocrinology. 2000; 141: 1041-1049Crossref PubMed Scopus (95) Google Scholar, 22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In addition, male mice have delayed triglyceride clearance (22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 18Saleh 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) although this has not been demonstrated in all studies (23Wetsel R.A. Kildsgaard J. Zsigmond E. Liao W. Chan L. J. Biol. Chem. 1999; 274: 19429-19433Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). To determine the influence of the leptin pathway on ASP action and obesity resistance, we examined the effect of ASP deficiency inob/ob mice, which are leptin-deficient. The ob/obmice have been used to test for protection from obesity in a number of double knockout models, such as the ob/ob VLDL receptor(−/−) or the ob/ob PAI-1(−/−). In most cases, the decrease in weight, which was evident in the single knockout, was enhanced when examined on the background of the ob/ob obese mouse model (24Yagyu H. Lutz E.P. Kako Y. Marks S. Hu Y. Choi S.Y. Bensadoun A. Goldberg I.J. J. Biol. Chem. 2002; 277: 10037-10043Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 25Goudriaan J.R. Tacken P.J. Dahlmans V.E. Gijbels M.J. van Dijk K.W. Havekes L.M. Jong M.C. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1488-1493Crossref PubMed Scopus (110) Google Scholar). Leptin is produced by adipocytes (26Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-432Crossref PubMed Scopus (11753) Google Scholar) and is involved in the regulation of body fat stores. Leptin is critically involved in the regulation of body energy balance via its central actions on food intake and energy expenditure (27Havel P.J. Am. J. Clin. Nutr. 1999; 70: 305-306Crossref PubMed Scopus (45) Google Scholar). Ob/ob mice lose an important negative feedback on food intake caused by a leptin gene mutation. It is well known that leptin acts via a receptor in the hypothalamus, while there is little evidence that ASP acts via this route. However, leptin also appears to have peripheral actions on substrate fluxes in the adipose tissue (28Brazilai N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (296) Google Scholar) and may act directly on adipocytes, where it has been reported to increase lipolysis and impair insulin-mediated lipogenesis (29Muller G. Ertl J. Gerl M. Preibisch G. J. Biol. Chem. 1997; 272: 10585-10593Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar, 30Fuhbeck G. Aguado M. Martinez J.A. Biochem. Biophys. Res. Commun. 1997; 240: 590-594Crossref PubMed Scopus (226) Google Scholar). Finally, leptin production is regulated by insulin responses to meals (31Havel P.H. Twonsend R. Chaump L. Teff K. Diabetes. 1999; 48: 334-341Crossref PubMed Scopus (229) Google Scholar), an effect that appears to involve increased adipocyte glucose metabolism (32Mueller W.M. Gregoire F.M. Stanhope K.C. Mobbs C.V. Mizuno T.M. Warden C.H. Stern J.S. Havel P.J. Endocrinology. 1998; 139: 551-558Crossref PubMed Scopus (354) Google Scholar). Leptin and ASP contrast both in their function and major site of action; however both alter energy disposition through altering either storage or oxidation and the aim of this paper was to determine how the absence of leptin coupled to ASP deficiency alters fat metabolism. The leptin and complement C3 double knockout (2KO) mouse strain was generated by crossing the Leptin (+/−) mice (C57Bl/6, Jackson Laboratories, Bar Harbor, ME) with complement C3 knockout (C3−/−) (129/Sv genetic background) (previously obtained from Dr. Harvey Coulton) to generate (Leptin+/−, The genetic background mice were to generate These mice were used to generate ob/ob C3(−/−) 2KO mice as well as ob/ob C3 and wild type the mice were of a genetic background were were in a and on mice the by the and were by the The mice were by with as previously for C3 (21Murray I. Havel P.J. Sniderman A.D. Cianflone K. Endocrinology. 2000; 141: 1041-1049Crossref PubMed Scopus (95) Google Scholar, 22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) and for the leptin gene M. Y. K. T. Y. K. 1998; 48: Google Scholar). were when the mice were weeks of were with of with were To the was of by for to the The was with and in of of was The used for ob/ob mice and for the wild type leptin gene and and for the leptin leptin for of and of the C3 and were used for the wild type complement C3 and and were used for in the complement C3 knockout The for for of and of the mice had body weight determined and food intake was from the to the of were as a 2KO mice were the mice were weeks a fat was to 2KO mice with ASP and ASP as well as wild type mice and and ob/ob mice and an of by of the was by a A. G. K. Wang H. R.A. 1999; 42: PubMed Scopus Google to as previously (21Murray I. Havel P.J. Sniderman A.D. Cianflone K. Endocrinology. 2000; 141: 1041-1049Crossref PubMed Scopus (95) Google Scholar, 22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, H. D. P. J. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, M. H. T. K. M. T. Y. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, P.H. K. H. R. S. A.D. R. J. J. Clin. Invest. 1995; PubMed Scopus Google Scholar, I. N. A. Walsh A. 1990; PubMed Scopus Google Scholar). There was a the and the fat was and by ASP was the of the fat ASP was and as mouse either ASP in of fatty acid or have demonstrated that of the in had effect of postprandial clearance in the mice with the mice as shown previously (21Murray I. Havel P.J. Sniderman A.D. Cianflone K. Endocrinology. 2000; 141: 1041-1049Crossref PubMed Scopus (95) Google Scholar, 22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). the mice were weeks a fat was to the 2KO mice the were The wild type mice and ob/ob mice were fat the was as was weeks and weeks fat and weeks by from mice with was by and insulin was a insulin which has to mouse insulin by the was a glucose non-esterified fatty (NEFA) and triglyceride were and production were the mouse was in a in the absence of food and were and the was the The was used in the results are as ± were by ANOVA, ANOVA, or as in the and was p < where p not We examined body weight in these double C3(−/−) (2KO) Compared with mice of the 2KO have body As shown in this is the the (4–17 there was a of body weight in the and a in the p < 0.0001) The effect was the in male and In mice, we have previously demonstrated a delayed postprandial triglyceride and non-esterified fatty (NEFA) clearance a fat in the male mice (21Murray I. Havel P.J. Sniderman A.D. Cianflone K. Endocrinology. 2000; 141: 1041-1049Crossref PubMed Scopus (95) Google Scholar, 22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), and we also examined these in the their the ob/ob mice have a to the wild type mice However, while the levels were in 2KO mice, demonstrate a delayed postprandial clearance with both and the wild type < by for 2KO wild administration of ASP a clearance were demonstrated in the triglyceride shown in where the ob/ob mice had a postprandial triglyceride which is delayed in the 2KO mice (p < the delayed and triglyceride clearance in the 2KO mice were in both male and mice, a from studies in mice, where the male mice demonstrated delayed triglyceride clearance (21Murray I. Havel P.J. Sniderman A.D. Cianflone K. Endocrinology. 2000; 141: 1041-1049Crossref PubMed Scopus (95) Google Scholar, 22Murray I. Sniderman A.D. Havel P.J. Cianflone K. J. Biol. Chem. 1999; 274: 36219-36225Abstract Full Text Full Text PDF PubMed Scopus (74) Google male and 2KO mice had delayed postprandial triglyceride clearance with ob/obmice or wild type The ob/ob mice had a to the wild type mice (p while the 2KO were (p < are shown as ± for The data were In to we also insulin and glucose in the three of The obesity in ob/ob mice is associated with increased plasma insulin and as by the HOMA index (the homeostasis model for insulin resistance, B.A. PubMed Scopus Google Scholar) and this is also shown There was in or postprandial glucose 2KO The glucose 2KO ± ob/ob ± wild type ± the 2KO mice had insulin levels and a HOMA index as with ob/ob mice wild ± ob/ob ± and ± p < suggesting insulin in the 2KO mice with the These in HOMA and in insulin are to the decrease in body weight in the 2KO as shown in A. both male and 2KO mice were in this The analysis of food intake is shown in although body weight is decreased in the 2KO with the ob/ob mice, the 2KO mice a In the 2KO food intake was ± 0.2 g/day, it was ± 0.2 in the ob/ob and 2.6 ± 0.1 in the wild type mice +9.1% ob/ob, p < increase wild type, p < This increase in food intake was in both and the decreased body weight is not a of decreased food 2KO mice have a reduced food efficiency for a increase in body weight 2KO ± of while the ob/ob ± of p < This is with HOMA The that the 2KO mice more food mice weight that there are important in energy expenditure and This was examined by and in the of mice ob/ob, and wild The results demonstrate that the ob/ob mice have wild type mice, while in 2KO mice is to the as the wild type type, ± ml/h; ob/ob, ± ml/h; 2KO, ± ml/h; ob/ob, p < 0.01; was obtained for production type, ± ob/ob, ± 2KO, ± < These both with body weight shown for was also with food efficiency and HOMA index the while the was increased in the ob/ob mice with the wild type mice an increase in the of fat it was not in the 2KO These results of the role of ASP in energy storage and energy ob/obmice demonstrate delayed postprandial triglyceride and as demonstrated previously in ASP deficient male mice (21Murray I. 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