In the last few years, there has been increasing interest in the physiological role of acylation-stimulating protein (ASP). Recent studies in rats and mice, in particular in C3 (-/-) mice that are ASP deficient, have advanced our understanding of the role of ASP. Of note, the background strain of the mice influences the phenotype of delayed postprandial triglyceride clearance in ASP-deficient mice. Administration of ASP in all types of lean and obese mice studied to date, however, enhances postprandial triglyceride clearance. On the other hand, regardless of the background strain, ASP-deficient mice demonstrate reduced body weight, reduced leptin and reduced adipose tissue mass, suggesting that ASP deficiency results in protection against development of obesity. In humans, a number of studies have examined the relationship between ASP, obesity, diabetes and dyslipidemia as well as the influence of diet, exercise and pharmacological therapy. While many of these studies have small subject numbers, interesting observations may help us to better understand the parameters that may influence ASP production and ASP action. The aim of the present review is to provide a comprehensive overview of the recent literature on ASP, with particular emphasis on those studies carried out in rodents and humans.

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 (VO 2 ) 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)1 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 (1, 2) via translocation of glucose transporters (GLUT1, GLUT3, and GLUT4) from intracellular sites to the cell surface (3, 4) and activation of diacylglycerol acyltransferase (DGAT) (2). These effects appear to be mediated through specific cell surface binding (5, 6) resulting in activation of a signal pathway that includes protein kinase C (7). In addition, ASP has been shown to inhibit hormone-sensitive lipase in adipocytes, independently and additively to insulin (8). There is a differentiation-dependent increase in ASP binding and ASP response in human adipocytes (1). The major site of action of ASP is adipocytes, as determined by competitive binding, stimulation of triglyceride synthesis, enhanced glucose transport, and transporter translocation (5).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 Cterminal arginine of C3a by carboxypeptidase N generates ASP (9). 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 (10). ASP production increases consequent to a...

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 agematched 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 over ob/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) 1 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 (1, 2). This occurs via translocation of glucose transporters (GLUT1, GLUT3, and GLUT4) from intracellular sites to the cell surface (3, 4) and an increase in diacylglycerol acyltransferase (DGAT) activity (2). These effects appear to be mediated through specific cell surface binding (6, 7), resulting in activation of a signaling pathway that includes protein kinase C (8). In addition, ASP has been shown to inhibit hormone-sensitive lipase in adipocytes, independently and additively to insulin (9). There is a differentiation-dependent increase in ASP binding and ASP response in adipocytes (1). The major site of action of ASP is adipocytes, as determined by competitive binding, stimulation of triglyceride synthesis, enhanced glucose transport, and transporter translocation (6).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 Cterminal arginine of C3a by carboxypeptidase N generates ASP (10). 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 (11). ASP production increases consequent to adipocyte differentiation (13), and plasma ASP levels are elevated in obesity (14, 15). Chylomicrons in vitro stimulate ASP production by adipocytes (16,17). In vivo arterial-venous gradients across a subcutaneous adipose tissue bed in humans demonstrate direct postprandial production of ASP (18). The postprandial increase in ASP is adipose tissue specifi...

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