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

Abstract

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...

Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes

“…Based on a number of studies in mice and adipocytes, ASP enhances adipose fat storage through increased fatty acid esterification (for review see Kalant et al 2 and Cianflone et al 7 ). ASP deficiency (C3 knockout mice) results in decreased adipose tissue and delayed postprandial TG clearance, [17][18][19][20][21] while acute administration of ASP increases postprandial TG clearance. [15][16][17]19 Related to glucose metabolism, ASP increases glucose transport in adipocytes and myotubes through translocation of GLUT1, GLUT3 and GLUT4.…”

“…ASP deficiency (C3 knockout mice) results in decreased adipose tissue and delayed postprandial TG clearance, [17][18][19][20][21] while acute administration of ASP increases postprandial TG clearance. [15][16][17]19 Related to glucose metabolism, ASP increases glucose transport in adipocytes and myotubes through translocation of GLUT1, GLUT3 and GLUT4. [61][62][63] As well, ASP has recently been demonstrated to stimulate insulin secretion from islet cells both ex vivo and in vivo.…”

“…[11][12][13] While no direct role for C3 has been proposed, ASP appears to be an important determinant of postprandial lipemia in both human 14 and mouse models. [15][16][17][18][19] In complement C3(À/À) ASP-deficient mice, the lack of ASP results in delayed postprandial triglyceride clearance, which is normalized acutely through ASP injection. The mice are characterized by reduced adipose tissue with a compensatory upregulation of energy expenditure.…”

“…The mice are characterized by reduced adipose tissue with a compensatory upregulation of energy expenditure. [17][18][19][20][21] Adiponectin is a hormone secreted exclusively from adipose tissue. It is thought to enhance insulin sensitivity by stimulating hepatic glucose utilization and reducing plasma nonesterified fatty acid levels (NEFA) (for a review, see Ukkola and Santaniem 22 ).…”

Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study

“…Mice with C3 and ASP deficiencies show resistance to weight gain despite increased food intake [14]. These animals also have increased energy expenditure [30]. However, it is unclear to what extent circulating C3 reflects the concentrations in the adipose tissue.…”