Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury.

Organ damage as a consequence of ischaemia and reperfusion (I/R) is a major clinical problem in an acute renal failure and transplantation. Ligands on surfaces of endothelial cells that are exposed due to the ischaemia may be recognized by pattern recognition molecules such as mannan-binding lectin (MBL), inducing complement activation. We examined the contribution of the MBL complement pathway in a bilateral renal I/R model (45 min of ischaemia followed by 24 h of reperfusion), using transgenic mice deficient in MBL-A and MBL-C [MBL double knockout (MBL DKO)] and in wildtype (WT) mice. Kidney damages, which were evaluated by levels of blood urea nitrogen (BUN) and creatinine, showed that MBL DKO mice were significantly protected compared with WT mice. MBL DKO mice, reconstituted with recombinant human MBL, showed a dose-dependent severity of kidney injury increasing to a comparable level to WT mice. Acute tubular necrosis was evident in WT mice but not in MBL DKO mice after I/R, confirming renal damages in WT mice. MBL ligands in kidneys were observed to be present after I/R but not in sham-operated mice. C3a (desArg) levels in MBL DKO mice were decreased after I/R compared with that in WT mice, indicating less complement activation that was correlated with less C3 deposition in the kidneys of MBL DKO mice. Our data implicate a role of MBL in I/R-induced kidney injury.

Increased acylation stimulating protein concentrations in nonalcoholic fatty liver disease are associated with insulin resistance.

OBJECTIVES: As acylation stimulating protein (ASP) acts on adipocytes mainly as a paracrine factor to increase triglyceride synthesis and storage; hypothetically, it may play a similar role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). METHODS: Forty-six male patients with NAFLD (group A), age-matched 30 male patients with chronic viral hepatitis (group B) and 30 age-matched and body mass index (BMI)-matched healthy male subjects were enrolled in the study. RESULTS: Among the NAFLD patients, 10 patients (24.4%) had simple steatosis and 36 patients (69.6%) had nonalcoholic steatohepatitis (NASH). The mean levels of ASP, complement 3, insulin, C-peptide, HOMA-IR, triglyceride, and very low-density lipoprotein (VLDL) were significantly higher in group A patients than both controls and group B. ASP levels correlated significantly in a positive manner with BMI, insulin, and HOMA-IR. CONCLUSIONS: Dysregulation of the ASP pathway may have important metabolic consequences in NASH and is associated with insulin resistance.

Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic Fatty liver disease.

OBJECTIVES: The aim of the present study was to examine the systemic parameters of oxidative stress and antioxidants in patients with nonalcoholic fatty liver disease and investigate the relationship between these parameters and clinical and biochemical outcomes. METHODS: Fifty-one male patients with nonalcoholic fatty liver disease (group I), 30 age-matched and body mass index (BMI)-matched healthy male subjects, and 30 age-matched male patients with chronic viral hepatitis (group II) were enrolled in the study. RESULTS: Increased systemic levels of malondialdehyde and depletion of antioxidants such as coenzyme Q10, CuZn-superoxide dismutase, and catalase activity were observed in group I. Coenzyme Q10 and CuZn-superoxide dismutase correlated negatively with increasing necroinflammatory activity and fibrosis. Body fat was negatively associated with plasma coenzyme Q10 levels, while an inverse association was found between plasma catalase levels and TG. However, LDL was positively associated with plasma malondialdehyde levels. CuZn-superoxide dismutase levels were negatively associated with glucose, insulin, and HOMA-IR. In addition, the levels of CuZn-superoxide dismutase correlated significantly in a negative manner with BMI. CONCLUSIONS: Our results concerning correlations suggest that disturbances in BMI, body fat, and lipid metabolism may contribute to altered oxidative status in NAFLD, and insulin resistance may be related to decreased antioxidants in NAFLD as well as products of lipid peroxidation. However, although our results suggest interesting correlations, this different mostly "weak" relationships must be taken with caution.

Differential regulation of fatty acid trapping in mouse adipose tissue and muscle by ASP.

Acylation-stimulating protein (ASP) is a lipogenic hormone secreted by white adipose tissue (WAT). Male C3 knockout (KO; C3(-/-)) ASP-deficient mice have delayed postprandial triglyceride (TG) clearance and reduced WAT mass. The objective of this study was to examine the mechanism(s) by which ASP deficiency induces differences in postprandial TG clearance and body composition in male KO mice. Except for increased (3)H-labeled nonesterified fatty acid (NEFA) trapping in brown adipose tissue (BAT) of KO mice (P = 0.02), there were no intrinsic tissue differences between wild-type (WT) and KO mice in (3)H-NEFA or [(14)C]glucose oxidation, TG synthesis or lipolysis in WAT, muscle, or liver. There were no differences in WAT or skeletal muscle hydrolysis, uptake, and storage of [(3)H]triolein substrate [in situ lipoprotein lipase (LPL) activity]. ASP, however, increased in situ LPL activity in WAT (+64.8%, P = 0.02) but decreased it in muscle (-35.0%, P = 0.0002). In addition, after prelabeling WAT with [(3)H]oleate and [(14)C]glucose, ASP increased (3)H-lipid retention, [(3)H]TG synthesis, and [(3)H]TG-to-[(14)C]TG ratio, whereas it decreased (3)H-NEFA release, indicating increased NEFA trapping in WAT. Conversely, in muscle, ASP induced effects opposite to those in WAT and increased lipolysis, indicating reduced NEFA trapping within muscle by ASP (P < 0.05 for all parameters). In conclusion, novel data in this study suggest that 1) there is little intrinsic difference between KO and WT tissue in the parameters examined and 2) ASP differentially regulates in situ LPL activity and NEFA trapping in WAT and skeletal muscle, which may promote optimal insulin sensitivity in vivo.

Bivariate linkage between acylation-stimulating protein and BMI and high-density lipoproteins.

OBJECTIVE: Given the importance of visceral adiposity in the metabolic syndrome, whether levels of adipokines have shared genetic effects (pleiotropy) with aspects of the metabolic syndrome should be addressed. Acylation-stimulating protein (ASP), an adipose-derived protein, influences lipid metabolism, obesity, and glucose use. Therefore, our objective was to examine the genetic regulation of ASP and associated pleiotropic effects. RESEARCH METHODS AND PROCEDURES: We assayed serum ASP levels in 435 Mexican Americans participating in the San Antonio Family Heart Study and performed univariate and bivariate variance components analysis. RESULTS: Additive genetic heritability of ASP was 26% (p = 0.0004). Bivariate genetic analysis detected significant genetic correlations between ASP and several lipid measures but not between ASP and adiposity or diabetes measures. We detected two potential quantitative trait loci influencing ASP levels. The strongest signal was on chromosome 17 near marker D17S1303 [log of the odds ratio (LOD) = 2.7]. The signal on chromosome 15 reached its peak near marker D15S641 (LOD = 2.1). Both signals localize in regions reported to harbor quantitative trait loci influencing obesity and lipid phenotypes in this population. Bivariate linkage analysis yielded LODs of 4.7 for ASP and BMI on chromosome 17 and 3.2 for ASP and high-density lipoprotein2a on chromosome 15. DISCUSSION: Given these findings, there seems to be a significant genetic contribution to variation in circulating levels of ASP and an interesting pattern of genetic correlation (i.e., pleiotropy) with other risk factors associated with the metabolic syndrome.

The adipocyte as an endocrine cell.

Communication between adipose and other tissues has been hypothesized since at least the 1940s to be bidirectional. Despite this expectation, early progress was largely limited to adipose tissue's role in metabolism and storage of fatty acids, its development, and its response to endocrine and neural cues. However, efforts of the last decade have identified several molecules that are secreted from adipocytes, apparently for the purpose of signaling to other tissues. Cloning of the mouse obesity gene in 1994 is perhaps the most famous impetus for recognition that adipocytes are active in the regulation of multiple body functions. The product of this gene, leptin, has since been found to inhibit feeding, enhance energy expenditure, and stimulate gonadotropes. Evidence for the roles of other adipocyte-derived signals is being generated. Resistin is a protein that can cause whole-body insulin resistance. Its expression is correlated with body fatness and is inhibited by thiazolidinediones, perhaps mediating the association of type 2 diabetes with obesity, and the effectiveness of these drugs. Resistin and a related molecule, RELM alpha, can also inhibit differentiation of preadipocytes. Adiponectin/Acrp30 secretion from adipocytes is diminished in obese states. This protein can enhance use of fatty acids in lean tissues, inhibit glucose production by liver, and consequently decrease both blood glucose and BW. Adiponectin may also be responsible for the effectiveness of thiazolidinediones, given that these drugs promote adiponectin secretion. Secretion of complement proteins has been observed in adipocytes, and these interact to generate a signal called acylation-stimulating protein, which can promote triacylglycerol synthesis. These signals seem to be largely unique to adipocytes. Other signals are derived from adipose tissue, and it is unlikely that all the adipocyte's endocrine signals have been identified. Certainly, there is much to learn about how these signals function; however, it is clear that these biomedical research discoveries comprise a useful model for our study of growth and development in livestock.

Addition of glucose to an oral fat load reduces postprandial free fatty acids and prevents the postprandial increase in complement component 3.

BACKGROUND: Elevated fasting plasma concentrations of complement component 3 (C3) are associated with elevated fasting and postprandial triacylglycerol concentrations, insulin resistance, obesity, and coronary artery disease. C3 is the central component of the complement system and the precursor of acylation-stimulating protein (ASP). Insulin and ASP are principal determinants of free fatty acid (FFA) trapping by adipose tissue. OBJECTIVE: Because controversy exists concerning postprandial changes in C3 and because meal composition may influence complement activation, we studied postprandial lipemia in relation to changes in plasma C3. DESIGN: After an overnight fast, 6 healthy men ( +/- SD age: 23 +/- 2 y) underwent 4 oral liquid challenges: fat (50 g/m(2) body surface), glucose (37.5 g/m(2)), fat and glucose (mixed test), and water (as a control test) in a random, crossover design. RESULTS: Plasma ASP concentrations did not change postprandially in any test. Changes in C3 concentration were observed only after the fat challenge: elevated concentrations occurred between 1 and 3 h, and a maximum increase of 11% occurred at 2 h (P = 0.05). Postprandial triacylglycerolemia did not differ significantly between the fat and mixed tests. The FFA response after the fat challenge was the highest of all the tests (P < 0.05 for all comparisons) and was accompanied by an increase in ketone bodies (maximum at 6 h); this increase did not occur after the mixed test, which suggests less hepatic FFA delivery. CONCLUSIONS: When glucose is added to an oral fat load, the postprandial FFA response is reduced, and the fat-specific increase in C3 is prevented. After ingestion of fat without glucose, the lack of insulin response may lead to C3-mediated peripheral FFA trapping, which probably serves as a backup system in case of insufficient or inefficient insulin-dependent FFA trapping.

ASP enhances in situ lipoprotein lipase activity by increasing fatty acid trapping in adipocytes.

Acylation-stimulating protein (ASP) increases triglyceride (TG) storage (fatty acid trapping) in adipose tissue and plays an important role in postprandial TG clearance. We examined the capacity of ASP and insulin to stimulate the activity of lipoprotein lipase (LPL) and the trapping of LPL-derived nonesterified fatty acid (NEFA) in 3T3-L1 adipocytes. Although insulin increased total LPL activity (secreted and cell-associated; P < 0.001) in 3T3-L1 adipocytes, ASP moderately stimulated secreted LPL activity (P = 0.04; 5% of total LPL activity). Neither hormone increased LPL translocation from adipocytes to endothelial cells in a coculture system. However, ASP and insulin increased the V(max) of in situ LPL activity ([(3)H]TG synthetic lipoprotein hydrolysis and [(3)H]NEFA incorporation into adipocytes) by 60% and 41%, respectively (P

Fasting acylation-stimulating protein is predictive of postprandial triglyceride clearance.

Postprandial plasma triglyceride (ppTG) and NEFA clearance were stratified by plasma acylation-stimulating protein (ASP) and gender to determine the contribution of fasting ASP in a normal population (70 men; 71 women). In the highest ASP tertile only, ASP decreased over 8 h (90 +/- 9.7 nM to 70 +/- 5.9 nM, P<0.05 males; 61.9 +/- 4.0 nM to 45.6 +/- 6.2 nM, P<0.01 females). Fasting ASP correlated positively with ppTG response. ppTG (P<0.0001, 2-way ANOVA, both genders) and NEFA levels progressively increased from lowest to highest ASP tertile, with the greatest differences in males. By stepwise multiple regression, the best prediction of ppTG was: (fasting ASP + apolipoprotein B + insulin + TG; r=0.806) for men and (fasting ASP + total cholesterol; r=0.574) for women. Leptin, body mass index, and other fasting variables did not improve the prediction. Thus, in men and women, ASP significantly predicted ppTG and NEFA clearance and, based on lower ASP, women may be more ASP sensitive than men. Plasma ASP may be useful as a fasting variable that will provide additional information regarding ppTG and NEFA clearance.

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.

ApoE phenotype influences plasma ASP in hyperapoB subjects.

Acylation stimulating protein (ASP) is increased in cardiovascular patients who often present with dyslipidemias. The aim of the present study was to examine the influence of apolipoprotein E (apoE) phenotype and lipids on ASP. Plasma ASP, lipids and apoE phenotype were measured in 407 subjects and separated according to the 75th percentile of apolipoprotein B (apoB) into a HyperapoB (HB) group (apoB=152+/-34 mg/dl, 117 men, 80 women) and a normal apoB (NB) group (apoB=88+/-19 mg/dl, 126 men, 84 women). Triglyceride (TG), cholesterol and LDL cholesterol were significantly increased in HB versus NB but there was no difference in age or body mass index (BMI). HB had increased ASP (42%>75th percentile, median=48.4 nM, P<0.001) versus NB (36.5 nM). There was no difference in ASP in NB with any apoE3 variant (E3/3=41 nM, n=98; E3/4=46 nM, n=55; E3/2=50 nM, n=41), but ASP was increased in E2/2 (126 nM, n=9), and E4/4 (186 nM, n=5, P<0.001 ANOVA). In HB, ASP was increased in three apoE phenotypes: E2/4 (209 nM, n=6), E2/2 (135 nM, n=6) and E4/4 (189 nM, n=26), P<0.001 ANOVA relative to the other apoE phenotypes (E3/3=50 nM, n=102; E3/4=41 nM, n=40; E3/2=87 nM, n=17) with a wide range of values. By stepwise regression analysis, the best model that predicted ASP was: [plasma non-esterified fatty acid (NEFA)+TG+cholesterol], where r=0.407, P=0.001. These data suggest that apoE phenotype may potentially influence ASP, although primarily in rare apoE phenotypes.

Studies of adipose tissue metabolism in human immunodeficiency virus-associated lipodystrophy.

We studied aspects of metabolism in subcutaneous adipose tissue (SAT) in 40 human immunodeficiency virus (HIV)-infected subjects with and without lipodystrophy and in healthy control subjects. HIV-infected subjects without lipodystrophy had less SAT and visceral adipose tissue (VAT). Glycerol release was higher in both HIV-infected groups, especially those without fat redistribution. Tumor necrosis factor (TNF) release from SAT and serum soluble TNF receptor 2 concentrations were significantly higher in HIV-infected individuals with lipodystrophy. The absolute production of acylation-stimulating protein (ASP) and the percentage conversion of the complement protein to ASP were significantly lower in HIV-infected subjects with lipodystrophy. Further studies are needed to dissect the factors that mediate lipoatrophy in HIV infection.

Acylation stimulating protein stimulates insulin secretion.

Acylation stimulating protein (ASP) is a hormone produced by adipocytes and is of importance for the storage of energy as fat. We examined whether ASP might also have effects on islet function. In clonal INS-1 cells, ASP dose-dependently augmented glucose-stimulated insulin secretion. The lowest effective dose of ASP at 10 mmol/l glucose was 5 micro mol/l. The effect was glucose-dependent because ASP did not increase insulin secretion at 1 mmol/l glucose but had clear effect at 10 and 20 mmol/l glucose. Similarly, ASP augmented glyceraldehyde-induced insulin secretion but the hormone did not enhance insulin secretion in response to depolarization by 20 mmol/l of KCl. ASP-induced insulin secretion was completely abolished by competitive inhibition of glucose phosphorylation by glucokinase with 5-thio-glucose and was partially inhibited by the calcium channel blocker, nifedipine, and by the protein kinase C inhibitor, GF109203. Furthermore, thapsigargin, an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum, did not affect ASP-induced insulin secretion. ASP (>5 micro mol/l) also augmented glucose-stimulated insulin secretion from islets isolated from C57BL/6J mice, and intravenous administration of ASP (50 nmol/kg) augmented the acute (1 and 5 min) insulin response to intravenous glucose (1 g/kg) in C57BL/6J mice. This was accompanied by an increased rate of glucose disposal. Minimal model analyses of data derived from the intravenous glucose tolerance test revealed that whereas ASP augmented insulin secretion, the hormone did not affect insulin sensitivity (S(I)) or glucose effectiveness (S(G)). We conclude that ASP augments glucose-stimulated insulin secretion through a direct action on the islet beta cells. The effect is dependent on glucose phosphorylation, calcium uptake and protein kinase C. Stimulation of insulin secretion by ASP in vivo results in augmented glucose disposal.

Acylation stimulating protein and triacylglycerol synthesis: potential drug targets?

Triacylglycerol storage in adipose tissue is mediated by a host of transporters, enzymes and binding proteins. Additionally, several hormones (both autocrine and endocrine) are known to interact with cell surface receptors and modulate triacylglycerol synthesis (such as acylation stimulating protein, ASP). The many proteins involved contribute to the robustness of the system and, in most cases, deletion of a single gene is not deleterious and adipose tissue is preserved. On the other hand, this does not mean that gene disruption is not without effect, and in fact often results in a leaner, and presumably "healthier" mouse. These insights provide valuable indications for potential drug tools to delay and/or reverse obesity. In this review we examine the potential of ASP as a candidate target. ASP deficiency in mice decreases adipose tissue mass, increases insulin sensitivity and energy expenditure even in obese ob/ob mice, suggesting that partial interference of ASP action could be advantageous. ASP interacts with a specific cell surface receptor present in adipose tissue and certain structural components, such as the tightly folded core region, are implicated in activity. We propose that interference of the ASP-receptor interaction using an antagonist offers future prospect for an anti-obesity target.

Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects.

We examined fasting plasma insulin, acylation-stimulating protein (ASP), leptin, adiponectin, ghrelin, and metabolic/cardiovascular risk profile before and 15 +/- 6 months after isolated Roux-en-Y gastric bypass surgery in 50 morbidly obese subjects. Average preoperative plasma lipids were mostly normal, whereas ASP, insulin, and leptin were elevated, and adiponectin and ghrelin were decreased. Postoperatively, body weight decreased significantly (-36.4 +/- 9.6%) and was best predicted by preoperative adiponectin concentration in weight-stable subjects (r = -0.59; P = 0.02). Plasma lipids and insulin resistance improved, leptin and ASP decreased (-76.3 +/- 14.6% and -35.9 +/- 52.2%; P < 0.001), and adiponectin increased (50.1 +/- 47.0%; P < 0.001). The decrease in apolipoprotein B was best predicted by the decrease in ASP (r = 0.55; P = 0.009), whereas the improved postoperative insulin sensitivity was best predicted by the increase in adiponectin (r = 0.70; P = 0.01). Despite bypassing 95% of the stomach and isolating the fundus from contact with ingested nutrients, circulating ghrelin did not decrease after surgery. In fact, plasma ghrelin increased postoperatively in the subset of subjects undergoing active weight loss (+60.5 +/- 23.2%; P < 0.001); ghrelin, however, remained unchanged in weight-stable subjects. In summary, 1) preoperative adiponectin concentrations may be predictive of the extent of weight loss; 2) changes in ASP and adiponectin are predictive of decreased apolipoprotein B and improved insulin action, respectively; and 3) plasma ghrelin increases after gastric bypass surgery in patients experiencing active weight loss.

Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes.

C3a and C5a anaphylatoxins are two proinflammatory peptides generated during complement system activation. C3a and C5a exert several biological activities through binding to their specific receptors, named C3aR and C5aR, respectively. We have previously shown that C3aR and C5aR are constitutively expressed by astrocytes, a cell type that actively participates in inflammatory events in the central nervous system. In this article, we focus on the transduction signal pathways activated by these two receptors on astrocytes. We show that the stimulation of C3aR or C5aR results in the activation of the mitogen activated protein kinase pathway by phosphorylation of the p44 and p42 kinases. On the contrary, the binding of C3a or C5a to their receptors on astrocytes decreases the production of cAMP, revealing an inhibition of the adenylyl cyclase pathway. Stimulation of C3aR and C5aR induces an increase in intracellular calcium concentration, arising from the opening of intracellular calcium channels. The observed calcium wave results from the activation of the phospholipase C pathway. Taken together, our results suggest that the binding of C3a or C5a to their receptors on astrocytes would be of functional importance since it induces the activation of two important transduction pathways leading to several cellular events such as neurotrophin and cytokine production.

The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein.

The orphan receptor C5L2 has recently been described as a high affinity binding protein for complement fragments C5a and C3a that, unlike the previously described C5a receptor (CD88), couples only weakly to G(i)-like G proteins (Cain, S. A., and Monk, P. N. (2002) J. Biol. Chem. 277, 7165-7169). Here we demonstrate that C5L2 binds the metabolites of C4a and C3a, C4a des-Arg(77), and C3a des-Arg(77) (also known as the acylation-stimulating protein or ASP) at a site distinct from the C5a binding site. The binding of these metabolites to C5L2 does not stimulate the degranulation of transfected rat basophilic leukemia cells either through endogenous rat G proteins or when co-transfected with human G(alpha 16). C3a des-Arg(77)/ASP and C3a can potently stimulate triglyceride synthesis in human skin fibroblasts and 3T3-L1 preadipocytes. Here we show that both cell types and human adipose tissue express C5L2 mRNA and that the human fibroblasts express C5L2 protein at the cell surface. This is the first demonstration of the expression of C5L2 in cells that bind and respond to C3a des-Arg(77)/ASP and C3a. Thus C5L2, a promiscuous complement fragment-binding protein with a high affinity site that binds C3a des-Arg(77)/ASP, may mediate the acylation-stimulating properties of this peptide.

Critical review of acylation-stimulating protein physiology in humans and rodents.

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) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice.

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 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.