Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice

Abstract

Acylation-stimulating protein (C3adesArg/ASP) is an adipokine that acts on its receptor C5L2 to stimulate triglyceride (TG) synthesis in adipose tissue. The present study investigated ASP levels in mouse models of obesity and leanness and the effect of ASP deficiency in C3 knockout (C3KO) mice on adipose tissue morphology. Plasma ASP levels in wild-type (WT) mice correlated positively with plasma nonesterified fatty acids (NEFA) (R ϭ 0.664, P Ͻ 0.001) and total cholesterol (R ϭ 0.515, P Ͻ 0.001). Plasma ASP was increased by 85% in obese ob/ob leptin-deficient mice and decreased in lean diacylglycerol acyltransferase 1 (DGAT1) KO mice (Ϫ54%) and C/EBP␣ ␤/␤ transgenic mice (Ϫ70%) compared with WT. Mice lacking alternative complement factor B or adipsin (FBKO or ADKO), required for ASP production, were also ASP deficient. Both FBKO and C3KO mice had delayed postprandial TG and NEFA clearance on low-fat (LF) and high-fat (HF) diets, suggesting that lack of ASP, not C3, drives the metabolic phenotype. Adipocyte size distribution in C3KO mice was polarized (increased number of both small and large cells), with decreased adipsin expression (Ϫ33% gonadal HF), DGAT1 expression (Ϫ31% to Ϫ50%) and DGAT activity (Ϫ41%). Overall, a reduction/deficiency in ASP is associated with an antiadipogenic state and ASP may provide a target for controlling fat storage. C3adesArg; complement C3; factor B; diacylglycerol acyltransferase 1; postprandial lipemia ACYLATION-STIMULATING PROTEIN (ASP/C3adesArg) is an adipose tissue-derived hormone that stimulates adipocyte triglyceride (TG) synthesis and glucose transport (20, 43). ASP acts through its receptor C5L2, a G protein-coupled receptor, to stimulate diacylglycerol acyltransferase (DGAT) activity, the rate-limiting enzyme in the TG synthesis pathway, and glucose transport (17,18).It has been suggested that ASP is generated through the alternative pathway of complement activation, based on differentiation-dependent expression of adipsin (factor D), complement C3, and factor B (FB) in adipose tissue (4, 5); however, this has not been shown directly. C3 convertase of the alternative pathway, a proteolytic complex formed by the interaction of C3b, FB, and adipsin (factor D), cleaves the third complement component (C3) into C3a and C3b (8). C3a is a potent anaphylatoxin interacting with its receptor C3aR. However, in the circulation, the terminal arginine of C3a is rapidly cleaved by carboxypeptidase B, inactivating the C3a anaphylatoxic function and generating C3adesArg (ASP) (8). Both ASP/C3adesArg and C3a interact with the receptor C5L2 to effectively stimulate TG synthesis in cultured adipocytes (18).C3 knockout (C3KO) mice are obligatorily ASP deficient, since they lack the precursor protein. We have previously reported that C3KO mice are lean yet hyperphagic (22, 40); the increased energy intake is being balanced by an increased energy expenditure (40). C3KO mice also displayed an altered plasma lipoprotein profile, mainly characterized by delayed postprandial TG clearance (23,24,40)...

Cross-talk between α7 nAChR-mediated cholinergic pathway and acylation stimulating protein signaling in 3T3-L1 adipocytes: role of NFκB and STAT3

“…Indeed, NFB-dependent pathways have been found to be activated in ASP-treated adipose tissue. Thus, both secretion of cytokines and activation of intracellular pathways, suggestive of an inflammatory response, occur after treatment with high physiological doses of ASP, comparable to those commonly found in biological samples (Cianflone et al 2003;Paglialunga et al 2008;Tahiri et al 2007). Data also indicate that ASP plays an important role in the balance between inflammation/injury versus proliferative response through regulation of STAT3 (He et al 2009).…”

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

“…Since the extent of steatosis is positively associated with the extent of IRI (7,8,39,40), and the C3 activation product C3adesArg (also known as acylation-stimulating protein) is involved in the regulation of lipid metabolism (41,42), a possible explanation for the reduced level of hepatic IRI seen in C3 Ϫ/Ϫ mice is that C3 Ϫ/Ϫ mice develop less liver steatosis. However, following a 4-wk high fat diet (60% calories from fat), we detected no significant quantitative or qualitative differences in steatosis between wt and C3 Ϫ/Ϫ mice.…”

Dual role of complement in adipose tissue

“…Properdin may, as C3, be tightly involved in adipocyte homoiostasis. C3adesarg is generated via the alternative pathway (Paglialunga et al, 2008), and properdin could, mechanistically, through stabilisation of the alternative pathway C3 convertase complex, ensure the provision of the C3adesArg precursor, and through binding to CD36, aid in the mediation of effects favoring differentiation to adipocytes. There is further support of an adipose tissue related role of properdin:…”