Disease relevance of Cfd

• RESULTS: MRL/lpr Df-/- mice had similar glomerular IgG deposition, proteinuria and autoantibody levels, as Df+/+ and Df+/- littermates [1].
• Adipsin is a serine protease that is secreted by adipocytes into the bloodstream; it is deficient in several animal models of obesity, representing a striking example of defective gene expression in this disorder [2].
• The mutant mice have no apparent abnormality in development and their body weights are similar to those of factor D-sufficient littermates [3].
• The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat [4].
• Hypoxia up-regulates mouse vascular endothelial growth factor D promoter activity in rat pulmonary microvascular smooth-muscle cells [5].

High impact information on Cfd

• Activated adipsin has little or no proteolytic activity toward most substrates but has the same activity as human complement factor D, cleaving complement factor B when it is complexed with activated complement component C3 [2].
• Pluripotent stem cell lines were isolated with homologously recombined insertions at three different loci: c-fos, which is expressed at a low level in ES cells, and two genes, adipsin and adipocyte P2 (aP2), which are transcribed specifically in adipose cells and are not expressed at detectable levels in ES cells [6].
• Adipsin and complement factor D activity: an immune-related defect in obesity [2].
• Like authentic factor D, adipsin can activate the alternative pathway of complement, resulting in red blood cell lysis [2].
• Adipsin, a serine protease homolog, is synthesized and secreted by adipose cells and is found in the bloodstream [7].

Chemical compound and disease context of Cfd

• Decreased (58 to 80 percent) complement factor D activity, relative to lean controls, was observed as a common feature of several experimental models of obesity, including the ob/ob, db/db, and monosodium glutamate (MSG)-injected mouse and the fa/fa rat [2].
• To map the region of the adipsin gene that confers this response to obesity, transgenic mice were made containing -114, -250, -400, -700, and -938 base pairs (bp) to +35 bp of the promoter linked to the bacterial chloramphenicol acetyltransferase gene [8].
• In the present study we evaluate the time course for the development of adipsin deficiency in obesity and its regulation by the sympathomimetic-thermogenic drug mixture ephedrine and caffeine [9].
• Reduced adipsin expression in murine obesity: effect of age and treatment with the sympathomimetic-thermogenic drug mixture ephedrine and caffeine [9].

Biological context of Cfd

• Complement activation in factor D-deficient mice [3].
• The sequence data also suggests a mechanism of alternative splicing which appears to account for the generation of two adipsin mRNA species differing by only three nucleotides and encoding two different signal peptides [10].
• While the basic exon structure characteristic of serine protease genes is conserved in adipsin, there is also a fusion of two exons that are separate in other serine proteases [10].
• The reduction of Pref-1 mRNA was most dramatic in differentiating preadipocytes treated with IL-11, occurring despite inhibition of adipogenesis, as judged by cell morphology and adipocyte-specific gene expression (adipsin and glycerol-3-phosphate dehydrogenase) [11].
• The function of the chimeras was studied by means of hemolytic assays and assays of the individual steps of the alternative complement pathway, i.e., binding to the C3b analogue cobra venom factor and factor D cleavage [12].

Anatomical context of Cfd

• Both human and murine adipocytes express mRNA and/or protein for the complement components C3 and factors B and D (adipsin) required to generate ASP [13].
• The coaddition of factor B and factor D to serum-free cultures of LPS-preactivated B cell blasts increased the proliferation of the responding cells up to the level obtained by restimulation with LPS [14].
• Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue [15].
• Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve [16].
• Vascular endothelial growth factor D is dispensable for development of the lymphatic system [17].

Associations of Cfd with chemical compounds

• We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls [18].
• However, glomerular C3 deposition, serum creatinine levels, and pathologic renal disease were significantly reduced in Df-/- mice [1].
• Genetic deficiencies in C1q, C4, factor B, or factor D all resulted in increased mortality in mice, suggesting that all activation pathways function together to limit WNV spread [19].
• The effect is factor D- and, at least in part, C5-dependent, indicating that local alternative pathway activation is essential [20].
• These results show that adipsin is a novel serine protease gene whose expression is regulated by a macrophage-derived factor which modulates expression of other adipocyte-specific RNAs [10].

Regulatory relationships of Cfd

• Macrophage factor B was cleaved and activated to factor Bb- and Ba-like fragments by factor D and cobra venom factor [21].
• However, TGF-alpha repressed the differentiation of the preadipocyte cell line 3T3-F442A in a dose-dependent and reversible manner as judged by morphological conversion and diminished expression of mRNAs encoding the adipocyte-specific markers adipsin and glycerophosphate dehydrogenase [22].
• However, sterol regulatory element-binding protein-1, apolipoprotein A4, and adipsin mRNAs were significantly induced in ICAM-1-deficient livers, suggesting that these genes and their associated pathways may be involved in the acute diet response observed in the knockout mice [23].

Other interactions of Cfd

• On differentiation, mRNA for C3 (fivefold) and factor D (> 50-fold) increased, whereas stimulation with tumour necrosis factor (TNF)-alpha and interleukin (IL) 1 beta led to eightfold increases in factor B mRNA [13].
• METHODS: Df-deficient mice were backcrossed with MRL/lpr mice for four to nine generations [1].
• Low level constitutive expression of PPAR gamma in 3T3-L1 adipocytes (at levels approximately 2- to 3-fold higher than in preadipocytes) partially blocked the inhibitory effect of TNF alpha on aP2 and adipsin expression [24].
• We find that ACRP30 overlaps with adipsin in intracellular compartments distinct from Glut4, but nonetheless exhibits insulin-stimulated secretion from cells [25].
• Expression of two adipocyte-specific factors, adipsin and leptin, is significantly reduced in the WAT of C/ebpalpha(beta/beta) mice [26].

Analytical, diagnostic and therapeutic context of Cfd

• To assess the contribution of the alternative pathway in complement activation and host defense and its possible role in the regulation of systemic energy balance in vivo, factor D-deficient mice were generated by gene targeting [3].
• Northern blot analysis was used to determine messenger RNA (mRNA) steady state expression of Pref-1 and two differentiation-specific genes, adipsin and glycerol-3-phosphate dehydrogenase [11].
• After intravenous injection of anti-r-adipsin Fab into BALB/c mice, the adipsin/factor D hemolytic activity of serum was abolished during a 4-h period [27].
• Exogenous administration of corticosterone completely blocks the effects of adrenalectomy on adipsin, suggesting that the effect of this endocrine ablation is through reduction of adrenal glucocorticoids [28].
• Using gel retardation assays, we showed that a 56-bp fragment of DNA mapping between -687 and -743 bp upstream from the start of adipsin expression was bound by protein factors in nuclear extracts prepared from adipose tissue [8].

References