Adipsin and Complement Factor D Activity: An Immune-Related Defect in Obesity

Rosen, Barry; Cook, Kathleen Sue; Yaglom, Julia A.; Groves, Douglas L.; Volanakis, John E.; Damm, D; White, Tyler; Spiegelman, Bruce M.

doi:10.1126/science.2734615

Cited by 271 publications

(176 citation statements)

References 48 publications

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“…However, its regulation in maintaining mature fat cells and fat cell function is not yet fully understood, especially in adipose tissues in animals. Adipsin is a serine protease involved in generating the active complement C3a, also known as acylation-stimulating protein (15). Acylation-stimulating protein stimulates triglyceride synthesis in adipocytes (2).…”

Section: Discussionmentioning

confidence: 99%

C/EBPβ, When Expressed from the C/ebpα Gene Locus, Can Functionally Replace C/EBPα in Liver but Not in Adipose Tissue

Chen

Johnson

et al. 2000

Molecular and Cellular Biology

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Knockout of C/EBP␣ causes a severe loss of liver function and, subsequently, neonatal lethality in mice. By using a gene replacement approach, we generated a new C/EBP␣-null mouse strain in which C/EBP␤, in addition to its own expression, substituted for C/EBP␣ expression in tissues. The homozygous mutant mice C/ebp␣ ␤/␤ are viable and fertile and show none of the overt liver abnormalities found in the previous C/EBP␣-null mouse line. Levels of hepatic PEPCK mRNA are not different between C/ebp␣ ␤/␤ and wild-type mice. However, despite their normal growth rate, C/ebp␣ ␤/␤ mice have markedly reduced fat storage in their white adipose tissue (WAT). Expression of two adipocyte-specific factors, adipsin and leptin, is significantly reduced in the WAT of C/ebp␣ ␤/␤ mice. In addition, expression of the non-adipocyte-specific genes for transferrin and cysteine dioxygenase is reduced in WAT but not in liver. Our study demonstrates that when expressed from the C/ebp␣ gene locus, C/EBP␤ can act for C/EBP␣ to maintain liver functions during development. Moreover, our studies with the C/ebp␣ ␤/␤ mice provide new insights into the nonredundant functions of C/EBP␣ and C/EBP␤ on gene regulation in WAT.

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Section: Discussionmentioning

confidence: 99%

C/EBPβ, When Expressed from the C/ebpα Gene Locus, Can Functionally Replace C/EBPα in Liver but Not in Adipose Tissue

Chen

Johnson

et al. 2000

Molecular and Cellular Biology

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“…52,53 The biological activities of the adipsin include reduction of elevated free fatty acid levels, increased fatty acid oxidation in muscle cells and weight reduction. 54 The functions of VDBP are still being defined, but they include the transport of vitamin D in the circulation and a role as the precursor of the group-specific component protein-derived macrophage-activating factor (GcMAF) which is derived by modification of VDBP in its carbohydrate moieties by b-galactosidase from B lymphocytes or sialidase from T lymphocytes. 55 MAFs are lymphokines involved in cytotoxicity of macrophages to tumors.…”

Section: Secretory Phenotype Of Sclc Ctc-induced Macrophagesmentioning

confidence: 99%

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

et al. 2015

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Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 C , CD163 weak and CD68 C macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

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“…5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages.…”

Section: Introductionmentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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Adipsin and Complement Factor D Activity: An Immune-Related Defect in Obesity

Cited by 271 publications

References 48 publications

C/EBPβ, When Expressed from the C/ebpα Gene Locus, Can Functionally Replace C/EBPα in Liver but Not in Adipose Tissue

C/EBPβ, When Expressed from the C/ebpα Gene Locus, Can Functionally Replace C/EBPα in Liver but Not in Adipose Tissue

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

Leptin in immuno-rheumatological diseases

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