The role of the complement system in metabolic organs and metabolic diseases

doi:10.1016/j.smim.2013.04.003

Seminars in Immunology

Volume 25, Issue 1, February 2013, Pages 47-53

https://doi.org/10.1016/j.smim.2013.04.003 Get rights and content

Highlights

•
Complement plays a major role in metabolic organs and in metabolic diseases.
•
Complement components affect insulin secretion and adipocyte maturation.
•
Complement contributes to the pathogenesis of T1DM and T2DM.
•
Complement regulates liver inflammation and steatosis.

Abstract

Emerging evidence points to a close crosstalk between metabolic organs and innate immunity in the course of metabolic disorders. In particular, cellular and humoral factors of innate immunity are thought to contribute to metabolic dysregulation of the adipose tissue or the liver, as well as to dysfunction of the pancreas; all these conditions are linked to the development of insulin resistance and diabetes mellitus. A central component of innate immunity is the complement system. Interestingly, the classical view of complement as a major system of host defense that copes with infections is changing to that of a multi-functional player in tissue homeostasis, degeneration, and regeneration. In the present review, we will discuss the link between complement and metabolic organs, focusing on the pancreas, adipose tissue, and liver and the diverse effects of complement system on metabolic disorders.

Section snippets

Introduction: the crosstalk between the immune system and metabolism

Emerging evidence the recent years, points to an important crosstalk between the innate and adaptive immune systems and metabolic disease. Immune cells and inflammation are not only an epiphenomenon of the dysfunction of metabolic and endocrine organs. Immune cells (e.g., macrophages and T cells), cytokines (e.g., TNF and IL-6) and further factors such as the inflammasome system all contribute directly and significantly to the metabolic dysfunction seen in insulin target organs, such as adipose

The role of complement in physiology and pathology of the pancreas

The pancreas is an organ with a major regulatory role in metabolism, since it is the source of insulin and other hormones regulating glucose homeostasis. The β-cells of the pancreatic islets produce and secrete insulin upon glucose stimulation. Interestingly, the complement degradation product, acylation stimulating protein (ASP), can stimulate glucose-dependent insulin secretion from islets [25]. In contrast, complement fH, which is produced by the liver and also locally in the pancreas, is

The role of complement in adipose tissue biology

AT biology can be influenced by a variety of complement components. Adipocytes are a major source of adipsin, which is identical to the murine factor D [56], [57] that participates in alternative complement activation, as described above in section one. Interestingly, adipsin contributes to the maturation of preadipocytes into adipocytes [56], [58], suggesting that this complement component has functions over and above its role in innate immunity. Subsequent studies have demonstrated the

The role of complement in liver homeostasis and fatty liver disease

The liver and hepatocytes represent the main source of plasma complement proteins, including factors of all three activation pathways (classical, lectin, and alternative) as well as fluid-phase regulators [89], [90], [91]. In addition, parenchymal (hepatocytes) and non-parenchymal cells (Kupffer cells, stellate and sinusoidal endothelial cells) express complement receptors C3aR, C5aR, and C5L2, which can also be upregulated by pro-inflammatory factors and under conditions of stress [79], [92],

Conclusion

Increasing evidence points to multiple functions of the complement system beyond pathogen killing. Interestingly, the effects of complement seem to be context- and organ-dependent. Here we have focused on the role of complement in metabolic organs such as pancreas, AT, and the liver in metabolic diseases (Fig. 1). Complement components C3 and C5 and their derivatives C3a, C3a^desArg (ASP), and C5a are central players influencing the physiology and pathology of these metabolic organs. Basal

Acknowledgments

Supported by grants from the Deutsche Forschungsgemeinschaft (CH279/5-1) (to T.C.), the Else-Kröner-Fresenius Stiftung (to T.C.) and the German Center for Diabetes Research (to T.C.) and NIH grants AI003040, AI068730, AI072106, EY020633, and DE021685 (to J.D.L.).

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Obesity is associated with insulin resistance, hypertension, and coronary artery diseases which are grouped as metabolic syndrome. Rather than being a storage for energy, the adipocytes could synthesis and secret diverse hormones and molecules, named as adipokines. Under obese status, the adipocytes are dysfunctional with excessively producing the inflammatory related cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α). Concerning on the vital role of adipokines, it is proposed that one of the critical pathological factors of obesity is the dysfunctional adipocytic pathways. Among these adipokines, acylation stimulating protein, as an adipokine synthesized by adipocytes during the process of cell differentiation, is shown to activate the metabolism of triglyceride (TG) by regulating the catabolism of glucose and free fatty acid (FFA). Recent attention has paid to explore the underlying mechanism whereby acylation stimulating protein influences the biological function of adipocyte and the pathological development of obesity. In the present review, we summarized the progression of acylation stimulating protein in modulating the physiological and hormonal catabolism which affects fat distribution. Furthermore, the potential mechanisms which acylation stimulating protein regulates the metabolism of adipose tissue and the process of metabolic syndrome were also summarized.
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Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat using a tamoxifen inducible-AdipoQ-Cre (Ai-DKO) leads to rapid and severe loss of adipocytes in all depots, associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over a few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation, and this effect can be mimicked by conditioned media from liver slices of Ai-DKO mice, but not by media of cultured Ai-DKO adipocytes, indicating a hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3 (APOC3), a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice. In vitro, purified and delipidated APOC3 stimulates preadipocyte proliferation, however, knockdown of hepatic APOC3 in vivo in Ai-DKO mice is not sufficient to block adipose regeneration. Thus, lipodystrophy is associated with presence of increased preadipocyte-stimulating growth factors in serum. Our study indicates that APOC3 is one contributing factor to preadipocyte proliferation, however, other still-unidentified circulating growth factors are also likely present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease.
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¹: These authors contributed equally.

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ReviewThe role of the complement system in metabolic organs and metabolic diseases

Highlights

Abstract

Section snippets

Introduction: the crosstalk between the immune system and metabolism

The role of complement in physiology and pathology of the pancreas

The role of complement in adipose tissue biology

The role of complement in liver homeostasis and fatty liver disease

Conclusion

Acknowledgments

Cell

American Journal of Pathology

Trends in Immunology

Immunobiology

Molecular Immunology

Clinical Immunology

Biochemical and Biophysical Research Communications

Clinical Immunology and Immunopathology

American Journal of Pathology

Molecular Immunology

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Lipid Research

Journal of Lipid Research

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Molecular Immunology

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Immunobiology

Blood

Molecular Immunology

Gastroenterology

Clinical Immunology

International Immunopharmacology

IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice

Journal of Clinical Investigation

Roles of liver innate immune cells in nonalcoholic fatty liver disease

World Journal of Gastroenterology

Type 2 diabetes as an inflammatory disease

Nature Reviews Immunology

Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes

Physiology (Bethesda)

Macrophage-mediated inflammation in metabolic disease

Nature Reviews Immunology

Lymphocytes in obesity-related adipose tissue inflammation

Diabetologia

Obesity is associated with macrophage accumulation in adipose tissue

Journal of Clinical Investigation

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

Journal of Clinical Investigation

TLR4 links innate immunity and fatty acid-induced insulin resistance

Journal of Clinical Investigation

Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance

Nature Medicine

Complement: a key system for immune surveillance and homeostasis

Nature Immunology

Complement regulators and inhibitory proteins

Nature Reviews Immunology

Therapeutic potential of complement modulation

Nature Reviews Drug Discovery

C5a receptor-dependent cell activation by physiological concentrations of desarginated C5a: insights from a novel label-free cellular assay

Journal of Immunology

Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3

Journal of Experimental Medicine

Complement activation in human lymph: modulation by the contact activation system and by leukocytes

International Archives of Allergy and Applied Immunology

Chemotactic activity generated from the fifth component of complement by plasma kallikrein of the rabbit

Journal of Experimental Medicine

Generation of C5a in the absence of C3: a new complement activation pathway

Nature Medicine

Acylation stimulating protein stimulates insulin secretion

International Journal of Obesity and Related Metabolic Disorders

Review
The role of the complement system in metabolic organs and metabolic diseases