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Published on: January 22, 2020
Stabilization and augmentation of circulating AIM in mice by synthesized IgM-Fc
Toshihiro Kai1, Tomoko Yamazaki1, Satoko Arai1
1Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
Owing to rapid and drastic changes in lifestyle and eating habits in modern society, obesity and obesity-associated diseases are among the most important public health problems. Hence, the development of therapeutic approaches to regulate obesity is strongly desired. In view of previous work showing that apoptosis inhibitor of macrophage (AIM) blocks lipid storage in adipocytes, thereby preventing obesity caused by a high-fat diet, we here explored a strategy to augment circulating AIM levels. We synthesized the Fc portion of the soluble human immunoglobulin (Ig)M heavy chain and found that it formed a pentamer containing IgJ as natural IgM does, and effectively associated with AIM in vitro. When we injected the synthesized Fc intravenously into mice lacking circulating IgM, it associated with endogenous mouse AIM, protecting AIM from renal excretion and preserving the circulating AIM levels. As the synthesized Fc lacked the antigen-recognizing variable region, it provoked no undesired immune response. In addition, a challenge with the Fc-human AIM complex in wild-type mice, which exhibited normal levels of circulating IgM and AIM, successfully maintained the levels of the human AIM in mouse blood. We also observed that the human AIM was effectively incorporated into adipocytes in visceral fat tissue, suggesting its functionality against obesity. Thus, our findings reveal potent strategies to safely increase AIM levels, which could form the basis for developing novel therapies for obesity.
Insights
Researchers developed a novel strategy to increase levels of apoptosis inhibitor of macrophage (AIM) by synthesizing a soluble immunoglobulin M (IgM) Fc fragment. This approach safely enhances AIM, offering a potential new therapy for obesity and related conditions.
Area of Science:
- Immunology
- Metabolic Diseases
- Drug Development
Background:
- Obesity and associated diseases are significant public health concerns driven by modern lifestyle and dietary changes.
- Apoptosis inhibitor of macrophage (AIM) has shown potential in preventing obesity by inhibiting lipid storage in adipocytes.
- A therapeutic strategy to increase circulating AIM levels is highly desirable.
Purpose of the Study:
- To explore a novel strategy for augmenting circulating levels of apoptosis inhibitor of macrophage (AIM).
- To develop a method for preventing obesity by enhancing AIM's therapeutic potential.
- To synthesize and evaluate a soluble human immunoglobulin M (IgM) Fc fragment for its ability to stabilize AIM.
Main Methods:
- Synthesis of the Fc portion of soluble human IgM heavy chain, confirmed to form a pentamer with IgJ.
- In vitro association of the synthesized Fc with AIM.
- Intravenous injection of the Fc fragment into mice to assess its effect on endogenous AIM levels and renal excretion.
- Administration of an Fc-human AIM complex to wild-type mice to evaluate AIM stability and uptake in visceral fat adipocytes.
Main Results:
- The synthesized Fc fragment effectively associated with AIM in vitro and in vivo, protecting it from renal excretion and maintaining circulating levels.
- The Fc fragment, lacking a variable region, did not provoke an undesired immune response.
- Human AIM, complexed with Fc, was successfully maintained in mouse blood and incorporated into visceral fat adipocytes, indicating functional potential against obesity.
Conclusions:
- The study presents a safe and effective strategy to increase circulating AIM levels using a synthesized IgM Fc fragment.
- This approach holds promise for developing novel therapeutic interventions for obesity.
- The findings lay the groundwork for future treatments targeting AIM for metabolic health.
