Stabilization and augmentation of circulating AIM in mice by synthesized IgM-Fc

PLoS One. 2014 May 7;9(5):e97037. doi: 10.1371/journal.pone.0097037. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / immunology
  • Animals
  • Apoptosis / immunology
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fc Fragments / biosynthesis
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Immunoglobulin M / biosynthesis
  • Immunoglobulin M / immunology*
  • Intra-Abdominal Fat / immunology
  • Intra-Abdominal Fat / pathology
  • Macrophages / immunology
  • Mice
  • Obesity / immunology*
  • Obesity / pathology
  • Obesity / therapy*
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Receptors, Scavenger

Substances

  • Apoptosis Regulatory Proteins
  • Cd5l protein, mouse
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Immunoglobulin M
  • Receptors, Immunologic
  • Receptors, Scavenger

Grant support

This work was supported by Grants-in-Aid for Scientific Research (A) (Japan Society for the Promotion of Science), CREST (JST), research grants by Dainippon Sumitomo Pharma Co., Ltd. and ONSENDO Co., Ltd. (to TM), Grants-in-Aid for Scientific Research (B) (Japan Society for the Promotion of Science) (to SA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.