Metabolic syndrome: variations on the theme of inflammation

Abstract

“It is too violent to gather up the four movements of such different characters under the name of Sonata! But this piece is incredibly beautiful...” This historic quote was made by Robert Schumann in reference to the second piano sonata by Frederic Chopin that contains the famous funeral march. When experiencing the sonata for the first time, one may feel that this piece is somewhat “slippery”, as the association between the movements appears obscure due to the musical independency and distinctive color of each movement. However, after having heard the whole piece, one will no longer find any cracks in the artistic structure and will be fully convinced that the four movements form a definite complex. In fact, this is brought about by the common motif with a minor third , which is used throughout the sonata in the form of various metaphors; thus, it is not obvious at first glance. This motif links all the movements, thereby providing unity to the masterpiece. The prominent increase in the incidence of obesity in modern society has been caused by rapid and extreme changes in lifestyle, particularly eating habits. Obesity induces multiple diseases, each of which threatens our health and is a burden on medical expenses. Examples includes type 2 diabetes, atherosclerosis followed by cardiovascular complications, fatty liver diseases giving rise to liver fibrosis and cancer, and, interestingly, autoimmune diseases. At a glance, these diseases appear independent of each other: the pathogenesis of each disease is distinctive, the major affected organ in each disease is different, and each disease is treated and studied by its own specialists. However, all these diseases are manifestations of metabolic syndrome, which is the most talked about disease complex in modern society. In this sense, the relationship between metabolic syndrome and its associated diseases is reminiscent of the second sonata by Chopin and its four movements. Then, what is the minor third motif that mechanistically links all these different diseases? Accumulating evidence indicates that the answer to this question is inflammation. The breakthrough in understanding the events which bridge obesity and its associated diseases was brought about by the discovery that the chronic, low-grade inflammation observed in obese adipose tissue is responsible for triggering insulin resistance. In recent years, it has become clear that infiltration of a large number of classically activated inflammatory macrophages (M1 macrophages) into adipose tissue is responsible for obesity-associated inflammation. Lean adipose tissue contains a resident population of alternatively activated macrophages (M2 macrophages), which can suppress inflammation in both adipocytes and macrophages themselves, partly via secreting interleukin 10. Hence, obesity induces a switch in the macrophage activation state in adipose tissue toward M1 polarization, which induces inflammation. Such subclinical inflammation of adipose tissue is closely associated with insulin resistance not only in adipose tissue, but also systemically, thus contributing to the development of multiple obesity-induced metabolic and cardiovascular diseases. In this issue, the authors introduce eight variations of obesity-associated disease linked by the motif of inflammation. Arai et al. discuss adipose tissue macrophage recruitment with a focus on the newly identified role of apoptosis inhibitor of macrophage (AIM), a macrophage-derived blood protein initially identified as an apoptosis inhibitor that supports macrophage survival. Under obese conditions, augmented blood AIM is incorporated into adipocytes via CD36-mediated endocytosis and induces vigorous lipolysis. The authors show how this AIM-induced lipolytic response influences the This article is a contribution to the special issue onMetabolic Syndrome Guest Editor: T. Miyazaki