Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation

Abstract

Obesity is associated with chronic low-grade inflammation of visceral adipose tissue (AT) characterized by an increasing number of AT macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures, as ATMs accumulate around dying adipocytes, and the occurrence of multinucleated giant cells (MGCs). However, to date, the function of MGCs in obesity is unknown. Therefore, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. We demonstrated that MGCs occurred in obese patients and after 24 weeks of a high-fat diet in mice, accompanying signs of AT inflammation and then representing ∼3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggered MGC formation. Most importantly, MGCs in obese AT had a higher capacity to phagocytize oversized particles, such as adipocytes, as shown by live imaging of AT, 45-µm bead uptake ex vivo, and higher lipid content in vivo. Finally, we showed that interleukin-4 treatment was sufficient to increase the number of MGCs in AT, whereas other factors may be more important for endogenous MGC formation in vivo. Most importantly, our data suggest that MGCs are specialized for clearance of dead adipocytes in obesity.

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

“…A permanent excess of nutrients can induce intracellular stress in adipocytes, leading to inflammation [125]. In addition, a systemic pro-inflammatory state is frequently induced by macrophage recruitment as a consequence of adipocyte apoptosis, AT-derived bacteria, accumulation of xenobiotics, altered fatty acid flux within AT, or others [126][127][128][129]. Cell culture experiments revealed the ability of macrophages to express higher levels of CCL2 mRNA after incubation with palmitic acid [130].…”

Innate-Immunity Genes in Obesity

“…Macrophages fuse to form giant multinucleated structures, containing up to 10% of macrophage-associated nuclei in adipose tissue. They seem to specialize in large-adipocyte destruction, and up to 15 macrophages aggregate around each dead adipocyte creating a "crownlike" structure [24,26]. For this purpose, additional monocytes and macrophages are attracted to senescent adipocytes.…”

Adipose Tissue Immunometabolism and Apoptotic Cell Clearance

“…In the setting of severe obesity, adipocyte apoptosis is prevalent and adipose tissue macrophages (ATMs) accumulate in the adipose tissue and form so-called crown-like structures around the dying adipocytes [ 35 , 36 ] ( Figure 1 c). As a result of the hypertrophic, lipid-overloaded adipocytes being larger than the ATMs, the ATMs fuse with each other to form a syncytial structure—a “giant”, multinucleated cell—that firmly encapsulates the dying adipocytes [ 37 , 38 ]. ATMs engulf cellular debris, lipid droplets, modified lipids, damage-associated molecules, apoptotic bodies, and fragments of adipocytes that are generated by secondary necrosis ( Figure 1 d) [ 39 ].…”