Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

Saverio Cinti,Grant Mitchell,Giorgio Barbatelli,Incoronata Murano,Enzo Ceresi,Emanuela Faloia,Shupei Wang,Melanie Fortier,Andrew S Greenberg,Martin S Obin

doi:10.1194/jlr.m500294-jlr200

Abstract

Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. The precipitating event(s) and function(s) of macrophage infiltration into WAT are unknown. We demonstrate that >90% of all macrophages in WAT of obese mice and humans are localized to dead adipocytes, where they fuse to form syncytia that sequester and scavenge the residual "free" adipocyte lipid droplet and ultimately form multinucleate giant cells, a hallmark of chronic inflammation. Adipocyte death increases in obese (db/db) mice (30-fold) and humans and exhibits ultrastructural features of necrosis (but not apoptosis). These observations identify necrotic-like adipocyte death as a pathologic hallmark of obesity and suggest that scavenging of adipocyte debris is an important function of WAT macrophages in obese individuals. The frequency of adipocyte death is positively correlated with increased adipocyte size in obese mice and humans and in hormone-sensitive lipase-deficient (HSL-/-) mice, a model of adipocyte hypertrophy without increased adipose mass. WAT of HSL-/- mice exhibited a 15-fold increase in necrotic-like adipocyte death and formation of macrophage syncytia, coincident with increased tumor necrosis factor-alpha gene expression. These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.

Highlights

Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity
These observations demonstrate that 1) the vast majority of WAT macrophages are aggregated in Crown-like structure (CLS) that form around individual adipocytes; and 2) the number of such “inflammatory” adipocytes increases dramatically in obese db/db mice
Bone marrow-derived macrophages accumulate in WAT of obese mice and humans, where they promote adipose and systemic inflammation and the development of obesity-related metabolic complications [5, 7, 38]

Summary

Introduction

Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. Adipocyte death increases in obese (db/db) mice (30-fold) and humans and exhibits ultrastructural features of necrosis (but not apoptosis) These observations identify necrotic-like adipocyte death as a pathologic hallmark of obesity and suggest that scavenging of adipocyte debris is an important function of WAT macrophages in obese individuals. WAT of HSL؊/؊ mice exhibited a 15-fold increase in necrotic-like adipocyte death and formation of macrophage syncytia, coincident with increased tumor necrosis factor-␣ gene expression. These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.—Cinti, S., G. Degradable tissue irritants (i.e., foreign bodies), macrophages remain activated and fuse to form multinucleate giant cells (MGCs) that can persist for weeks or months surrounding the unresolved site. MGCs actively phagocytose debris and can acutely produce proinflammatory cytokines (interleukin-1␣, TNF-␣) until the insult is either cleared by phagocytosis or encapsulated [12]

Methods

Results

Conclusion