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Journal of Lipid Research, Vol. 46, 2347-2355, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology
Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans
* Institute of Normal Human Morphology, University of Ancona, Ancona, Italy
Endocrinology Unit, University of Ancona, Ancona, Italy
Division of Medical Genetics, Research Center, Hopital Ste.-Justine, Montreal, Canada
** Obesity and Metabolism Laboratory, Jean Meyer United States Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University, Boston, MA
Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200
1 To whom correspondence should be addressed. e-mail: andrew.greenberg{at}tufts.edu
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-
gene expression.
These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.
Abbreviations: ADRP, adipocyte differentiation-related protein; BMI, body mass index; CLS, crown-like structures; HSL–/–, hormone-sensitive lipase-deficient; MGC, multinucleate giant cell; PPAR
, peroxisome proliferator-activated receptor ; TNF-, tumor necrosis factor-; WAT, white adipose tissue
Supplementary key words obesity • inflammation • apoptosis • necrosis • adipocyte hypertrophy • multinucleate giant cells • insulin resistance • type 2 diabetes
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