Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200

By S. Cinti, G. Mitchell, G. Barbatelli, I. Murano, E. Ceresi, E. Faloia, Shupei Wang, M. Fortier, A. Greenberg, M. Obin. Journal of Lipid Research, 2005

2,409 citations recorded by the source corpus.

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-α gene expression. These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/2ef363e69a6abde6e3635d99e9da280f085caa4e

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Citations in the corpus

Adipocytokines in Obesity and Metabolic Disease (2014, positive): “Infiltrated http://joe.endocrinology-journals.org DOI: 10.1530/JOE-13-0339 2014 Society for Endocrinology Printed in Great Britain macrophages in adipose tissues have also been proposed to be a mechanism to remove apoptotic cells (Cinti et al. 2005, Strissel et al. 2007).”
Adipose Tissue Heterogeneity: Implication of depot differences in adipose tissue for Obesity Complications (2012, background): “CLS are also more numerous in visceral than sc in human (Cinti et al. 2005;Cancello et al. 2006;Harman-Boehm et al. 2007).”
Obesity, inflammation, and atherosclerosis (2009, background): “reported the clustering of macrophages around necrotic fat cells, suggesting that adipocyte death mediates macrophage infiltration and activation in obesity”
Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice (2014, background): “Large increases in adipocyte size (hypertrophy) are associated with recruitment of inflammatory macrophages that express CD11c and MMP-12 and aggregate in inflammatory CLS’ around moribund adipocytes (Cinti et al., 2005; Strissel et al., 2007; Shaul et al., 2010).”
Dietary factors and low-grade inflammation in relation to overweight and obesity (2011, positive): “It appears that macrophage aggregates within the adipose tissue are localised around apoptotic adipocytes, suggesting that one of their functions is to clean up the debris of dying and dead cells((84)).”
Type 2 diabetes as an inflammatory disease (2011, background): “This is readily apparent in mice fed a high-fat diet, as dead adipocytes are located throughout their fat pad”
Chronic Inflammation in Obesity and the Metabolic Syndrome (2010, background): “Macrophage crowns surrounding dead adipocytes in adipose tissue, as shown by Cinti and collaborators [71], are compatible with this hypothesis.”
TNF-α and adipocyte biology (2007, background): “Indeed, obesity in both rodents and humans is associated with increased numbers of apoptotic and necrotic adipocytes in white and brown adipose tissue (WAT and BAT, respectively)[32-34], and one study finds that the majority of macrophages in WAT of obese mice and humans are localised to dead adipoc”
Adipokines: the missing link between insulin resistance and obesity. (2008, background): “[98] Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al.”
Fat Treg cells: a liaison between the immune and metabolic systems (2009, background): “Fat tissue, especially from obese individuals, can host substantial numbers of macrophages, which accumulate in so-called 'crown-like' structures that are replete with dead adipocyte residue”
CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity (2009, background): “In obese epididymal adipose tissues, we found a number of CD8 + cells within 'crown-like structures' (CLSs), which reflect the focal convergence of macrophages surrounding necrotic adipocyte”
Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. (2010, background): “However, in the presence of adipose tissue, isoproterenol induced the expression of the gene Adfp that encodes the lipid droplet protein that coats lipid droplets in ATMs (19).”
Developmental origin of fat: tracking obesity to its source. (2007, positive): “…is not know, recent studies have demonstrated that white fat pads may contain dead or dying adipocytes that are often surrounded by macrophages that 252 Cell 131, October 19, 2007 ©2007 Elsevier Inc. phagocytose the lipid droplets and ultimately form multinucleate giant cells (Cinti et al., 2005).”
What We Talk About When We Talk About Fat (2014, positive): “These macrophages can be observed histologically as ‘‘crown-like structures’’ surrounding adipocytes, particularly in obese visceral fat; their uneven distribution has been attributed to clustering around dead or dying adipocytes (Cinti et al., 2005).”
Increased Infiltration of Macrophages in Omental Adipose Tissue Is Associated With Marked Hepatic Lesions in Morbid Human Obesity (2006, background): “More recently, arrangement of macrophages in a “crown” around single adipocytes exhibiting features of necrosis has been reported in obese subjects (6,11).”