Obesity is associated with macrophage accumulation in adipose tissue
Open accessAbstract
Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications.To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (A y ) and obese (Lep ob ).We found that the expression of 1,304 transcripts correlated significantly with body mass.Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass.Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80 + ) was significantly and positively correlated with both adipocyte size and body mass.Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68.Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1 op/op ) mice suggest that these F4/80 + cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages.Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-α expression and significant amounts of iNOS and IL-6 expression.Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.
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Aging is associated with macrophage infiltration into primarily visceral adipose depots which drives a pro-inflammatory state and further increases adipose dysfunction.
“Aging is also associated with macrophage infiltration into primarily visceral adipose depots which drives a pro-inflammatory state and further increases adipose dysfunction (40).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [40]
The Discussion (pp. 10–11) links macrophage accumulation to adiposity and suggests it may increase inflammatory-molecule production and affect adipose function. It does not establish an association with aging; it examines both visceral and subcutaneous depots rather than showing infiltration occurs primarily in visceral fat. The claim also states the proposed effects more definitively than the paper does. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMetabolic syndrome is associated with significant macrophage accumulation in adipose tissue.
“As metabolic syndrome is associated with significant macrophage accumulation in adipose tissue,69”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [69]
The Discussion (p. 10) reports that adipose-tissue macrophage accumulation increases with measures of adiposity in mice and humans. The paper establishes this association for obesity, but the cited passages do not establish it for metabolic syndrome as a distinct condition. (LLM, conf=0.88)
Experimental — accuracy not yet measuredActivated monocytes that give rise to M1 and M2 macrophages produce more inflammatory compounds that probably appear in the circulation.
“Activated monocytes that give rise to M1 and M2 macrophages produce even more inflammatory compounds that probably appear in the circulation57.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [57]
In adipose tissue from lean subjects, approximately 10% of cells stained positive for macrophages, but in obese subjects, this number increased to up to 50%.
“In adipose tissue from lean subjects, approximately 10% of cells stained positive for macrophages, but in obese subjects, this number increased to up to 50% [38].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [38]
More than 40% of total adipose tissue cell content from obese rodents and humans is comprised of macrophages, compared with approximately 10% in lean counterparts.
“In fact, more than 40% of the total adipose tissue cell content from obese rodents and humans was comprised of macrophages compared with approximately 10% in lean counterparts (101).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [101]
Macrophages are responsible for the majority of Tnfa expression in adipose tissue and contribute significantly to Il6 and Ikbkb expression.
“In addition, macrophages were responsible for the majority of Tnfa expression in adipose tissue and contributed significantly to Il6 and Ikbkb expression (101, 102).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [101]
Adipose tissue from obese mice and humans is infiltrated with macrophages.
“In 2003, the novel discovery that adipose tissue from obese mice and humans is infiltrated with macrophages provided a major mechanistic advance into understanding how obesity propagates inflammation (101, 102).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [101]
The intermuscular adipose depot in skeletal muscle has about three times more macrophages in obese mice than in lean mice.
“Moreover, this intermuscular adipose depot is infiltrated with approximately 3 times more macrophages in skeletal muscle from obese compared with lean mice (101).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [101]
These adipokine changes include increased production of inflammatory cytokines, plasminogen activator inhibitor-1, and other bioactive products, while the protective adipokine adiponectin is reduced.
“These include increased production of inflammatory cytokines, 35,36 plasminogen activator inhibitor-1, 37 and other bioactive products 38 -40 ; at the same time the potentially protective adipokine, adiponectin, is reduced.41,42”
From Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement (2005) · cites this paper as [36]
Macrophages constitute up to 10% of adipose tissue cells in mice and are the largest population of resident immune cells in visceral adipose tissue.
“Macrophages comprise the largest population of resident immune cells in visceral AT, constituting up to 10% of AT cells in mice (10).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [10]
Subcutaneous adipose tissue macrophage infiltration is increased in obese patients, as it is in obese mice.
“Weisberg et al. demonstrated that subcutaneous AT macrophage infiltration was increased in obese patients, similar to that observed in obese mice (10).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [10]
Visceral adipose tissue macrophage counts are higher in insulin-resistant obese patients than in lean or insulin-sensitive obese patients.
“Several detailed studies have also reported a higher macrophage count in visceral AT of insulin-resistant obese patients compared with lean or insulin-sensitive obese counterparts, an effect that was significantly mitigated following bariatric surgery (10,(114)(115)(116).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [10]
Bariatric surgery significantly reduces the elevated visceral adipose tissue macrophage count in insulin-resistant obese patients.
“Several detailed studies have also reported a higher macrophage count in visceral AT of insulin-resistant obese patients compared with lean or insulin-sensitive obese counterparts, an effect that was significantly mitigated following bariatric surgery (10,(114)(115)(116).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [10]
The combination of microhypoxia and lipid overload triggers the recruitment of immune cells, such as macrophages in adipose tissue, and their activation.
“The combination of microhypoxia and lipid overload triggers the recruitment of immune cells, such as macrophages in the adipose tissue and their activation ([103](#B103), [129](#B129), [171](#B171)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [171]
Infiltration of macrophages into expanding adipose tissue is an important physiological phenomenon.
“In 2003, two independent articles in the JCI highlighted the infiltration of macrophages into expanding AT as an important physiological phenomenon (5,6).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [6]
Excess body adiposity is associated with activation of macrophages and associated inflammation in white adipose tissue, liver, skeletal muscle and the vasculature, and eventually with increased circulating plasma levels of pro-inflammatory cytokines.
“Excess body adiposity has been associated with activation of macrophages and associated inflammation in a variety of peripheral tissues including WAT, liver, skeletal muscle and the vasculature and eventually is accompanied by increased circulating plasma levels of pro-inflammatory cytokines (193, 207).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [193]
Visceral adipose tissue has an increased number of adipose resident macrophages.
“Visceral adipose tissue has an increased number of adipose resident macrophages.”
From The Vasculature in Prediabetes (2018) · cites this paper as [81]
Increased recruitment of pro-inflammatory macrophages to muscle and adipose results in transforming growth factor β (TGFβ)-mediated fibrosis.
“Increased recruitment of pro-inflammatory macrophages to muscle167 and adipose81 results in transforming growth factor β (TGFβ)-mediated fibrosis.168”
From The Vasculature in Prediabetes (2018) · cites this paper as [81]
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- Authors
- Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Corresponding author
- Ferrante, Anthony W.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-12-15
- Volume
- 112
- Issue
- 12
- Pages
- 1796-1808
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC296995
- OpenAlex
- W2008869160
- Cited by
- 10,041
- References
- 99
- Citations by year
- 2026: 265 · 2025: 337 · 2024: 420 · 2023: 373 · 2022: 460 · 2021: 504 · 2020: 524 · 2019: 494 · 2018: 536 · 2017: 537 · 2016: 530 · 2015: 558 · 2014: 575 · 2013: 683 · 2012: 554
- FWCI
- 130.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Clinical Investigation (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Russell Berrie Foundation
- National Institutes of Health (K08 DK)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK064773, R01DK052431, K08DK059960, R01DK066525)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- obesity, adipose tissue macrophages, macrophage accumulation, perigonadal adipose tissue, F4/80, CD68, bone marrow-derived macrophages, adipose tissue inflammation, TNF-α, inducible nitric oxide synthase, interleukin-6, adipocyte size, body mass, subcutaneous adipose tissue
- MeSH terms
- CD68 Molecule, Adipose Tissue, Animals, Body Weight, Cell Separation, Female, Flow Cytometry, Humans, Immunohistochemistry, Liver, Macrophages, Male, Mice, Inbred C57BL, Obesity, RNA, Messenger, Time Factors, Tumor Necrosis Factor-alpha, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Interleukin-6, Immunophenotyping, Leukocyte Common Antigens, Nitric Oxide Synthase, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice, Nitric Oxide Synthase Type II
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