Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
Open accessAbstract
Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.
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Chronic sterile low-grade inflammation is associated with obesity and aging and is thought to be a major contributor to insulin resistance.
“Chronic, sterile, low-grade inflammation is associated with both obesity and aging and is thought to be a major contributing factor for the development of insulin resistance (Fig. 1) (14,52).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [52]
Senescent cells in adipose tissue could drive the macrophage infiltration proposed to contribute to adipose tissue inflammation and insulin resistance in obesity.
“Because the SASP includes macrophage attractant proteins such as MCP-1, it is possible that senescent cells in adipose tissue could be a driver of the macrophage infiltration that has been proposed to play an important role in adipose tissue inflammation leading to insulin resistance in obesity (12,52).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [52]
Vitamin D suppresses TNF-α expression in monocytes and macrophages.
“Vitamin D also suppresses TNF-a expression in monocytes/macrophages (734) and down-regulates the expression of TLR2 and TLR4 in human monocytes (735 -737) .”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [734]
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 [102]
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 [102]
Large clusters of macrophage-related inflammatory genes are significantly altered in obese adipose tissue.
“Supporting this hypothesis, large clusters of macrophage-related inflammatory genes were identified as significantly altered in obese AT (5).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [5]
A macrophage-orchestrated inflammatory response co-exists with obesity-induced insulin resistance.
“these reports also fueled the publication of numerous additional papers, thus firmly establishing the phenomenon of a macrophage-orchestrated inflammatory response co-existing with obesity-induced insulin resistance.”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [5]
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 [5]
Increased expression levels of MCP-1, CXCL14, MIP-1α, MCP-2, MCP-3, and RANTES can be observed in adipose tissue of mice with genetic or diet-induced obesity.
“In particular, increased expression levels of MCP-1, CXCL14, MIP-1α, MCP-2, MCP-3, and RANTES can be observed in AT of mice with genetic or DIO (5,16,18).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [5]
Rodent studies revealed increased levels of macrophage markers in adipose tissue of leptin-deficient, leptin receptor-deficient and diet-induced obese mouse models.
“Rodent studies revealed increased levels of macrophage markers present in AT of leptin-deficient, leptin receptor-deficient and diet-induced obese (DIO) mouse models (5).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [5]
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 [207]
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 [82]
The non-adipose stroma vascular fraction (SVF) of WAT, comprising infiltrated macrophages among other cellular types, is a source of inflammation-related molecules that may exert a local action on adipose tissue biology, particularly within the enlarged WAT.
“Although some molecules secreted by WAT, such as leptin and adiponectin, are synthesized by mature adipocytes [8], the non-adipose SVF, comprising infiltrated macrophages among other cellular types, is a source of inflammation-related molecules that may exert a local action on adipose tissue biology, particularly within the enlarged WAT [9-11].”
From Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity (2008) · cites this paper as [9]
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- Authors
- Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., & Chen, H.
- Affiliations
- Takeda Oncology (United States) (US)
- Corresponding author
- Chen, Hong
- Venue
- Journal of Clinical Investigation
- Published
- 2003-12-15
- Volume
- 112
- Issue
- 12
- Pages
- 1821-1830
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC296998
- OpenAlex
- W2136024338
- Cited by
- 6,760
- References
- 62
- Citations by year
- 2026: 138 · 2025: 177 · 2024: 203 · 2023: 227 · 2022: 257 · 2021: 315 · 2020: 313 · 2019: 347 · 2018: 359 · 2017: 367 · 2016: 401 · 2015: 388 · 2014: 372 · 2013: 499 · 2012: 400
- FWCI
- 103.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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, insulin resistance, chronic inflammation, white adipose tissue, macrophages, high-fat diet-induced obesity, rosiglitazone, adipocyte lipolysis, multinucleated giant cells, adipose tissue macrophage infiltration, inflammatory genes
- MeSH terms
- Rosiglitazone, Adipose Tissue, Animals, Body Weight, Cells, Cultured, Gene Expression Regulation, Immunohistochemistry, Inflammation, Insulin Resistance, Lymphocytes, Macrophages, Male, Mice, Inbred C57BL, Mice, Obese, Models, Biological, Neutrophils, Obesity, RNA, RNA, Messenger, Time Factors, Down-Regulation, Giant Cells, Up-Regulation, In Situ Hybridization, Adipocytes, Reverse Transcriptase Polymerase Chain Reaction, Thiazolidinediones, Mice
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