The DOI matches its Crossref record; 128 of the 128 references it cites were found in a registry or an index; none of the 138 sources its claims cite is checked for support yet.
The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.
Open accessAbstract
There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential. The interactions of these processes during AT expansion reflect both a linear progression as well as feed-forward mechanisms. For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis. Therefore, the relationship between the members of this triad is complex but important for our understanding of the pathogenesis of obesity. Here we untangle some of these intricacies to highlight the contributions of inflammation, angiogenesis, and the ECM to both "healthy" and "unhealthy" AT expansion.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that obesity-associated adipose tissue dysfunction arises from an ominous triad of unresolved inflammation, fibrosis/ECM remodeling, and impaired angiogenesis, with hypoxia and cellular senescence as key drivers. It synthesizes rodent and human evidence to distinguish early “healthy” adipose expansion from chronic pathologic remodeling.
Key findings
- Early high-fat feeding triggers mild hypoxia that can drive adaptive angiogenesis, ECM remodeling, and balanced inflammation; chronic overnutrition leads to persistent hypoxia, fibrosis, senescence, necrotic adipocyte death, and unhealthy adipose expansion.
- In rodents, one week of high-fat feeding can increase adipocyte triglyceride storage four-fold, double visceral adipose weight within one week, and cause macrophage infiltration within one day; over 12 weeks, adipocyte size increases three-fold in inguinal and seven-fold in epididymal fat, while dead epididymal adipocytes rise from 0.1% at one week to as much as 16% at 12 weeks.
- HIF-1α and HIF-2α have opposing roles: HIF-1α is pro-angiogenic but also pro-fibrotic and proinflammatory and dominates in obesity, whereas HIF-2α attenuates HFD-induced inflammation; PHD1 KO mice show greater fat pad mass and impaired glucose tolerance, while adipocyte-specific PHD2 deletion produces resistance to HFD-induced obesity and improved glucose tolerance/insulin sensitivity despite elevated HIF-1α and HIF-2α.
- Human data are conflicting: VEGF is reported as reduced in obese humans but also elevated and correlated with insulin resistance; most human studies report fibrosis in obese AT, yet some find less visceral fibrosis in diabetic or metabolically unhealthy obese subjects; about 40% of patients had elevated AT inflammation 12 months after bariatric surgery.
Methods
- Design: narrative review, not a primary research study; no original experiments or systematic review methodology are described.
- Data/sample: synthesizes cited rodent models (e.g., HFD feeding, ob/ob, PHD knockouts, VEGF manipulations) and human studies of obesity, insulin resistance, bariatric surgery, and adipose tissue biopsies.
- Main analysis: conceptual integration of inflammation, ECM/fibrosis, angiogenesis, hypoxia signaling, and cellular senescence into a model of healthy versus unhealthy adipose tissue expansion, with two summary figures.
Limitations
- Stated: the exact roles of HIF-1α and HIF-2α in adipose expansion require further study; mechanisms of pathologic angiogenesis in obesity are not fully understood; it is debated whether human adipose oxygen tension is low enough to be called hypoxic; no consensus exists on how to define fibrosis; and several key questions remain about angiogenic mechanisms, stages of expansion, depot-specific effects, and combination therapies.
- Evident: as a narrative review, it lacks a described systematic search strategy, inclusion criteria, or quantitative synthesis, so conclusions depend on selected cited studies.
- Evident: the human literature cited is heterogeneous and contradictory, especially for VEGF, inflammation, and fibrosis, limiting definitive translation from rodent models.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 138 cited sources checked · 0 supported · 0 flagged
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The current pervasive state of chronic overnutrition results in an increase in unresolved AT hypoxia.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“as CD8 + T cell infiltration has been observed to precede and induce AT macrophage accumulation in other settings (11).”
What the sources say
- Not checked yetcites [11] source
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“In contrast, HIF-2α attenuates HFD-induced inflammation (3).”
What the sources say
- Not checked yetcites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Although few studies have directly addressed the effect of mild hypoxia during early AT expansion on AT inflammatory processes, there have been reports of both pro-and antiinflammatory responses during the first four days of HFF.”
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Interestingly, populations of white adipocyte progenitors have been identified in the mural compartment of vascular structures.”
What the sources say
- Not checked yetcites [20] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Gupta et al. used a genetic reporter mouse driven by the promoter of a transcription factor that is important for pre-adipocyte determination, ZFP423, to demonstrate a perivascular origin of pre-adipocytes for both white and brown ATs (21)(22)(23).”
What the sources say
- Not checked yetcites (21)(22)(23)
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As an early event in AT expansion, hypoxia likely plays a fundamental role in the initiation of inflammation.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Tang et al. demonstrated that these mural cells with high adipogenic potential can be identified by expression of PDGFR-β (20).”
What the sources say
- Not checked yetcites [20] source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Adipocytes release proinflammatory factors such as IL-6 and macrophage migration inhibitory factor (12).”
What the sources say
- Not checked yetcites [12] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“There is no direct evidence for the existence of these types of angiogenesis in obese adult AT, but we could speculate that distinct angiogenic mechanisms participate during AT expansion and are dependent on the extent of hypoxia and the complex regulation in early or late stages of expansion.”
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- It may state two separate claims as one. 61
- Probably not a substantial claim. 12
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At some point during the progression of obesity, adipose depots expand beyond the tissue's capacity for adequate angiogenesis, resulting in persistent hypoxia, fibrosis, cellular senescence, and necrotic adipocyte death (Figure 1)”
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None of the sources cited for this claim have been checked yet.
In the paper
“For example, VEGF is upregulated in AT of mice fed a HFD for three days, but there are reports of both enhanced and reduced VEGF expression in chronic obesity (3,13,43,44), suggesting that sprouting angiogenesis is activated early and may or may not persist.”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Macrophages are responsible for many housekeeping processes, such as removal of apoptotic and necrotic cells, modulation of angiogenesis, ECM remodeling, and differentiation of adipocyte precursors (8).”
What the sources say
- Not checked yetcites [8] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The actions of NKT cells are likely beneficial for the adaptation of AT to acute HFF because mice deficient in CD1d do not activate AT NKT cells and display exacerbated insulin resistance (17).”
What the sources say
- Not checked yetcites [17] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Pathologic activation of both innate and adaptive immunity has been observed during obesity, even though the degree to which each component participates differs temporally.”
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“HIF-1α activation is classically described as pro-angiogenic, but recent studies have shown it to also be pro-fibrotic and proinflammatory (4).”
What the sources say
- Not checked yetcites [4] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“For example, circulating stem cells can contribute to adipogenesis (19).”
What the sources say
- Not checked yetcites [19] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For instance, ApoE3-Leiden mice, which exhibit a more humanized lipid metabolism compared with WT mice, display increased acute-phase response genes within one week of HFF, whereas chronic inflammatory responses are increased after six weeks of HFF (2).”
What the sources say
- Not checked yetcites [2] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“VEGF is a major regulator of sprouting angiogenesis (42).”
What the sources say
- Not checked yetcites [42] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Within three days of HFF, rapid adipocyte hypertrophy along with mitochondrial uncoupling increase the demand for oxygen and reduce oxygen availability (3).”
What the sources say
- Not checked yetcites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ensuing hypoxia is mild but induces a stress signal that drives angiogenesis and remodeling of the extracellular matrix (ECM) to facilitate further expansion of AT and reduce hypoxia (Figure 1).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Among these factors, the VEGF-A/VEGFR2 signaling pathway is considered to play a particularly important role in angiogenesis and is one of the most potent activators of beiging in the subcutaneous depots of rodents.”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Immune cells, particularly monocytes, migrate to areas of hypoxia, where they differentiate into proinflammatory macrophages (13,14).”
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None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, others have reported that acute HFD stress leads to activation of antiinflammatory macrophages (17,18).”
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PHD1 KO mice exhibit a greater fat pad mass and impaired glucose tolerance but do not show exacerbated diet-induced metabolic changes compared with WT mice (6).”
What the sources say
- Not checked yetcites [6] Thomas, 2016, Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice, Sci Rep source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“that acute HFF induces antiinflammatory immune cell actions, cell repair signaling, and angiogenesis (1,17,18).”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Macrophages comprise the largest population of resident immune cells in visceral AT, constituting up to 10% of AT cells in mice (10).”
What the sources say
- Not checked yetcites [10] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Angiogenesis can be divided into two major subtypes: (a) sprouting angiogenesis, which is slow and the major developmental form of vessel growth and (b) looping/splitting angiogenesis, which is fast and occurs predominantly during adult wound healing.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Although HIF-1α and HIF-2α pathways can interact, HIF-1α signaling dominates in obesity, playing a causative role in early AT dysfunction (3).”
What the sources say
- Not checked yetcites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Adipocytes respond by inducing glycolysis and angiogenesis in an attempt to alleviate the hypoxia (3).”
What the sources say
- Not checked yetcites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“In contrast, adipocyte-specific deletion of PHD2 produces mice that are resistant to HFD-induced obesity and, despite elevated levels of both HIF-1α and HIF-2α, the mice display improved glucose tolerance and insulin sensitivity (7).”
What the sources say
- Not checked yetcites [7] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although a proinflammatory program is activated during early AT expansion, the immune response is dominated by antiinflammatory signals.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“Thus, in early AT expansion, there is a strong ECM degradation signal to promote AT growth, which is important for maintaining whole body metabolic homeostasis (49).”
What the sources say
- Not checked yetcites [49] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Furthermore, the actions of MMP-9 both break down the fibrous collagen matrix to make space for new blood vessels and release matrix-bound VEGF (53).”
What the sources say
- Not checked yetcites [53] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Genetic introduction of dominant-active HIF-1α in mice was unable to induce an angiogenic response but instead increased the expression of several fibrotic genes (4).”
What the sources say
- Not checked yetcites [4] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, both ANG-2 and VEGF-A promote an antiinflammatory macrophage polarization (60,61).”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Indeed, it has been argued that the oxygen tension in AT is not low enough to be defined as hypoxic (84).”
What the sources say
- Not checked yetcites [84] source
Strength:hedged· not yet calibratedTests✗ Asserted: fails✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
In the paper
“Men fed a high-calorie diet for one week gained significant weight accompanied with insulin resistance (77).Oxidative damage was detected in AT biopsies without an increase in inflammatory cell markers.”
What the sources say
- Not checked yetcites [77] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“ANG-2 binds the endothelial cell RTK Tie2, activating endothelial cell migration and proliferation, but also initiating an NF-κB-dependent inflammatory signaling cascade (59).”
What the sources say
- Not checked yetcites [59] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been suggested that the production of ROS and RNS by immune cells contribute to the oxidative damage observed in obese AT (74,75).”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Increased oxidative stress and reduced antioxidant defense have been demonstrated in obese AT (74).”
What the sources say
- Not checked yetcites [74] source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Adipose-specific overexpression of a dominant-negative form of TNF-α causes severe glucose intolerance and a reduction in the insulin-sensitizing adipokine adiponectin in mice fed a HFD (82).”
What the sources say
- Not checked yetcites [82] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although the majority of studies have shown that obese AT is hypoxic, we do not know if the degree of hypoxia is sufficient to enforce persistent angiogenesis, particularly in human AT.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Blood vessels facilitate the physical infiltration of macrophages and leukocytes into tissues.These cells in turn promote endothelial cell proliferation and new blood vessel formation by secreting pro-angiogenic factors (54)(55)(56).”
What the sources say
- Not checked yetcites (54)(55)(56)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bona fide fibrosis, defined as excessive ECM protein deposition, is a pathological consequence of long-term obesity, but acute ECM remodeling is essential for early healthy AT expansion.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Interestingly, unlike acute AT expansion, the hypoxia response of obese ob/ob mice fails to induce VEGF expression, and instead a decrease in vascular density is observed (4).”
What the sources say
- Not checked yetcites [4] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Many ECM molecules, such as hyaluronic acid (HA), signal through direct binding of cell receptors (45).”
What the sources say
- Not checked yetcites [45] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Other factors produced by inflammatory cells have since been shown to inhibit insulin signaling in the adipocyte including IL-6, IFN-γ and CCL2 (72,73).”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“As in obese AT, tumor vasculature is significantly more permeable than that of normal tissue (87), a characteristic that promotes immune cell extravasation and fibrosis.”
What the sources say
- Not checked yetcites [87] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example collagen VI is cleaved at the C5 domain of the α3 subunit and the resulting peptide induces multiple processes including increasing collagen deposition, endothelial cell migration and macrophage infiltration (46,47).”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It downregulates the major insulin-responsive glucose transporter GLUT4 and inhibits insulin-dependent tyrosine phosphorylation of the insulin receptor and IRS-1 through ceramide production (70,71).”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In mice, the chronology of oxidative stress and inflammation onset is not known; however, treatment of mice with antioxidants can attenuate diet-induced inflammation and insulin resistance, suggesting a strong influence of oxidative stress on obesity-associated disease (78)(79)(80).”
What the sources say
- Not checked yetcites (78)(79)(80)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Under the persistent metabolic challenge of chronic HFF, the demand for oxygen is great but the capacity to form new blood vessels is poor.The consequence is disorganized and pathologic angiogenesis; however, the underlying mechanisms are not fully understood.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The prevention of cellular senescence through inhibition of the major senescence regulator p53 attenuates metabolic abnormalities (102, 103).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Additionally, a recent study suggested treatment with docosahexaenoic acid might improve insulin resistance through attenuation of AT angiogenesis (90).”
What the sources say
- Not checked yetcites [90] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This study established a strong link between cell senescence and obesity by demonstrating that inducing genomic instability through ablation of polymerase η increased the number of senescent AT cells and exacerbated AT dysfunction.”
What the sources say
- Not checked yetcites [102] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fibrosis occurs during chronic obesity and has been accepted as a major contributor to obesity-associated AT dysfunction.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Although growth arrested, senescent cells are highly metabolic and exhibit a senescence-associated secretory phenotype (SASP), producing factors that have profound effects on neighboring cells such as proinflammatory cytokines (IL-6, IL-8, TNF-α, monocyte chemoattractant protein 1 [MCP-1]), VEGF, MMPs, and PDGF-AA (100).”
What the sources say
- Not checked yetcites [100] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In HFD-challenged mice, VEGF-A significantly increased WAT vascularization and beiging, which augmented energy expenditure and prevented unfavorable metabolic changes, while blockade of VEGF-A/VEGFR2 caused aggravated systemic insulin insensitivity.”
What the sources say
- Not checked yetcites [22] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Increased AT DNA damage and resulting cellular senescence have been identified in mice fed a HFD for 20 weeks (102).”
What the sources say
- Not checked yetcites [102] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Additionally, HA accumulates in insulin-resistant AT in obese mice and is thought to negatively regulate adipocyte insulin signaling (96).”
What the sources say
- Not checked yetcites [96] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“In this model, the loss of senescent cells blunted age-related fat loss and enhanced adipogenic transcription factor expression within three weeks.”
What the sources say
- Not checked yetcites [101] Xu, 2015, Targeting senescent cells enhances adipogenesis and metabolic function in old age, Elife source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Weisberg et al. demonstrated that subcutaneous AT macrophage infiltration was increased in obese patients, similar to that observed in obese mice (10).”
What the sources say
- Not checked yetcites [10] source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SASP has recently been shown to have a beneficial effect on wound healing by recruiting immune cells to clear dead cells, promote angiogenesis, limit fibrosis, and stimulate wound closure (100, 111, 112).”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In contrast, in ob/ob mice with pre-existing obesity, inhibiting the VEGF-A/ VEGFR2 signaling pathway resulted in improved insulin sensitivity and decreased body weight.”
What the sources say
- Not checked yetcites [22] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Cells undergo so-called replicative senescence during natural aging when they have reached the genetically determined limit of division.”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Systemically, the circulating endothelial cell precursor population undergoes premature senescence in obese individuals (107), contributing to the impairments in vascular function and repair observed in obesity.”
What the sources say
- Not checked yetcites [107] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Senescent cells can originate from most cell types and are potent modulators of inflammation, angiogenesis, and fibrosis.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Mice genetically deficient in interferon regulatory factor 5 display enhanced expansion of subcutaneous AT but limited expansion of visceral AT on a HFD (98).”
What the sources say
- Not checked yetcites [98] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although deposition of fibrous collagen proteins is well known to promote metabolic dysfunction in obesity, many other ECM components are dysregulated in obese AT.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Upregulation of HIF-1α also increases the fibrotic program in AT.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“However, contradictory reports have demonstrated elevated levels of VEGF in obese subjects as well as a positive correlation between VEGF expression and insulin resistance (43).”
What the sources say
- Not checked yetcites [43] Tinahones, 2012, Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels, BMC Physiol source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The integrated responses among those three factors promote significant hypotrophy in adipose tissue, and the consequence is an unhealthy AT expansion as well as obesity-associated metabolic consequences.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Similar to findings in mice, human studies have reported that VEGF expression is reduced in obese humans (13).”
What the sources say
- Not checked yetcites [13] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hypoxia during early AT expansion induces stress signaling that facilitates angiogenesis via upregulation of an array of genes including VEGF, initiates inflammatory cell infiltration, and induces organized ECM remodeling to encourage appropriate AT expansion.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“Less fibrosis was associated with adipocyte hypertrophy, reduced pre-adipocyte hyperplasia, and AT dysfunction (122).”
What the sources say
- Not checked yetcites [122] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the role of ECM remodeling and fibrosis in human AT dysfunction is stage dependent and likely fat depot specific.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This hypoxic condition fails to induce VEGF, resulting in impaired angiogenesis.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Chronic obesity can cause AT oxidative stress, DNA damage, and increased exposure to high glucose and ceramide concentrations.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
The paper relies on this without support.
Rodent models of diet-induced and genetic obesity are sufficiently representative of human obesity-associated adipose tissue dysfunction for the review's conclusions.
“Long-term HFF results in abnormal regulation of VEGF-A expression; not only do the VEGF-A levels decrease in the AT of obese mice and humans (13), but there is also evidence that the presence of VEGF in obese mice can block the regulation of neovascularization and vessel normalization (83).”
The paper relies on this without support.
The role of cellular senescence in obesity-associated disease is not well understood.
“Little is known about the role of cellular senescence in obesity-associated disease.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Impaired insulin-mediated inhibition of lipolysis is further exacerbated by AT dysfunction (Crewe et al., 2017).”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Crewe et al., 2017
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“AT dysfunction and the resulting impaired AT expandability cause local and systemic low-grade inflammation, fat overflow, and ectopic fat deposition, all of which are associated with insulin resistance”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Crewe et al., 2017
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“These cells are responsible for adipogenesis, angiogenesis, extracellular matrix modeling, and regulation of inflammation and, hence, contribute to both the function and dysfunction of AT (Crewe et al., 2017).”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Crewe et al., 2017
The cited source says what the claim attributes to it.
In the citing paper
“which is characterized by an unhealthy AT expansion characterized by the presence of hypertrophic adipocytes, excessive accumulation of extracellular matrix (ECM) components, interstitial fibrosis, exaggerated pro-inflammatory macrophage infiltration, and dysregulated angiogenesis”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Crewe et al., 2017
In the citing paper
“ECM expansion occurs in adipose tissue of obese subjects and limits adipocyte fat storage,185 leading to ectopic fat stores in liver and skeletal muscle, lipotoxicity, oxidative stress, and inflammation.186”
From The Vasculature in Prediabetes (2018) · cites this paper as [185]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure describes adipose-tissue shrinkage and expansion together
MinorThe Figure 1 caption says the combined responses cause significant hypotrophy, or reduced tissue size, but then describes their consequence as adipose-tissue expansion.
“The integrated responses among those three factors promote significant hypotrophy in adipose tissue”
“and the consequence is an unhealthy AT expansion as well as obesity-associated metabolic consequences.”
Citations
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Inflammatory mechanisms linking obesity and metabolic disease
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Metadata
- Authors
- Crewe, C., An, Y. A., & Scherer, P. E.
- Corresponding author
- Scherer, Philipp E.
- Venue
- Journal of Clinical Investigation
- Published
- 2017-01-03
- Volume
- 127
- Issue
- 1
- Pages
- 74-82
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5199684
- OpenAlex
- W2563017338
- Semantic Scholar
- 05df31fe5ca54d54369bca71ae47034f71f0f3f6
- Cited by
- 732
- References
- 128
- Citations by year
- 2026: 76 · 2025: 70 · 2024: 92 · 2023: 95 · 2022: 102 · 2021: 89 · 2020: 79 · 2019: 53 · 2018: 51 · 2017: 21
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (CPRIT RP140412, RP140412)
- National Institute on Aging (P01AG051459)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055758, P01DK088761, R01DK099110)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- adipose tissue dysfunction, obesity, adipose tissue inflammation, adipose tissue fibrosis, angiogenesis, extracellular matrix remodeling, immune cell infiltration, adipose tissue expansion, feed-forward mechanism
- MeSH terms
- Adipose Tissue, Animals, Fibrosis, Humans, Inflammation, Neovascularization, Physiologic
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