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Cited by 1,941Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismCardiovascular Disease and Adiposity

Adipose tissue remodeling and obesity

Open access
Sun, Kai, Kusminski, Christine M., Scherer, Philipp E.·2011·Journal of Clinical Investigation
DOI 10.1172/jci45887PMC PMC3104761
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Abstract

To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that adipose tissue expansion is a highly coordinated remodeling process involving adipocytes, endothelial precursors, immune cells, and preadipocytes, and that hypoxia is an early determinant distinguishing healthy from pathological expansion. It draws explicit parallels between adipose expansion and solid tumor growth, noting that interventions promoting healthy adipose adaptation might also promote tumor growth.

Key findings

  • Adipose tissue can expand almost without limit in a non-transformed state, but adipocytes rapidly reach the diffusional limit of oxygen; hypoxia is therefore an early determinant limiting healthy expansion, and obese white adipose tissue O₂ tension can fall to as low as 15 mmHg versus 45–50 mmHg in lean tissue.
  • Four proposed mechanisms initiate macrophage infiltration into expanding adipose tissue: adipocyte death (with crown-like structures surrounding necrotic adipocytes), chemotactic regulation (e.g., MCP-1/CCR2), hypoxia, and fatty acid flux (FFAs as TLR4 ligands).
  • Obesity involves a phenotypic switch in adipose tissue macrophages from an anti-inflammatory M2 state (F4/80, CD301, IL-10, arginase 1) to a proinflammatory M1 state (F4/80, CD11c, TNF-α, IL-6, iNOS, CCR2); conditional ablation of CD11c⁺ macrophages in high-fat-diet-fed obese mice produced rapid whole-body normalization of insulin sensitivity.
  • In high-fat-diet-fed mice, approximately 80% of adipocyte death was evident in epididymal adipose tissue at 16 weeks, falling to approximately 16% at 20 weeks alongside emergence of smaller adipocytes (<5,000 μm²), suggesting an initial necrotic wave followed by hyperplastic expansion; acute weight loss, a 24-hour fast, or β3-adrenergic lipolysis induction caused transient macrophage accumulation (up to 65% increase in infiltration).
  • Using ¹⁴C tracing, the average adipocyte half-life was estimated at approximately 8.3 years, with new adipocytes constantly replacing lost ones; adipocyte diameter can reach 150–200 μm, exceeding average tissue O₂ diffusion distance.

Methods

  • Narrative review article; no primary experimental data are reported. The authors synthesize published literature on adipose tissue remodeling, macrophage biology, hypoxia/HIF-1 signaling, angiogenesis, and extracellular matrix dynamics.
  • Evidence cited includes rodent models (leptin-deficient, leptin receptor-deficient, diet-induced obese, and transgenic HIF-1α-ΔODD and inducible lipoatrophy mice), human clinical observations, and in vitro adipocyte systems.
  • The authors also describe their own prior transgenic mouse work (adipocyte-specific dominant-active HIF-1α-ΔODD), in which classical HIF-1α targets such as VEGF-A were not induced; instead an enhanced fibrotic response was observed (upregulation of lysyl oxidase, elastin, collagens I and III, TIMP1, and connective tissue growth factor).

Limitations

  • The paper states no formal limitations section; as a narrative review it does not describe a systematic search strategy or inclusion criteria (evident from the text).
  • The authors explicitly note unresolved questions, including the precise temporal steps of macrophage recruitment to expanding fat pads, whether adipocytes in vivo preferentially undergo necrosis versus apoptosis (described as technically difficult to determine), and the precise function of angiopoietins in adipose tissue, which "has not been directly examined."
  • The text notes conflicting evidence on adiponectin's angiogenic role, stating that anti-angiogenic findings rely on recombinant protein preparations of variable quality and that other in vivo studies suggest pro-angiogenic effects; much of the mechanistic evidence derives from rodent models.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci45887

Cites

109 of 109 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 129 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Massive adipocyte death can drive rapid accumulation of adipose tissue macrophages as an integral element in the remodeling of fat pads.

    “Using a transgenic model of inducible lipoatrophy, we have previously demonstrated that massive adipocyte death can indeed drive rapid accumulation of ATMΦs as an integral element in the remodeling of fat pads (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

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  • Findingcitation

    In a transgenic mouse model overexpressing a dominant active deletion mutant of HIF-1α specifically in adipocytes, the model failed to induce classical HIF-1α targets such as VEGF-A.

    “To investigate the effects of HIF-1α in white AT, we analyzed a transgenic mouse model in which we overexpressed a dominant active (degradation-resistant) deletion mutant of HIF-1α (HIF-1α-ΔODD) specifically in adipocytes (4).Unexpectedly, our model failed to induce any classical HIF-1α targets, such as VEGF-A.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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  • Findingown data

    The most striking alteration observed in the HIF-1α-ΔODD model was an enhanced fibrotic response, including upregulation of lysyl oxidase, elastin, collagens I and III, tissue inhibitor of metalloproteinase I, and connective tissue growth factor.

    “The most striking alteration we observed in this model was an enhanced fibrotic response, which included an upregulation lysyl oxidase (LOX), elastin, collagens I and III, tissue inhibitor of metalloproteinase I, and connective tissue growth factor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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  • Findingcitation

    In the HIF-1α-ΔODD transgenic mouse model, there were no increases in key components of the angiogenic or anaerobic glycolytic programs.

    “Moreover, we did not detect any increases in key components of the angiogenic or anaerobic glycolytic programs (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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  • Findingcitation

    Adiponectin has potent angiomimetic properties in tumor vascularization.

    “Using a genetic approach, our laboratory identified that adiponectin has potent angiomimetic properties in tumor vascularization (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] source

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  • May combine two claims. 37
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    A healthy murine epididymal fat pad has densely packed, hexagonal adipocytes and limited immune cell infiltration.

    “Trichrome stain of a healthy murine epididymal fat pad with densely packed, hexagonal adipocytes and limited immune cell infiltration”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An unhealthy ob/ob epididymal fat pad contains a high level of immune cell infiltration and enhanced ECM.

    “Trichrome stain of an unhealthy ob/ob epididymal fat pad, containing a high level of immune cell infiltration and enhanced ECM (blue areas)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AT remodeling is an ongoing process that is pathologically accelerated in the obese state, and features such as reduced angiogenic remodeling, ECM overproduction, heightened immune cell infiltration and subsequent proinflammatory responses prevail in many obese fat-pads.

    “AT remodeling is an ongoing process that is pathologically accelerated in the obese state, and thus, features such as reduced angiogenic remodeling, ECM overproduction, a heightened state of immune cell infiltration and subsequent proinflammatory responses prevail in many obese fat-pads (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] source

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  • May combine two claims.

    Premisecitation

    A 24-hour fast in a mouse is associated with a dramatic loss of adipose tissue mass and an acute remodeling process that involves rapid infiltration of macrophages.

    “A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages;”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

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  • May combine two claims.

    Interpretationreasoning

    Adipocytes can rapidly reach the diffusional limit of oxygen during growth, and hypoxia is therefore an early determinant that limits healthy adipose tissue expansion.

    “Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HIF-1 is a master regulator of hypoxia and oxygen homeostasis.

    “A master regulator of hypoxia and oxygen homeostasis is HIF-1 (26,27).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] source

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    • cites [27] source

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  • May combine two claims.

    Interpretationown data

    As a result of the aberrant HIF-mediated transcriptional program, ECM in white adipose tissue accumulates fibrillar collagens, and the upregulation of ECM causes local fibrosis.

    “As the result of this aberrant HIF-mediated transcriptional program, we proposed that the ECM in white AT accumulates fibrillar collagens; the upregulation of ECM thus causes local fibrosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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  • May combine two claims.

    Premisecitation

    FFAs can serve as ligands for the TLR4 complex, thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives adipose tissue macrophage accumulation.

    “However, FFAs can also serve as ligands for the TLR4 complex (33), thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives ATMΦ accumulation (34,35).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [33] source

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    • cites [34] source

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    • cites [35] Nguyen, 2005, J Biol Chem. source

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  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    Necrosis of adipocytes, driven by hypertrophy and accelerated by obesity, is a prominent phagocytic stimulus that regulates adipose tissue macrophage infiltration.

    “Cinti and colleagues hypothesized that necrosis of adipocytes, driven by hypertrophy and accelerated by obesity, is a prominent phagocytic stimulus that regulates ATMΦ infiltration (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Cinti, 2005, J Lipid Res. source

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  • May combine two claims.

    Premisecitation

    Weight reduction regimens result in a lowering of inflammatory markers, suggesting that macrophage infiltration is reversible.

    “Conversely, weight reduction regimens resulted in a lowering of inflammatory markers, which suggested that this infiltration is reversible (7).”
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    • cites [7] source

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  • May combine two claims.

    Interpretationreasoning

    While the four mechanisms of macrophage recruitment and infiltration into adipose tissue may act independently, the metabolic and inflammatory pathways are tightly interconnected.

    “While these four mechanisms of macrophage recruitment and infiltration into AT may act independently, the metabolic and inflammatory pathways are tightly interconnected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Conditional ablation of CD11c+ macrophages in the adipose tissue of high-fat-diet-fed obese mice results in a profound reduction of proinflammatory ATM accumulation, accompanied by rapid whole-body normalization of insulin sensitivity.

    “Such conditional ablation resulted in a profound reduction of proinflammatory ATM accumulation, accompanied by rapid whole-body normalization of insulin sensitivity (43).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] source

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  • May combine two claims.

    Premisecitation

    Adipose tissue expansion can lead to hypoxia, adipocyte cell death, enhanced chemokine secretion, and dysregulation in fatty acid fluxes.

    “This expansion can lead to a myriad of effects, including hypoxia, adipocyte cell death, enhanced chemokine secretion, and dysregulation in fatty acid fluxes (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Sun K, Scherer PE.Adipose Tissue Dysfunction: A Multistep Process . Berlin, Germany: Springer-Verlag Berlin Heidelberg; 2010:67–75. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Either high rates of lipolysis or an influx of saturated FFAs into adipocytes do cause temporary inflammation within adipose tissue.

    “Even though we do not consider AT as a conventional tissue suffering from lipotoxic side effects, either high rates of lipolysis or an influx of saturated FFAs into adipocytes do cause temporary inflammation within the tissue (33).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] source

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  • May combine two claims.

    Premisecitation

    The M1 macrophage population demonstrates a positive correlation with insulin resistance and dominates in states of overnutrition by targeting FFA-mediated increases in proinflammatory responses.

    “The M1 population demonstrates a positive correlation with insulin resistance and dominates in states of overnutrition by targeting FFA-mediated increases in proinflammatory responses (14,40).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] source

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    • cites [40] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductreasoning

    It is almost impossible to determine whether adipocytes in vivo preferentially undergo a simple necrotic death or apoptosis, due to technical difficulties of reproducibly demonstrating apoptosis in adipocytes.

    “It is almost impossible to determine whether adipocytes in vivo preferentially undergo a simple necrotic death or apoptosis, due to the technical difficulties of reproducibly demonstrating apoptosis in adipocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    At the 20-week stage, the percentage of necrotic cells is reduced to approximately 16%, accompanied by an increased emergence of smaller adipocytes (<5,000 μm2), thus restoring the adipocyte number.

    “However, a fascinating twist to these findings was that at the 20-week stage, the percentage of necrotic cells was reduced to approximately 16%; this was accompanied by an increased emergence of smaller adipocytes (<5,000 μm 2 ), thus restoring the adipocyte number (13).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] source

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  • May combine two claims.

    Premisecitation

    Ang-1 is an agonist of the Tie-2 receptor, which is constitutively expressed in several tissues, including AT.

    “Ang-1 is an agonist of the Tie-2 receptor, which is constitutively expressed in several tissues, including AT (83)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] source

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Adipocyte cell number is relatively fixed by early adulthood, and any alterations in fat mass during adulthood are merely credited to alterations in adipocyte hypertrophy.

    “This group postulated that adipocyte cell number is relatively fixed by early adulthood, and that any alterations in fat mass during adulthood are merely credited to alterations in adipocyte hypertrophy (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] source

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  • May combine two claims.

    Premisecitation

    Upon proper nutritional stimulation, adipose tissue synthesizes HGF and VEGF, both of which play key pro-angiogenic roles.

    “Moreover, upon proper nutritional stimulation, AT also synthesizes HGF and VEGF (71), both of which play key pro-angiogenic roles (71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] source

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  • May combine two claims.

    Premisecitation

    Blockade of VEGF-R2, but not VEGF-R1, restricts AT expansion and thus prevents the progression of DIO.

    “Blockade of VEGF-R2, but not VEGF-R1, restricts AT expansion and thus prevents the progression of DIO (81)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

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    • Rests on an assumption: VEGF functions by binding two tyrosine kinase receptors, VEGF-R1 and VEGF-R2.
    • Rests on an assumption: VEGF-R2 is expressed in vascular endothelial cells.
    • Rests on an assumption: Signaling through VEGF-R2 is critical for both physiological and pathological blood vessel formation.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Angiogenesis plays a critical role in tumor growth and metastasis formation, and blocking angiogenesis prevents tumor growth and forces regression of existing lesions.

    “Angiogenesis plays a critical role in tumor growth and metastasis formation, and blocking angiogenesis prevents tumor growth and forces regression of existing lesions (59)(60)(61).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [59] Boehm, 1997, Nature. source

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    • cites [60] Folkman, 1997, EXS.

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    • cites [61] source

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  • May combine two claims.

    Premisecitation

    Some studies have suggested anti-angiogenic properties for adiponectin, but these studies rely on recombinant preparations of the protein, and the quality of these preparations varies widely.

    “Some studies have suggested anti-angiogenic properties for adiponectin (72), but these studies rely on recombinant preparations of the protein, and the quality of these preparations varies widely.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Vona-Davis, 2007, Endocr Relat Cancer. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute weight loss (days 0-7), a 24-hour fast, or pharmacological induction of adipocyte lipolysis using a β3-adrenergic agonist all result in a transient accumulation of lipid-laden adipose tissue macrophages, with an increase of up to 65% of macrophage infiltration.

    “Ironically, acute weight loss (days 0-7), a 24-hour fast, or pharmacological induction of adipocyte lipolysis using a β3-adrenergic agonist all resulted in a transient accumulation of lipid-laden ATMΦs (an increase of up to 65% of macrophage infiltration was observed).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] source

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  • May combine two claims.

    Premisecitation

    VEGF levels are regulated by hypoxia, insulin stimulation, certain growth factors, and specific cytokines.

    “VEGF levels are known to be regulated by hypoxia, insulin stimulation, certain growth factors, and specific cytokines (79)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] source

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  • May combine two claims.

    Premisecitation

    bFGF can promote vascular endothelial cell growth and hence the process of angiogenesis.

    “In addition, bFGF can promote vascular endothelial cell growth (70) and hence the process of angiogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] source

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  • May combine two claims.

    Interpretationreasoning

    A transient influx of adipose tissue macrophages is a physiologically healthy response, and a maladaptive inflammatory reaction occurs in the chronic state.

    “Collectively, these studies suggest that a transient influx of ATMΦs is a physiologically healthy response and further implicates a maladaptive inflammatory reaction in the chronic state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ang-2 is an antagonist for the Tie-2 receptor and is exclusively expressed in sites of vascular remodeling.

    “Ang-2, on the other hand, is an antagonist for the Tie-2 receptor and is exclu-sively expressed in sites of vascular remodeling (83,84,88)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] source

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    • cites [84] source

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    • cites [88] Suri, 1998, Science. source

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  • May combine two claims.

    Interpretationreasoning

    Pathological expansion of adipose tissue is associated with chronic inflammation, which ultimately results in the development of systemic insulin resistance.

    “Such pathological expansion is associated with chronic inflammation, which ultimately results in the development of systemic insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mast cells are abundant in obese adipose tissue and may elicit a pathogenic role in adipose tissue functionality.

    “Mast cells have recently been highlighted as another AT-associated cell type; abundant in obese AT, these inflammatory cells may elicit a pathogenic role in AT functionality (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] source

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  • May combine two claims.

    Interpretationreasoning

    Hypoxia is a key player in expanding AT that serves as a driving force for macrophage infiltration.

    “We have discussed hypoxia as a key player in expanding AT that serves as a driving force for macrophage infiltration”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    O2 tension in the center of solid tumors may be so low that cells essentially become anoxic.

    “O 2 tension in the center of solid tumors may be so low that cells essentially become anoxic”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] source

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    • cites [93] source

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    • cites [94] source

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  • May combine two claims.

    Premisecitation

    Weakening of the ECM that surrounds AT by elimination of collagen VI leads to improved survival rates of adipocytes and improvements in metabolism.

    “We have demonstrated that the weakening of the ECM that surrounds AT by elimination of collagen VI leads to improved survival rates of adipocytes and improvements in metabolism (102)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Khan, 2009, Mol Cell Biol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Low O2 tension in solid tumors has profound effects on tumor metabolism.

    “this is recognized to have profound effects on the tumor metabolism (92)(93)(94)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] source

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    • cites [93] source

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    • cites [94] source

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  • May combine two claims.

    Interpretationcitation

    Promoting an angiogenic cascade in healthy fat pads can effectively counteract hypoxic conditions and could thus be associated with metabolically beneficial effects.

    “Promoting an angiogenic cascade in healthy fat pads can effectively counteract hypoxic conditions and could thus be associated with metabolically beneficial effects”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    A well-orchestrated set of interactions between a number of critical cell types has to take place in a defined chronological order for AT to rapidly remodel and release or accept large amounts of calorically dense lipids.

    “A well-orchestrated set of interactions between a number of critical cell types has to take place in a defined chronological order”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TIMP1 is upregulated with obesity, and TIMP4 is downregulated in states of obesity.

    “More specifically, TIMP1 is upregulated with obesity, and conversely, TIMP4 is downregulated in states of obesity (106)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Many pathological changes can occur during that process.

    “with many pathological changes that can occur during that process”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Ultimately, M1-stage macrophages prevail, leading to an inflammatory phenotype that is strongly associated with systemic insulin resistance.

    “Ultimately, M1-stage macrophages prevail, leading to an inflammatory phenotype that is strongly associated with systemic insulin resistance”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    As a result of pathological AT expansion, HIF-1α is induced, which in turn can cause the induction of a fibrotic program.

    “As a result, HIF-1α is induced, which in turn can cause the induction of a fibrotic program”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In DIO mice, expression levels of MMP3, -11, -12, -13, and -14 are all upregulated, whereas levels of MMP7, -9, -16, and -24 are downregulated.

    “Maquoi and colleagues further demonstrated that in DIO mice, expression levels of MMP3, -11, -12, -13, and -14 are all upregulated, whereas levels of MMP7, -9, -16, and -24 are downregulated (106)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] source

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  • May combine two claims.

    Interpretationnone given

    Pathological AT expansion consists of massive enlargement of existing adipocytes, limited angiogenesis, and ensuing hypoxia.

    “In contrast, pathological AT expansion consists of massive enlargement of existing adipocytes, limited angiogenesis, and ensuing hypoxia”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Healthy AT expansion consists of an enlargement of AT through effective recruitment of adipogenic precursor cells to the adipogenic program, along with an adequate angiogenic response and appropriate remodeling of the ECM.

    “Healthy AT expansion consists of an enlargement of AT through effective recruitment of adipogenic precursor cells to the adipogenic program, along with an adequate angiogenic response and appropriate remodeling of the ECM”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The absence of MT1-MMP impairs white AT development and hence causes lipodystrophy.

    “The absence of MT1-MMP impairs white AT development and hence causes lipodystrophy (101)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] source

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44 of 44

  • The paper relies on this without support.

    Adipose tissue has an almost unlimited capacity to expand in a non-transformed state.

    “To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state.”

  • The paper relies on this without support.

    Rodent models recapitulate physiologically relevant processes of human adipose tissue remodeling.

    “Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate.”

  • The authors state this as an assumption.

    The inducible lipodystrophy mouse model indicates the rate of lipid droplet removal under normal physiological conditions.

    “If the situation in the inducible lipodystrophy model in the mouse is an indication of the rate of lipid droplet removal under normal physiological conditions, then this is likely a relatively slow process, occurring over a period of days to weeks (15).”

  • The paper relies on this without support.

    VEGF functions by binding two tyrosine kinase receptors, VEGF-R1 and VEGF-R2.

    “VEGF functions by binding two tyrosine kinase receptors, VEGF-R1 and VEGF-R2”

  • The paper relies on this without support.

    VEGF-R2 is expressed in vascular endothelial cells.

    “the latter is expressed in vascular endothelial cells”

  • The paper relies on this without support.

    Signaling through VEGF-R2 is critical for both physiological and pathological blood vessel formation.

    “signaling through this receptor is critical for both physiological and pathological blood vessel formation”

  • The paper relies on this without support.

    The functions of angiopoietins and Tie-2 in AT have not been directly examined.

    “to date, the functions of this family of proteins have not been directly examined”

  • The paper relies on this without support.

    Individual adipocytes can acquire a diameter of 150-200 μm.

    “the large diameter that an individual adipocyte can acquire (150-200 μm)”

  • The paper relies on this without support.

    The functions of several other MMPs highly expressed in AT remain to be identified.

    “The function of several other MMPs highly expressed in AT remains to be further identified”

  • The paper relies on this without support.

    There are strong individual differences in the potential for AT expansion.

    “There are strong individual differences with respect to the potential for AT expansion”
10 of 10

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?

  • Under excess caloric intake, white adipose tissue reaches its upper limit for further lipid storage.

    “In fact, under excess caloric intake, WAT reaches its upper limit for further lipid storage ([157](#B157), [169](#B169)).”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [157]

  • Dysregulation of adipose tissue metabolism has been previously linked to an age-related process of ECM deposition, and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms.

    “Dysregulation of adipose tissue metabolism has been previously linked to an age‐related process of ECM deposition and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms (36, 259, 260).”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [259]

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Nishimura, 2008, J Clin Invest., 118, 710
  2. Marques, 1998, Am J Physiol., 275, R1898
  3. Folkman, 1997, EXS., 79, 1
  4. Ribatti, 2003, Ital J Anat Embryol., 108, 1
  5. Muona, 1993, Am J Pathol., 142, 1586

Cited by

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Related

Authors
Sun, K., Kusminski, C. M., & Scherer, P. E.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Scherer, Philipp E.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2011-06-01
Volume
121
Issue
6
Pages
2094-2101
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci45887
PMC
PMC3104761
OpenAlex
W2085957571
Semantic Scholar
2136fd975d5a354a657552c0fc7acefa1a973e5a
Cited by
1,941
References
109
Citations by year
2026: 100 · 2025: 103 · 2024: 124 · 2023: 134 · 2022: 134 · 2021: 149 · 2020: 167 · 2019: 116 · 2018: 135 · 2017: 152 · 2016: 133 · 2015: 137 · 2014: 136 · 2013: 128 · 2012: 74
FWCI
13.26
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Michigan
  • National Institutes of Health
  • National Cancer Institute (R01CA112023)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 55758, R01DK055758, RC1DK086629, P01DK088761)
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
adipose tissue remodeling, obesity, adipose tissue expansion, hypoxia, endothelial progenitor cells, immune cells, preadipocytes, tumor growth
MeSH terms
Adaptation, Physiological, Adipose Tissue, Animals, Cell Division, Energy Metabolism, Extracellular Matrix, Fatty Acids, Humans, Inflammation, Macrophages, Mice, Transgenic, Obesity, Weight Loss, Cell Hypoxia, Adipocytes, Neovascularization, Physiologic, Endothelial Cells, Cell Size, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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