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.
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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
- Interpretationreasoning§ An old perspective on a new problem
Chronic overnutrition leads to unresolved adipose tissue hypoxia.
“The current pervasive state of chronic overnutrition results in an increase in unresolved AT hypoxia.”
Quote in the paperSubstantial claim - Premisecitation§ jci.org Volume 127 Number 1 January 2017
CD8+ T cell infiltration can precede and induce adipose tissue macrophage accumulation in some settings.
“as CD8 + T cell infiltration has been observed to precede and induce AT macrophage accumulation in other settings (11).”
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- Premisecitation§ The adipocyte stress signal: mild hypoxia
HIF-2α attenuates high-fat-diet-induced inflammation.
“In contrast, HIF-2α attenuates HFD-induced inflammation (3).”
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- Premisecitation§ jci.org Volume 127 Number 1 January 2017
Reports exist of both pro- and anti-inflammatory responses during the first four days of high-fat feeding.
“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.”
Quote in the paperNot a substantial claim - Premisecitation§ Healthy angiogenesis.
White adipocyte progenitors have been identified in the mural compartment of vascular structures.
“Interestingly, populations of white adipocyte progenitors have been identified in the mural compartment of vascular structures.”
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- Premisecitation§ Healthy angiogenesis.
Pre-adipocytes for both white and brown adipose tissues have a perivascular origin.
“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).”
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- Interpretationnone given§ jci.org Volume 127 Number 1 January 2017
Hypoxia likely plays a fundamental role in initiating inflammation during early adipose tissue expansion.
“As an early event in AT expansion, hypoxia likely plays a fundamental role in the initiation of inflammation.”
Quote in the paperSubstantial claim - Premisecitation§ Healthy angiogenesis.
Mural cells with high adipogenic potential can be identified by PDGFR-β expression.
“Tang et al. demonstrated that these mural cells with high adipogenic potential can be identified by expression of PDGFR-β (20).”
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- Premisecitation§ jci.org Volume 127 Number 1 January 2017
Adipocytes release proinflammatory factors such as IL-6 and macrophage migration inhibitory factor.
“Adipocytes release proinflammatory factors such as IL-6 and macrophage migration inhibitory factor (12).”
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- Premisenone given§ jci.org Volume 127 Number 1 January 2017
There is no direct evidence for sprouting or looping/splitting angiogenesis in obese adult adipose tissue.
“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.”
Quote in the paperNot a substantial claim - Premisecitation§ An old perspective on a new problem
In rodents, one week of high-fat feeding is enough to enlarge adipocytes, which store four times as much triglyceride per cell as at baseline.
“It takes as little as one week of high-fat feeding (HFF) in rodents for adipocytes to become enlarged, storing four-fold the amount of triglyceride per cell compared with baseline (1).”
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- Premisecitation§ jci.org Volume 127 Number 1 January 2017
Adipose tissue secretes several adipokines and endogenous angiogenesis inhibitors that modulate new blood vessel formation, including adiponectin, leptin, resistin, visfatin/thrombospondin 1, and plasminogen activator inhibitor.
“In addition to authentic angiogenic factors, AT secretes several important adipokines and endogenous angiogenesis inhibitors to modulate the balance of new blood vessel formation, including adiponectin (36,37), leptin (34), resistin (38), visfatin/thrombospondin 1 (39), and plasminogen activator inhibitor (40).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [36] Lee, 2015, Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway, Oncotarget source
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- cites [37] source
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- cites [34] source
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- cites [38] Robertson, 2009, Induction of angiogenesis by murine resistin: putative role of PI3-kinase and NO-dependent pathways, Regul Pept source
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- Interpretationreasoning§ The adipocyte stress signal: mild hypoxia
Hypoxia signaling is paramount to the early adipose tissue response to nutrient excess.
“Therefore, although further studies are required to understand the exact role for HIF-1α and HIF-2α in the regulation of AT expansion, it is clear that hypoxia signaling is paramount to the early response of AT to nutrient excess.”
Quote in the paperSubstantial claim - Premisecitation§ jci.org Volume 127 Number 1 January 2017
Lee et al. demonstrated a mild proinflammatory response in the epididymal adipose depot of mice fed a high-fat diet for three days.
“Lee et al. demonstrated a mild proinflammatory response in the epididymal adipose depot of mice fed a HFD for three days (16), and the proinflammatory polarization of macrophages was of particular importance in this response.”
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- Premisecitation§ The adipocyte stress signal: mild hypoxia
PHD enzyme abundance determines the relative activity of HIF-1α versus HIF-2α because PHDs differ in specificity for prolyl hydroxylation sites between HIFα isoforms.
“An important determinant of HIF-1α activity relative to HIF-2α activity is the abundance of specific PHD enzymes, which have differential specificities for prolyl hydroxylation sites between the HIFα isoforms (5).”
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- Premisecitation§ jci.org Volume 127 Number 1 January 2017
Adipocytes can secrete pro-angiogenic lipid species such as monobutyrin.
“Moreover, adipocytes can secrete pro-angiogenic lipid species such as monobutyrin (41).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Wilkison, 1991, Biosynthetic regulation of monobutyrin, an adipocyte-secreted lipid with angiogenic activity, J Biol Chem source
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- Interpretationreasoning§ Appropriate ECM remodeling.
The early response to adipose tissue expansion is likely a balance between pro- and anti-inflammatory signals.
“Thus, the early response to AT expansion is likely the result of a balanced action between pro-and antiinflammatory signals.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ An old perspective on a new problem
Adipose tissue plasticity is essential for maintaining metabolic homeostasis when food is abundant or scarce.
“It is this plasticity that has made AT an essential organ for maintaining metabolic homeostasis during times when food is either abundant or scarce.”
Quote in the paperNot a substantial claim - Premisecitation§ jci.org Volume 127 Number 1 January 2017
Macrophage infiltration into adipose tissue occurs within one day of high-fat feeding.
“Macrophage infiltration into AT occurs within one day of HFF (15).”
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- Interpretationreasoning§ An old perspective on a new problem
Unhealthy adipose tissue expansion is a major contributor to the systemic metabolic disturbances of obesity and type 2 diabetes.
“ultimately leading to unhealthy AT tissue expansion, a major contributor to the systemic metabolic disturbances that are characteristic of obesity and type 2 diabetes.”
Quote in the paperSubstantial claim - Interpretationnone given§ An old perspective on a new problem
When nutrients are excessive, adipocytes store lipids in droplets that expand until oxygen diffusion becomes limiting.
“When nutrient availability is in excess, adipocytes store various lipid species in lipid droplets, which quickly expand in size and, in the process, reach the diffusional limit of oxygen.”
Quote in the paperSubstantial claim - Premisecitation§ An old perspective on a new problem
Mouse visceral adipose tissue weight can double within one week of starting a high-fat diet.
“The mouse visceral AT weight can double within one week of the initiation of a high-fat diet (HFD) (2) but can undergo a dramatic reduction within 24 hours of fasting.”
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- Premisecitation§ Healthy angiogenesis.
Local hypoxia is a potent stimulus for new blood vessel formation through pro-angiogenic actions of HIF-1α and HIF-2α.
“Local hypoxia is a potent stimulus for new blood vessel formation through the pro-angiogenic actions of HIF-1α and HIF-2α (24,25).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation§ Unresolved inflammation.
The balance of pro- and anti-inflammatory signals is critical for disease progression in obese adipose tissue.
“The regulation of immune cell function and cytokine production in obese AT has been well studied (68), and it is now evident that the balance of pro-and antiinflammatory signals is critical for disease progression.”
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- Premisecitation§ Unresolved inflammation.
B2 cells produce over a hundred different antibodies associated with insulin resistance in human adipose tissue.
“In addition to cytokines, B2 cells also produce over a hundred different antibodies that have been associated with insulin resistance in human AT (8,9).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Unresolved inflammation.
Mice with heterozygous deletion of MMP-14 cannot appropriately remodel the ECM, resulting in reduced capacity for adipose expansion.
“Mice with heterozygous deletion of MMP-14 are not able to appropriately re-model the ECM, resulting in reduced capacity for adipose expansion (48).”
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- Premisecitation§ Unresolved inflammation.
Mechanical forces during rapid tumor growth induce intussusceptive/splitting angiogenesis.
“Mechanical forces that exist during the rapid growth of a tumor induce this kind of angiogenesis (86).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [86] Kreuger, 2016, Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis, Nat Rev Drug Discov source
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- Interpretationreasoning§ jci.org Volume 127 Number 1 January 2017
The combination of low VEGF signaling and increased myofibroblast activation suggests that splitting angiogenesis occurs more frequently during chronic obesity.
“In contrast, the combination of low VEGF signaling and increased myofibroblast activation suggests that splitting angiogenesis occurs more frequently during chronic obesity.”
Quote in the paperSubstantial claim - Premisecitation§ Unresolved inflammation.
Chemical angiogenic inhibitors such as angiostatin, endostatin, thalidomide, and VEGFR2-blocking antibody TNP-470 reduce body weight and fat pad mass in diet-induced obese or genetically obese ob/ob mice.
“Chemical angiogenic inhibitors such as angiostatin, endostatin, and thalidomide as well as the VEGFR2-blocking antibody TNP-470, have been tested in diet-induced obese mice or genetically obese ob/ob mice and shown to significantly reduce body weight and fat pad mass (88,89).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ Unresolved inflammation.
Hypoxia is a powerful trigger for ECM remodeling and inflammation to facilitate angiogenesis.
“Hypoxia is a powerful trigger for ECM remodeling and inflammation as a means to facilitate angiogenesis.”
Quote in the paperSubstantial claim - Premisecitation§ Unresolved inflammation.
TNF-α produced by immune cells was the first cytokine demonstrated to directly impede insulin action in adipocytes.
“TNF-α, produced by immune cells, was the first cytokine demonstrated to directly impede insulin action in the adipocyte (69).”
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- Interpretationreasoning§ Unresolved inflammation.
In the context of non-pathologic hypoxic stress, well-controlled inflammation and angiogenesis promote healthy adipose tissue expansion with net beneficial effect on metabolic homeostasis.
“The relationship between angiogenesis and immune cell signaling is complex, but at least in the context of a non-pathologic hypoxic stress signal, well-controlled inflammation and angiogenesis promote the healthy expansion of AT with a net beneficial effect on metabolic homeostasis.”
Quote in the paperSubstantial claim - Premisecitation§ Unresolved inflammation.
Oxidative modification of cellular components such as glutathionylated 4-hydroxy-2-nonenal can directly stimulate a macrophage-mediated proinflammatory response.
“In addition, oxidative modification of cellular components such as glutathionylated 4-hydroxy-2-nonenal can directly stimulate a macrophage-mediated proinflammatory response (81).”
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- Premisecitation§ Unresolved inflammation.
LYVE-1+ macrophages promote angiogenesis by secreting MMP-9, -12, and -7 to remodel ECM and angiogenic factors such as VEGF to stimulate a dense vascular network.
“These LYVE-1 + macrophages promote angiogenesis through secretion of MMP-9, -12, and -7 to remodel the ECM and angiogenic factors like VEGF to stimulate the growth of a dense vascular network.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] source
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- Interpretationreasoning§ Unresolved inflammation.
During chronic obesity, innate and adaptive immunity are activated and skewed to a proinflammatory response triggered by adipocyte death, hypoxia, and reduced fatty acid storage capacity in dysfunctional adipocytes.
“During chronic obesity, both innate and adaptive immunity are activated and skewed to a proinflammatory response triggered by adipocyte death, hypoxia, and reduced fatty acid storage capacity in dysfunctional adipocytes.”
Quote in the paperSubstantial claim - Premisenone given§ Unresolved inflammation.
Hyaluronic acid can participate in TGF-β1-dependent fibroblast proliferation to promote fibrosis.
“Finally, HA can participate in TGF-β1-dependent proliferation of fibroblasts to promote fibrosis.”
Quote in the paperNot a substantial claim - Premisecitation§ Unresolved inflammation.
Mice deficient in collagen VI exhibit unimpeded tissue expansion.
“Conversely, mice deficient in collagen VI exhibit unimpeded tissue expansion (49).”
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- Premisecitation§ Unresolved inflammation.
Hyaluronic acid is a potent inducer of innate immune response through binding and activation of TLR2 and TLR4.
“HA is also a potent inducer of the innate immune response through binding and activation of immune cell TLR2 and -4 (51).”
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- Premisecitation§ Unresolved inflammation.
Overexpression of dominant-negative HIF-1α or pharmacologic inhibition of HIF-1α significantly reduced adipose tissue fibrosis and improved adipose tissue function in mice fed a high-fat diet.
“Conversely, either overexpression of a dominant-negative HIF-1α or pharmacologic inhibition of HIF-1α significantly reduced AT fibrosis and improved AT function in mice fed a HFD (85).”
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- Premisecitation§ Unresolved inflammation.
Adipose tissue inflammation is required for appropriate expansion of adipose tissue and safe storage of potentially toxic lipid species.
“Although the detrimental consequences of proinflammatory signaling in obese AT are evident, our group has shown that it is also required for appropriate expansion of AT and safe storage of potentially toxic lipid species (82).”
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- Premisecitation§ Unresolved inflammation.
LMW-HA production likely occurs in cells cultured in low oxygen through enhanced activity of the HA-degrading enzyme hyaluronidase.
“Gao et al. have demonstrated that LMW-HA production likely occurs in cells cultured in low oxygen through enhanced activity of the HA-degrading enzyme hyaluronidase (50).”
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- Premisecitation§ Unresolved inflammation.
Hypoxic regions at the tip of the mouse epididymal fat pad promote infiltration of macrophages expressing LYVE-1.
“The hypoxic regions at the tip of the mouse epididymal fat pad have been shown to promote infiltration of a specific species of macrophage expressing the lymphatic endothelial marker LYVE-1.”
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- Premisecitation§ Unresolved inflammation.
The new vasculature provides a framework for adipogenesis and growth of the fat pad.
“This new vasculature provides the framework for adipogenesis and growth of the fat pad (52).”
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- Premisecitation§ Unresolved inflammation.
Several cytokines produced by inflammatory cells, including TNF, IL-6, and IL-8, have angiogenic effects.
“Additionally, several cytokines produced by inflammatory cells have angiogenic effects, including TNF, IL-6, and IL-8 (57, 58).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data§ Unresolved inflammation.
Adipose tissue inflammation in obese individuals cannot be assigned a strictly pathologic role.
“Thus, AT inflammation in obese individuals cannot be assigned a strictly pathologic role.”
Quote in the paperSubstantial claim - Premisecitation§ Unresolved inflammation.
Genes involved in collagen breakdown, particularly MMP14, are significantly upregulated in mice fed a high-fat diet for one week.
“Genes involved in collagen breakdown, particularly MMP14, are significantly upregulated in mice fed a HFD for one week (48).”
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- Interpretationown data§ Unresolved inflammation.
TNF-α plays an essential role in adaptation of adipose tissue to high-fat feeding.
“In fact, TNF-α plays an essential role in the adaptation of AT to HFF.”
Quote in the paperSubstantial claim - Interpretationreasoning§ jci.org Volume 127 Number 1 January 2017
Compared with other tissues, a disproportionate level of vascular remodeling persists in adipose tissue even at steady state.
“However, given the circumstantial evidence, it seems clear that, compared with any other tissue, a disproportionate level of vascular remodeling persists in AT, even at steady state.”
Quote in the paperNot a substantial claim - Premisecitation§ Impaired angiogenesis.
Long-term high-fat feeding results in abnormal regulation of VEGF-A expression, with decreased VEGF-A levels in adipose tissue of obese mice and humans.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- Rests on an assumption: Rodent models of diet-induced and genetic obesity are sufficiently representative of human obesity-associated adipose tissue dysfunction for the review's conclusions.
- Interpretationcitation§ Unresolved inflammation.
A potential mechanism for hypoxia-induced angiogenesis during early adipose tissue expansion is production of pro-angiogenic low-molecular-weight hyaluronic acid.
“A potential mechanism for hypoxia-induced angiogenesis during early AT expansion is the production of pro-angiogenic, low-molecular-weight HA (LMW-HA).”
Quote in the paperSubstantial claim - Premisecitation§ Unresolved inflammation.
Several natural plant products have effectively reduced body weight in ob/ob and HFD-induced obese mice by inhibiting angiogenesis.
“Several natural products extracted from plants (91)(92)(93) have also effectively reduced body weight in ob/ob and HFD-induced obese mice by inhibiting angiogenesis.”
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- Premisecitation§ Impaired angiogenesis.
Proinflammatory cytokines from senescent cells, such as MCP-1, TNF-α, and IL-1β, are considered among the most important drivers of dysfunctional adipose tissue and chronic fibrotic disease.
“In contrast, the proinflammatory cytokines released from senescent cells, including MCP-1, TNF-α, and IL-1β, are among those considered most important for the progression to dysfunctional AT and chronic fibrotic disease (65,113).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Impaired angiogenesis.
Division-competent cells can be pushed to senescence by damaging stresses such as oncogene induction, oxidative stress, and double-strand DNA breaks.
“Division-competent cells can also be pushed to senescence though damaging stresses such has oncogene induction, oxidative stress, and double-strand DNA breaks (99).”
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- Premisecitation§ Impaired angiogenesis.
MAGP1 actions protect mice from obesity and associated metabolic defects.
“The actions of MAGP1 have been shown to protect mice from obesity and associated metabolic defects (95).”
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- Interpretationnone given§ Unresolved inflammation.
Metabolic improvements from systemically introduced angiogenesis inhibitors cannot be directly attributed to reduced angiogenesis in adipose tissue.
“Any metabolic improvements afforded by these systemically introduced compounds cannot be directly attributed to reduced angiogenesis in AT.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Impaired angiogenesis.
In chronic obesity, the short-term beneficial effects of cellular senescence on wound healing are replaced by the harmful effects of chronic SASP.
“Therefore, in chronic obesity the beneficial effects of time-limited cellular senescence in wound healing are replaced by the detrimental effects of chronic SASP.”
Quote in the paperSubstantial claim - Premisecitation§ Impaired angiogenesis.
MAGP1 binds active TGF-β and sequesters it in the ECM.
“MAGP1 binds active TGF-β, sequestering it in the ECM (95).”
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- Premisecitation§ Impaired angiogenesis.
Genetic knockout of the collagen-binding receptor integrin in muscle of diet-induced obese mice increases vascularization.
“Genetic knockout of the collagen-binding receptor integrin in the muscle of diet-induced obese mice increases vascularization (97).”
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- Interpretationcitation§ Unresolved inflammation.
Inhibition of angiogenesis as a therapeutic strategy for obesity remains controversial.
“Despite these results, the inhibition of angiogenesis as a therapeutic strategy for obesity remains a controversial notion (94).”
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- Premisecitation§ Impaired angiogenesis.
Restricted epididymal adipose tissue expansion in IRF5-deficient mice was associated with a large increase in antiinflammatory macrophage infiltration, collagen deposition, and improved insulin sensitivity.
“Restricted epididymal AT expansion was associated with a large increase in antiinflammatory macrophage infiltration, collagen deposition, and improved insulin sensitivity.”
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- Premisecitation§ Impaired angiogenesis.
Targeting senescent cells or their products alleviates age-related dysfunction of adipocyte progenitors and metabolism in INK4-ATTAC mice.
“Targeting senescent cells or their products alleviates age-related dysfunction of adipocyte progenitors and metabolism, as elegantly demonstrated in mice expressing a p16INK4a promoter-driven inducible caspase-8 (INK4-ATTAC mice) (101).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [101] Xu, 2015, Targeting senescent cells enhances adipogenesis and metabolic function in old age, Elife source
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- Premisecitation§ Inflammation.
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).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given§ Impaired angiogenesis.
Fibrosis has been suggested to limit adipose tissue angiogenic capacity.
“Fibrosis has been suggested to limit AT angiogenic capacity.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Impaired angiogenesis.
Senescence of adipocytes, endothelial cells, or their precursors may substantially affect adipose tissue homeostasis.
“Thus, cell senescence of adipocytes, endothelial cells, or their precursors might have major effects on AT homeostasis.”
Quote in the paperSubstantial claim - Premisecitation§ Impaired angiogenesis.
Preadipocytes, mature adipocytes, and endothelial cells can become senescent during obesity.
“Surprisingly, preadipocytes and mature adipocytes as well as endothelial cells can become senescent during obesity (105-109).”
Quote in the paperSubstantial claim0 of 5 sources checked - Premisecitation§ Impaired angiogenesis.
Obesity is proposed to drive cellular senescence through mechanisms that include oxidative stress, high glucose in the local microenvironment, and increased IGF and ceramides.
“Obesity is thought to promote cell senescence through various means including oxidative stress, high glucose concentrations in the microenvironment, and increased IGF and ceramides (104).”
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- Premisecitation§ Unresolved inflammation.
WAT-specific overexpression of VEGF-A has differential metabolic effects in mice challenged with HFD versus genetically obese mice.
“Our group has reported that WAT-specific overexpression of VEGF-A resulted in differential metabolic effects in mice challenged with a HFD or mice that are genetically obese (22).”
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- Interpretationcitation§ Impaired angiogenesis.
Cellular senescence plays an important role in many diseases including those associated with obesity.
“Recent studies have identified an important role for cellular senescence in many diseases including those associated with obesity.”
Quote in the paperNot a substantial claim - Premisecitation§ Impaired angiogenesis.
Reduced blood flow, as occurs in obese adipose tissue, is sufficient to trigger endothelial cell senescence.
“Reduced blood flow, as seen in obese AT, is sufficient to trigger endothelial cell senescence (105, 110).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ Impaired angiogenesis.
Factors secreted by senescent cells probably influence adipose tissue immunity, angiogenesis, and fibrosis substantially.
“SASP factors are also likely to have considerable effects on AT immunity, angiogenesis, and fibrosis.”
Quote in the paperSubstantial claim - Interpretationcitation§ Impaired angiogenesis.
The detrimental effects of fibrosis-mediated restriction of adipose tissue expansion during obesity on metabolic health may depend on the adipose depot affected.
“Interestingly, the detrimental effects of fibrosis-mediated restriction of AT expansion during obesity on metabolic health may be dependent on the adipose depot affected.”
Quote in the paperSubstantial claim - Premisecitation§ Inflammation.
In non-diabetic obese individuals, higher VEGF-A expression correlates with better capillary density and insulin sensitivity.
“Consistent with mouse models of adipocyte-specific overexpression of VEGF-A, higher VEGF-A expression correlated with improved capillary density and insulin sensitivity in non-diabetic obese individuals (118).”
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- Premisecitation§ Inflammation.
Healthy men can become insulin insensitive during acute excessive caloric intake without showing inflammatory changes in adipose tissue.
“Boden et al. showed that healthy men can become insulin insensitive during acute excessive caloric intake but do not display inflammatory changes in AT (77).”
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- Interpretationreasoning§ Concluding remarks
Persistent stress signaling becomes injury signaling due to long-term and severe hypoxia.
“However, persistent stress signaling translates into injury signaling, caused by long-term and severe hypoxia.”
Quote in the paperSubstantial claim - Premisecitation§ Inflammation.
A recent human study comparing obese patients with and without type 2 diabetes found significantly less visceral adipose tissue fibrosis in the diabetic subjects.
“However, a recent human study compared obese patients with or without T2D and found significantly less fibrosis in the visceral AT of the diabetic subjects (122).”
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- Premisecitation§ Inflammation.
Another independent study reported lower collagen content in visceral adipose tissue from metabolically unhealthy obese patients.
“Another independent study also reported less collagen content in visceral AT from metabolically unhealthy obese patients (123).”
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- Interpretationreasoning§ Concluding remarks
Limited oxygen supply triggers chronic low-grade inflammation characterized mainly by proinflammatory macrophage infiltration.
“Limited oxygen supply also triggers chronic low-grade inflammation predominantly characterized by proinflammatory macrophage infiltration.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Inflammation.
In both rodent models and human studies, VEGF-A-mediated adipose tissue angiogenesis has opposing effects on adipose tissue expansion and function.
“Thus, in both rodent models and human studies, VEGF-A-mediated AT angiogenesis exerts dichotomous effects in AT expansion and function.”
Quote in the paperSubstantial claim - Premisecitation§ Inflammation.
Most human studies have reported fibrosis in obese adipose tissue.
“The majority of human studies have reported fibrosis in obese AT (119-121).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Inflammation.
Twelve months after bariatric surgery, adipose tissue inflammation remains elevated in about 40% of patients.
“Moreover, others have shown that 12 months after bariatric surgery, AT inflammation remained elevated in approximately 40% of patients (117).”
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- Interpretationreasoning§ Concluding remarks
These deleterious factors can drive cellular senescence in many cell types.
“These deleterious factors can drive cellular senescence in many cells types.”
Quote in the paperNot a substantial claim - Premisecitation§ Inflammation.
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).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ Concluding remarks
SASP factors can promote adipose tissue dysfunction by dysregulating extracellular matrix remodeling, inflammation, and angiogenesis.
“SASP factors can promote AT dysfunction through dysregulation of AT ECM remodeling, inflammation, and angiogenesis.”
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Interpretationreasoning§ An old perspective on a new problemDuring obesity progression, adipose depots can expand beyond their angiogenic capacity, causing persistent hypoxia, fibrosis, cellular senescence, and necrotic adipocyte death.
“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)”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ jci.org Volume 127 Number 1 January 2017VEGF is upregulated in adipose tissue of mice fed a high-fat diet for three days, but reports in chronic obesity show both enhanced and reduced VEGF expression.
“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.”
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- cites [13] source
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- cites [43] Tinahones, 2012, Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels, BMC Physiol source
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- cites [44] source
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Premisecitation§ jci.org Volume 127 Number 1 January 2017Macrophages perform housekeeping processes including removal of apoptotic and necrotic cells, modulation of angiogenesis, ECM remodeling, and differentiation of adipocyte precursors.
“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).”
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Premisecitation§ jci.org Volume 127 Number 1 January 2017NKT cell actions are likely beneficial for adaptation of adipose tissue to acute high-fat feeding because CD1d-deficient mice do not activate adipose NKT cells and display exacerbated insulin resistance.
“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).”
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Premisereasoning§ jci.org Volume 127 Number 1 January 2017Pathologic activation of both innate and adaptive immunity occurs during obesity, though the temporal participation of each component differs.
“Pathologic activation of both innate and adaptive immunity has been observed during obesity, even though the degree to which each component participates differs temporally.”
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Premisecitation§ The adipocyte stress signal: mild hypoxiaHIF-1α activation is pro-angiogenic, pro-fibrotic, and proinflammatory.
“HIF-1α activation is classically described as pro-angiogenic, but recent studies have shown it to also be pro-fibrotic and proinflammatory (4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] source
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Premisecitation§ Healthy angiogenesis.Circulating stem cells can contribute to adipogenesis.
“For example, circulating stem cells can contribute to adipogenesis (19).”
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Premisecitation§ jci.org Volume 127 Number 1 January 2017ApoE3-Leiden mice display increased acute-phase response genes within one week of high-fat feeding and increased chronic inflammatory responses after six weeks.
“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).”
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Premisecitation§ jci.org Volume 127 Number 1 January 2017VEGF is a major regulator of sprouting angiogenesis.
“VEGF is a major regulator of sprouting angiogenesis (42).”
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Premisecitation§ The adipocyte stress signal: mild hypoxiaWithin three days of high-fat feeding, rapid adipocyte hypertrophy and mitochondrial uncoupling raise oxygen demand and lower oxygen availability.
“Within three days of HFF, rapid adipocyte hypertrophy along with mitochondrial uncoupling increase the demand for oxygen and reduce oxygen availability (3).”
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Interpretationreasoning§ An old perspective on a new problemMild hypoxia from adipose expansion triggers a stress signal that drives angiogenesis and extracellular matrix remodeling, supporting further expansion and reducing hypoxia.
“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).”
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Premisenone given§ Healthy angiogenesis.The VEGF-A/VEGFR2 signaling pathway is considered particularly important in angiogenesis and is one of the most potent activators of beiging in subcutaneous depots of rodents.
“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.”
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Premisecitation§ jci.org Volume 127 Number 1 January 2017Monocytes migrate to hypoxic areas and differentiate into proinflammatory macrophages.
“Immune cells, particularly monocytes, migrate to areas of hypoxia, where they differentiate into proinflammatory macrophages (13,14).”
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Premisecitation§ jci.org Volume 127 Number 1 January 2017Acute high-fat-diet stress leads to activation of antiinflammatory macrophages in some reports.
“In contrast, others have reported that acute HFD stress leads to activation of antiinflammatory macrophages (17,18).”
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Premisecitation§ The adipocyte stress signal: mild hypoxiaPHD1 knockout mice have greater fat pad mass and impaired glucose tolerance but do not show exacerbated diet-induced metabolic changes compared with wild-type mice.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Thomas, 2016, Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice, Sci Rep source
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Premisecitation§ Appropriate ECM remodeling.Acute high-fat feeding induces antiinflammatory immune cell actions, cell repair signaling, and angiogenesis.
“that acute HFF induces antiinflammatory immune cell actions, cell repair signaling, and angiogenesis (1,17,18).”
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Premisecitation§ jci.org Volume 127 Number 1 January 2017Macrophages 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).”
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Interpretationnone given§ The adipocyte stress signal: mild hypoxiaThree dominant contributors to dysfunctional adipose tissue in obesity are unresolved inflammation, inappropriate ECM remodeling, and insufficient angiogenic potential.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone given§ jci.org Volume 127 Number 1 January 2017Angiogenesis can be divided into sprouting angiogenesis, which is slow and developmental, and looping/splitting angiogenesis, which is fast and occurs predominantly during adult wound healing.
“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.”
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Premisecitation§ The adipocyte stress signal: mild hypoxiaHIF-1α signaling dominates over HIF-2α in obesity and causally contributes to early adipose tissue dysfunction.
“Although HIF-1α and HIF-2α pathways can interact, HIF-1α signaling dominates in obesity, playing a causative role in early AT dysfunction (3).”
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Premisecitation§ The adipocyte stress signal: mild hypoxiaAdipocytes respond to hypoxia by inducing glycolysis and angiogenesis.
“Adipocytes respond by inducing glycolysis and angiogenesis in an attempt to alleviate the hypoxia (3).”
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Interpretationreasoning§ The adipocyte stress signal: mild hypoxiaInflammation and inadequate angiogenic remodeling can drive fibrosis, which can promote immune cell migration into adipose depots and impede further angiogenesis.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ The adipocyte stress signal: mild hypoxiaAdipocyte-specific deletion of PHD2 produces mice resistant to HFD-induced obesity and, despite elevated HIF-1α and HIF-2α, improved glucose tolerance and insulin sensitivity.
“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).”
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Interpretationnone given§ Unresolved inflammation.During early adipose tissue expansion, a proinflammatory program is activated but the immune response is dominated by antiinflammatory signals.
“Although a proinflammatory program is activated during early AT expansion, the immune response is dominated by antiinflammatory signals.”
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Interpretationcitation§ Unresolved inflammation.In early adipose tissue expansion, a strong ECM degradation signal promotes adipose growth and is important for whole-body metabolic homeostasis.
“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).”
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Premisecitation§ Unresolved inflammation.MMP-9 breaks down fibrous collagen matrix to make space for new blood vessels and releases matrix-bound VEGF.
“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).”
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Premisecitation§ Unresolved inflammation.Genetic introduction of dominant-active HIF-1α in mice was unable to induce an angiogenic response but increased expression of several fibrotic genes.
“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).”
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Premisecitation§ Unresolved inflammation.Both ANG-2 and VEGF-A promote antiinflammatory macrophage polarization.
“Interestingly, both ANG-2 and VEGF-A promote an antiinflammatory macrophage polarization (60,61).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
Premisecitation§ Impaired angiogenesis.It has been argued that oxygen tension in adipose tissue is not low enough to be defined as hypoxic.
“Indeed, it has been argued that the oxygen tension in AT is not low enough to be defined as hypoxic (84).”
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Premisecitation§ Unresolved inflammation.Men fed a high-calorie diet for one week gained significant weight and developed insulin resistance, with oxidative damage detected in adipose tissue biopsies without an increase in inflammatory cell markers.
“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.”
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Premisecitation§ Unresolved inflammation.ANG-2 binds endothelial cell RTK Tie2, activating endothelial migration and proliferation and initiating an NF-κB-dependent inflammatory signaling cascade.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] source
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Premisecitation§ Unresolved inflammation.ROS and RNS produced by immune cells are suggested to contribute to oxidative damage in obese adipose tissue.
“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).”
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Premisecitation§ Unresolved inflammation.Increased oxidative stress and reduced antioxidant defense have been demonstrated in obese adipose tissue.
“Increased oxidative stress and reduced antioxidant defense have been demonstrated in obese AT (74).”
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Premisecitation§ Unresolved inflammation.Adipose-specific overexpression of a dominant-negative TNF-α causes severe glucose intolerance and reduces the insulin-sensitizing adipokine adiponectin in mice fed a high-fat diet.
“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).”
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Premisenone given§ Impaired angiogenesis.It is unknown whether the degree of hypoxia in obese adipose tissue is sufficient to enforce persistent angiogenesis, particularly in human adipose tissue.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Unresolved inflammation.Blood vessels facilitate physical infiltration of macrophages and leukocytes into tissues, and these cells promote endothelial cell proliferation and new blood vessel formation by secreting pro-angiogenic factors.
“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).”
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Interpretationcitation§ Unresolved inflammation.Bona fide fibrosis, defined as excessive ECM protein deposition, is a pathological consequence of long-term obesity, while acute ECM remodeling is essential for early healthy adipose tissue expansion.
“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.”
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Premisecitation§ Impaired angiogenesis.In obese ob/ob mice, the hypoxia response fails to induce VEGF expression and vascular density decreases.
“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).”
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Premisecitation§ Appropriate ECM remodeling.Hyaluronic acid signals through direct binding of cell receptors.
“Many ECM molecules, such as hyaluronic acid (HA), signal through direct binding of cell receptors (45).”
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Premisecitation§ Unresolved inflammation.IL-6, IFN-γ, and CCL2 inhibit insulin signaling in adipocytes.
“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).”
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Premisecitation§ Unresolved inflammation.Tumor vasculature is significantly more permeable than normal tissue, promoting immune cell extravasation and fibrosis.
“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.”
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Premisecitation§ Unresolved inflammation.Collagen VI is cleaved at the C5 domain of the α3 subunit, and the resulting peptide increases collagen deposition, endothelial cell migration, and macrophage infiltration.
“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).”
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Premisecitation§ Unresolved inflammation.TNF-α downregulates GLUT4 and inhibits insulin-dependent tyrosine phosphorylation of the insulin receptor and IRS-1 through ceramide production.
“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).”
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Premisecitation§ Unresolved inflammation.In mice, treatment with antioxidants can attenuate diet-induced inflammation and insulin resistance, suggesting a strong influence of oxidative stress on obesity-associated disease.
“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).”
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Interpretationreasoning§ Impaired angiogenesis.Under chronic high-fat feeding, oxygen demand is high but capacity to form new blood vessels is poor, resulting in disorganized and pathologic angiogenesis.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Impaired angiogenesis.Blocking p53, a major regulator of senescence, prevents cellular senescence and reduces metabolic abnormalities.
“The prevention of cellular senescence through inhibition of the major senescence regulator p53 attenuates metabolic abnormalities (102, 103).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Unresolved inflammation.A recent study suggested docosahexaenoic acid treatment might improve insulin resistance through attenuation of adipose tissue angiogenesis.
“Additionally, a recent study suggested treatment with docosahexaenoic acid might improve insulin resistance through attenuation of AT angiogenesis (90).”
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Premisecitation§ Impaired angiogenesis.In a mouse model, inducing genomic instability by ablating polymerase η raised the number of senescent adipose tissue cells and worsened adipose tissue dysfunction.
“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.”
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Interpretationnone given§ Impaired angiogenesis.Fibrosis occurs during chronic obesity and is accepted as a major contributor to obesity-associated adipose tissue dysfunction.
“Fibrosis occurs during chronic obesity and has been accepted as a major contributor to obesity-associated AT dysfunction.”
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Premisecitation§ Impaired angiogenesis.Senescent cells are growth arrested but highly metabolic and exhibit a SASP producing proinflammatory cytokines, VEGF, MMPs, and PDGF-AA.
“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).”
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Premisecitation§ Unresolved inflammation.In HFD-challenged mice, VEGF-A increased WAT vascularization and beiging, augmented energy expenditure, and prevented unfavorable metabolic changes, while VEGF-A/VEGFR2 blockade aggravated systemic insulin insensitivity.
“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.”
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Premisecitation§ Impaired angiogenesis.In mice given a high-fat diet for 20 weeks, adipose tissue DNA damage and cellular senescence are increased.
“Increased AT DNA damage and resulting cellular senescence have been identified in mice fed a HFD for 20 weeks (102).”
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Premisecitation§ Impaired angiogenesis.Hyaluronic acid accumulates in insulin-resistant adipose tissue of obese mice and is thought to negatively regulate adipocyte insulin signaling.
“Additionally, HA accumulates in insulin-resistant AT in obese mice and is thought to negatively regulate adipocyte insulin signaling (96).”
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Premisecitation§ Impaired angiogenesis.In INK4-ATTAC mice, loss of senescent cells blunted age-related fat loss and enhanced adipogenic transcription factor expression within three weeks.
“In this model, the loss of senescent cells blunted age-related fat loss and enhanced adipogenic transcription factor expression within three weeks.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [101] Xu, 2015, Targeting senescent cells enhances adipogenesis and metabolic function in old age, Elife source
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Premisecitation§ Inflammation.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).”
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Premisecitation§ Impaired angiogenesis.Senescence-associated secretory phenotype factors aid wound healing by attracting immune cells that remove dead cells, supporting angiogenesis, restricting fibrosis, and promoting wound closure.
“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).”
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Premisecitation§ Unresolved inflammation.In ob/ob mice with pre-existing obesity, inhibiting VEGF-A/VEGFR2 signaling improved insulin sensitivity and decreased body weight.
“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.”
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Premisenone given§ Impaired angiogenesis.Cells undergo replicative senescence during natural aging when they reach the genetically determined limit of division.
“Cells undergo so-called replicative senescence during natural aging when they have reached the genetically determined limit of division.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Impaired angiogenesis.In obese individuals, circulating endothelial cell precursors undergo premature senescence, contributing to impaired vascular function and repair.
“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.”
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Interpretationnone given§ Impaired angiogenesis.Senescent cells can originate from most cell types and are potent modulators of inflammation, angiogenesis, and fibrosis.
“Senescent cells can originate from most cell types and are potent modulators of inflammation, angiogenesis, and fibrosis.”
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Premisecitation§ Impaired angiogenesis.Mice genetically deficient in IRF5 display enhanced expansion of subcutaneous adipose tissue but limited expansion of visceral adipose tissue on a high-fat diet.
“Mice genetically deficient in interferon regulatory factor 5 display enhanced expansion of subcutaneous AT but limited expansion of visceral AT on a HFD (98).”
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Interpretationnone given§ Impaired angiogenesis.Deposition of fibrous collagen proteins promotes metabolic dysfunction in obesity, and many other ECM components are dysregulated in obese adipose tissue.
“Although deposition of fibrous collagen proteins is well known to promote metabolic dysfunction in obesity, many other ECM components are dysregulated in obese AT.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ Concluding remarksUpregulation of HIF-1α also increases the fibrotic program in adipose tissue.
“Upregulation of HIF-1α also increases the fibrotic program in AT.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Inflammation.Other reports have found elevated VEGF levels in obese subjects and a positive correlation between VEGF expression and insulin resistance.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Tinahones, 2012, Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels, BMC Physiol source
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Interpretationreasoning§ Concluding remarksThe integrated responses among these three factors promote significant hypotrophy in adipose tissue, resulting in unhealthy adipose tissue expansion and obesity-associated metabolic consequences.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Inflammation.Human studies have reported lower VEGF expression in obese humans, matching findings in mice.
“Similar to findings in mice, human studies have reported that VEGF expression is reduced in obese humans (13).”
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Interpretationnone given§ Concluding remarksDuring early adipose tissue expansion, hypoxia induces stress signaling that promotes angiogenesis through upregulation of genes including VEGF, initiates inflammatory cell infiltration, and induces organized extracellular matrix remodeling to support appropriate adipose tissue expansion.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Inflammation.Less fibrosis is associated with adipocyte hypertrophy, reduced pre-adipocyte hyperplasia, and adipose tissue dysfunction.
“Less fibrosis was associated with adipocyte hypertrophy, reduced pre-adipocyte hyperplasia, and AT dysfunction (122).”
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Interpretationreasoning§ Inflammation.The role of extracellular matrix remodeling and fibrosis in human adipose tissue dysfunction is stage dependent and likely specific to fat depot.
“Thus, the role of ECM remodeling and fibrosis in human AT dysfunction is stage dependent and likely fat depot specific.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Concluding remarksThis hypoxic condition fails to induce VEGF, leading to impaired angiogenesis.
“This hypoxic condition fails to induce VEGF, resulting in impaired angiogenesis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationnone given§ Concluding remarksChronic obesity can cause adipose tissue oxidative stress, DNA damage, and increased exposure to high glucose and ceramide concentrations.
“Chronic obesity can cause AT oxidative stress, DNA damage, and increased exposure to high glucose and ceramide concentrations.”
Quote in the paperNot a substantial claim
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.”
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Impaired insulin-mediated inhibition of lipolysis is further exacerbated by adipose tissue dysfunction.
“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
The “Unresolved inflammation” section says that inflammatory signaling in adipose tissue causes insulin resistance and that TNF-α directly impedes insulin action in adipocytes. This supports a general link between adipose tissue dysfunction and impaired insulin action, but the passages do not establish that dysfunction further weakens insulin’s inhibition of lipolysis specifically. Page numbers were unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAT dysfunction and the resulting impaired AT expandability cause local and systemic low-grade inflammation, fat overflow, and ectopic fat deposition, all associated with insulin resistance.
“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
“An old perspective on a new problem” links unhealthy adipose-tissue expansion to systemic metabolic disturbances, and “Unresolved inflammation” links adipose inflammation to insulin resistance. Our copy does not establish the claimed sequence from impaired expandability to fat overflow and ectopic fat deposition, or specifically describe the resulting inflammation as systemic and low-grade. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNon-adipocytes in adipose tissue are responsible for adipogenesis, angiogenesis, extracellular matrix modeling, and regulation of inflammation and contribute to both the function and dysfunction of adipose tissue.
“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
AT dysfunction is characterized by unhealthy AT expansion with hypertrophic adipocytes, excessive ECM accumulation, interstitial fibrosis, exaggerated pro-inflammatory macrophage infiltration, and dysregulated angiogenesis.
“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
ECM expansion occurs in adipose tissue of obese subjects and limits adipocyte fat storage, leading to ectopic fat stores in liver and skeletal muscle, lipotoxicity, oxidative stress, and inflammation.
“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.”
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Dermal Adipocytes: From Irrelevance to Metabolic Targets?
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“…authentic angiogenic factors, AT secretes several important adi-pokines and endogenous angiogenesis inhibitors to modulate the balance of new blood vessel formation, including adiponectin (36, 37), leptin (34), resistin (38), visfatin/thrombospondin 1 (39), and plasminogen activator inhibitor (40).”
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Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities
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Self-citationReduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis
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Biosynthetic regulation of monobutyrin, an adipocyte-secreted lipid with angiogenic activity
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“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).”
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- 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 · 2015: 1
- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Physiology › 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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