The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.

In the paper

“The current pervasive state of chronic overnutrition results in an increase in unresolved AT hypoxia.”

In the paper

“as CD8 + T cell infiltration has been observed to precede and induce AT macrophage accumulation in other settings (11).”

What the sources say

• Not checked yetcites [11] source

In the paper

“In contrast, HIF-2α attenuates HFD-induced inflammation (3).”

What the sources say

• Not checked yetcites [3] source

In the paper

“Although few studies have directly addressed the effect of mild hypoxia during early AT expansion on AT inflammatory processes, there have been reports of both pro-and antiinflammatory responses during the first four days of HFF.”

In the paper

“Interestingly, populations of white adipocyte progenitors have been identified in the mural compartment of vascular structures.”

What the sources say

• Not checked yetcites [20] source

In the paper

“Gupta et al. used a genetic reporter mouse driven by the promoter of a transcription factor that is important for pre-adipocyte determination, ZFP423, to demonstrate a perivascular origin of pre-adipocytes for both white and brown ATs (21)(22)(23).”

What the sources say

• Not checked yetcites (21)(22)(23)

In the paper

“As an early event in AT expansion, hypoxia likely plays a fundamental role in the initiation of inflammation.”

In the paper

“Tang et al. demonstrated that these mural cells with high adipogenic potential can be identified by expression of PDGFR-β (20).”

What the sources say

• Not checked yetcites [20] source

In the paper

“Adipocytes release proinflammatory factors such as IL-6 and macrophage migration inhibitory factor (12).”

What the sources say

• Not checked yetcites [12] source

In the paper

“There is no direct evidence for the existence of these types of angiogenesis in obese adult AT, but we could speculate that distinct angiogenic mechanisms participate during AT expansion and are dependent on the extent of hypoxia and the complex regulation in early or late stages of expansion.”

In the paper

“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).”

What the sources say

• Not checked yetcites [1] source

In the paper

“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).”

What the sources say

• Not checked yetcites [36] Lee, 2015, Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway, Oncotarget source
• Not checked yetcites [37] source
• Not checked yetcites [34] source
• Not checked yetcites [38] Robertson, 2009, Induction of angiogenesis by murine resistin: putative role of PI3-kinase and NO-dependent pathways, Regul Pept source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [16] source

In the paper

“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).”

What the sources say

• Not checked yetcites [5] source

In the paper

“Moreover, adipocytes can secrete pro-angiogenic lipid species such as monobutyrin (41).”

What the sources say

• Not checked yetcites [41] Wilkison, 1991, Biosynthetic regulation of monobutyrin, an adipocyte-secreted lipid with angiogenic activity, J Biol Chem source

In the paper

“Thus, the early response to AT expansion is likely the result of a balanced action between pro-and antiinflammatory signals.”

In the paper

“It is this plasticity that has made AT an essential organ for maintaining metabolic homeostasis during times when food is either abundant or scarce.”

In the paper

“Macrophage infiltration into AT occurs within one day of HFF (15).”

What the sources say

• Not checked yetcites [15] source

In the paper

“ultimately leading to unhealthy AT tissue expansion, a major contributor to the systemic metabolic disturbances that are characteristic of obesity and type 2 diabetes.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [2] source

In the paper

“Local hypoxia is a potent stimulus for new blood vessel formation through the pro-angiogenic actions of HIF-1α and HIF-2α (24,25).”

What the sources say

• Not checked yetcites [24] source
• Not checked yetcites [25] García-Martín, 2015, Adipocyte-specific hypoxia-inducible factor 2α deficiency exacerbates obesity-induced brown adipose tissue dysfunction and metabolic dysregulation, Mol Cell Biol source

In the paper

“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.”

What the sources say

• Not checked yetcites [68] source

In the paper

“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).”

What the sources say

• Not checked yetcites [8] source
• Not checked yetcites [9] source

In the paper

“Mice with heterozygous deletion of MMP-14 are not able to appropriately re-model the ECM, resulting in reduced capacity for adipose expansion (48).”

What the sources say

• Not checked yetcites [48] source

In the paper

“Mechanical forces that exist during the rapid growth of a tumor induce this kind of angiogenesis (86).”

What the sources say

• Not checked yetcites [86] Kreuger, 2016, Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis, Nat Rev Drug Discov source

In the paper

“In contrast, the combination of low VEGF signaling and increased myofibroblast activation suggests that splitting angiogenesis occurs more frequently during chronic obesity.”

In the paper

“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).”

What the sources say

• Not checked yetcites [88] source
• Not checked yetcites [89] source

In the paper

“Hypoxia is a powerful trigger for ECM remodeling and inflammation as a means to facilitate angiogenesis.”

In the paper

“TNF-α, produced by immune cells, was the first cytokine demonstrated to directly impede insulin action in the adipocyte (69).”

What the sources say

• Not checked yetcites [69] source

In the paper

“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.”

In the paper

“In addition, oxidative modification of cellular components such as glutathionylated 4-hydroxy-2-nonenal can directly stimulate a macrophage-mediated proinflammatory response (81).”

What the sources say

• Not checked yetcites [81] source

In the paper

“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.”

What the sources say

• Not checked yetcites [52] source

In the paper

“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.”

In the paper

“Finally, HA can participate in TGF-β1-dependent proliferation of fibroblasts to promote fibrosis.”

In the paper

“Conversely, mice deficient in collagen VI exhibit unimpeded tissue expansion (49).”

What the sources say

• Not checked yetcites [49] source

In the paper

“HA is also a potent inducer of the innate immune response through binding and activation of immune cell TLR2 and -4 (51).”

What the sources say

• Not checked yetcites [51] source

In the paper

“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).”

What the sources say

• Not checked yetcites [85] source

In the paper

“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).”

What the sources say

• Not checked yetcites [82] source

In the paper

“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).”

What the sources say

• Not checked yetcites [50] source

In the paper

“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.”

What the sources say

• Not checked yetcites [52] source

In the paper

“This new vasculature provides the framework for adipogenesis and growth of the fat pad (52).”

What the sources say

• Not checked yetcites [52] source

In the paper

“Additionally, several cytokines produced by inflammatory cells have angiogenic effects, including TNF, IL-6, and IL-8 (57, 58).”

What the sources say

• Not checked yetcites [57] Kwon, 2013, Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis, Biochim Biophys Acta source
• Not checked yetcites [58] source

In the paper

“Thus, AT inflammation in obese individuals cannot be assigned a strictly pathologic role.”

In the paper

“Genes involved in collagen breakdown, particularly MMP14, are significantly upregulated in mice fed a HFD for one week (48).”

What the sources say

• Not checked yetcites [48] source

In the paper

“In fact, TNF-α plays an essential role in the adaptation of AT to HFF.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [13] source
• Not checked yetcites [83] source

In the paper

“A potential mechanism for hypoxia-induced angiogenesis during early AT expansion is the production of pro-angiogenic, low-molecular-weight HA (LMW-HA).”

In the paper

“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.”

What the sources say

• Not checked yetcites (91)(92)(93)

In the paper

“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).”

What the sources say

• Not checked yetcites [65] source
• Not checked yetcites [113] source

In the paper

“Division-competent cells can also be pushed to senescence though damaging stresses such has oncogene induction, oxidative stress, and double-strand DNA breaks (99).”

What the sources say

• Not checked yetcites [99] source

In the paper

“The actions of MAGP1 have been shown to protect mice from obesity and associated metabolic defects (95).”

What the sources say

• Not checked yetcites [95] source

In the paper

“Any metabolic improvements afforded by these systemically introduced compounds cannot be directly attributed to reduced angiogenesis in AT.”

In the paper

“Therefore, in chronic obesity the beneficial effects of time-limited cellular senescence in wound healing are replaced by the detrimental effects of chronic SASP.”

In the paper

“MAGP1 binds active TGF-β, sequestering it in the ECM (95).”

What the sources say

• Not checked yetcites [95] source

In the paper

“Genetic knockout of the collagen-binding receptor integrin in the muscle of diet-induced obese mice increases vascularization (97).”

What the sources say

• Not checked yetcites [97] source

In the paper

“Despite these results, the inhibition of angiogenesis as a therapeutic strategy for obesity remains a controversial notion (94).”

What the sources say

• Not checked yetcites [94] source

In the paper

“Restricted epididymal AT expansion was associated with a large increase in antiinflammatory macrophage infiltration, collagen deposition, and improved insulin sensitivity.”

What the sources say

• Not checked yetcites [98] source

In the paper

“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).”

What the sources say

• Not checked yetcites [101] Xu, 2015, Targeting senescent cells enhances adipogenesis and metabolic function in old age, Elife source

In the paper

“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).”

What the sources say

• Not checked yetcites [10] source
• Not checked yetcites [114] source
• Not checked yetcites [115] source

In the paper

“Fibrosis has been suggested to limit AT angiogenic capacity.”

In the paper

“Thus, cell senescence of adipocytes, endothelial cells, or their precursors might have major effects on AT homeostasis.”

In the paper

“Surprisingly, preadipocytes and mature adipocytes as well as endothelial cells can become senescent during obesity (105-109).”

What the sources say

• Not checked yetcites [105] source
• Not checked yetcites [106] source
• Not checked yetcites [107] source
• Not checked yetcites [108] source
• Not checked yetcites [109] source

In the paper

“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).”

What the sources say

• Not checked yetcites [104] source

In the paper

“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).”

What the sources say

• Not checked yetcites [22] source

In the paper

“Recent studies have identified an important role for cellular senescence in many diseases including those associated with obesity.”

In the paper

“Reduced blood flow, as seen in obese AT, is sufficient to trigger endothelial cell senescence (105, 110).”

What the sources say

• Not checked yetcites [105] source
• Not checked yetcites [110] source

In the paper

“SASP factors are also likely to have considerable effects on AT immunity, angiogenesis, and fibrosis.”

In the paper

“Interestingly, the detrimental effects of fibrosis-mediated restriction of AT expansion during obesity on metabolic health may be dependent on the adipose depot affected.”

In the paper

“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).”

What the sources say

• Not checked yetcites [118] source

In the paper

“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).”

What the sources say

• Not checked yetcites [77] source

In the paper

“However, persistent stress signaling translates into injury signaling, caused by long-term and severe hypoxia.”

In the paper

“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).”

What the sources say

• Not checked yetcites [122] source

In the paper

“Another independent study also reported less collagen content in visceral AT from metabolically unhealthy obese patients (123).”

What the sources say

• Not checked yetcites [123] source

In the paper

“Limited oxygen supply also triggers chronic low-grade inflammation predominantly characterized by proinflammatory macrophage infiltration.”

In the paper

“Thus, in both rodent models and human studies, VEGF-A-mediated AT angiogenesis exerts dichotomous effects in AT expansion and function.”

In the paper

“The majority of human studies have reported fibrosis in obese AT (119-121).”

What the sources say

• Not checked yetcites [119] source
• Not checked yetcites [120] source
• Not checked yetcites [121] source

In the paper

“Moreover, others have shown that 12 months after bariatric surgery, AT inflammation remained elevated in approximately 40% of patients (117).”

What the sources say

• Not checked yetcites [117] source

In the paper

“These deleterious factors can drive cellular senescence in many cells types.”

In the paper

“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).”

What the sources say

• Not checked yetcites [10] source
• Not checked yetcites [114] source
• Not checked yetcites [115] source

In the paper

“SASP factors can promote AT dysfunction through dysregulation of AT ECM remodeling, inflammation, and angiogenesis.”