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

In the paper

“At some point during the progression of obesity, adipose depots expand beyond the tissue's capacity for adequate angiogenesis, resulting in persistent hypoxia, fibrosis, cellular senescence, and necrotic adipocyte death (Figure 1)”

In the paper

“For example, VEGF is upregulated in AT of mice fed a HFD for three days, but there are reports of both enhanced and reduced VEGF expression in chronic obesity (3,13,43,44), suggesting that sprouting angiogenesis is activated early and may or may not persist.”

What the sources say

• Not checked yetcites [3] source
• Not checked yetcites [13] source
• Not checked yetcites [43] Tinahones, 2012, Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels, BMC Physiol source
• Not checked yetcites [44] source

In the paper

“Macrophages are responsible for many housekeeping processes, such as removal of apoptotic and necrotic cells, modulation of angiogenesis, ECM remodeling, and differentiation of adipocyte precursors (8).”

What the sources say

• Not checked yetcites [8] source

In the paper

“The actions of NKT cells are likely beneficial for the adaptation of AT to acute HFF because mice deficient in CD1d do not activate AT NKT cells and display exacerbated insulin resistance (17).”

What the sources say

• Not checked yetcites [17] source

In the paper

“Pathologic activation of both innate and adaptive immunity has been observed during obesity, even though the degree to which each component participates differs temporally.”

In the paper

“HIF-1α activation is classically described as pro-angiogenic, but recent studies have shown it to also be pro-fibrotic and proinflammatory (4).”

What the sources say

• Not checked yetcites [4] source

In the paper

“For example, circulating stem cells can contribute to adipogenesis (19).”

What the sources say

• Not checked yetcites [19] source

In the paper

“For instance, ApoE3-Leiden mice, which exhibit a more humanized lipid metabolism compared with WT mice, display increased acute-phase response genes within one week of HFF, whereas chronic inflammatory responses are increased after six weeks of HFF (2).”

What the sources say

• Not checked yetcites [2] source

In the paper

“VEGF is a major regulator of sprouting angiogenesis (42).”

What the sources say

• Not checked yetcites [42] source

In the paper

“Within three days of HFF, rapid adipocyte hypertrophy along with mitochondrial uncoupling increase the demand for oxygen and reduce oxygen availability (3).”

What the sources say

• Not checked yetcites [3] source

In the paper

“The ensuing hypoxia is mild but induces a stress signal that drives angiogenesis and remodeling of the extracellular matrix (ECM) to facilitate further expansion of AT and reduce hypoxia (Figure 1).”

In the paper

“Among these factors, the VEGF-A/VEGFR2 signaling pathway is considered to play a particularly important role in angiogenesis and is one of the most potent activators of beiging in the subcutaneous depots of rodents.”

In the paper

“Immune cells, particularly monocytes, migrate to areas of hypoxia, where they differentiate into proinflammatory macrophages (13,14).”

What the sources say

• Not checked yetcites [13] source
• Not checked yetcites [14] source

In the paper

“In contrast, others have reported that acute HFD stress leads to activation of antiinflammatory macrophages (17,18).”

What the sources say

• Not checked yetcites [17] source
• Not checked yetcites [18] source

In the paper

“PHD1 KO mice exhibit a greater fat pad mass and impaired glucose tolerance but do not show exacerbated diet-induced metabolic changes compared with WT mice (6).”

What the sources say

• Not checked yetcites [6] Thomas, 2016, Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice, Sci Rep source

In the paper

“that acute HFF induces antiinflammatory immune cell actions, cell repair signaling, and angiogenesis (1,17,18).”

What the sources say

• Not checked yetcites [1] source
• Not checked yetcites [17] source
• Not checked yetcites [18] source

In the paper

“Macrophages comprise the largest population of resident immune cells in visceral AT, constituting up to 10% of AT cells in mice (10).”

What the sources say

• Not checked yetcites [10] source

In the paper

“There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential.”

In the paper

“Angiogenesis can be divided into two major subtypes: (a) sprouting angiogenesis, which is slow and the major developmental form of vessel growth and (b) looping/splitting angiogenesis, which is fast and occurs predominantly during adult wound healing.”

In the paper

“Although HIF-1α and HIF-2α pathways can interact, HIF-1α signaling dominates in obesity, playing a causative role in early AT dysfunction (3).”

What the sources say

• Not checked yetcites [3] source

In the paper

“Adipocytes respond by inducing glycolysis and angiogenesis in an attempt to alleviate the hypoxia (3).”

What the sources say

• Not checked yetcites [3] source

In the paper

“For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis.”

In the paper

“In contrast, adipocyte-specific deletion of PHD2 produces mice that are resistant to HFD-induced obesity and, despite elevated levels of both HIF-1α and HIF-2α, the mice display improved glucose tolerance and insulin sensitivity (7).”

What the sources say

• Not checked yetcites [7] source

In the paper

“Although a proinflammatory program is activated during early AT expansion, the immune response is dominated by antiinflammatory signals.”

In the paper

“Thus, in early AT expansion, there is a strong ECM degradation signal to promote AT growth, which is important for maintaining whole body metabolic homeostasis (49).”

What the sources say

• Not checked yetcites [49] source

In the paper

“Furthermore, the actions of MMP-9 both break down the fibrous collagen matrix to make space for new blood vessels and release matrix-bound VEGF (53).”

What the sources say

• Not checked yetcites [53] source

In the paper

“Genetic introduction of dominant-active HIF-1α in mice was unable to induce an angiogenic response but instead increased the expression of several fibrotic genes (4).”

What the sources say

• Not checked yetcites [4] source

In the paper

“Interestingly, both ANG-2 and VEGF-A promote an antiinflammatory macrophage polarization (60,61).”

What the sources say

• Not checked yetcites [60] source
• Not checked yetcites [61] source

In the paper

“Indeed, it has been argued that the oxygen tension in AT is not low enough to be defined as hypoxic (84).”

What the sources say

• Not checked yetcites [84] source

In the paper

“Men fed a high-calorie diet for one week gained significant weight accompanied with insulin resistance (77).Oxidative damage was detected in AT biopsies without an increase in inflammatory cell markers.”

What the sources say

• Not checked yetcites [77] source

In the paper

“ANG-2 binds the endothelial cell RTK Tie2, activating endothelial cell migration and proliferation, but also initiating an NF-κB-dependent inflammatory signaling cascade (59).”

What the sources say

• Not checked yetcites [59] source

In the paper

“It has been suggested that the production of ROS and RNS by immune cells contribute to the oxidative damage observed in obese AT (74,75).”

What the sources say

• Not checked yetcites [74] source
• Not checked yetcites [75] source

In the paper

“Increased oxidative stress and reduced antioxidant defense have been demonstrated in obese AT (74).”

What the sources say

• Not checked yetcites [74] source

In the paper

“Adipose-specific overexpression of a dominant-negative form of TNF-α causes severe glucose intolerance and a reduction in the insulin-sensitizing adipokine adiponectin in mice fed a HFD (82).”

What the sources say

• Not checked yetcites [82] source

In the paper

“Although the majority of studies have shown that obese AT is hypoxic, we do not know if the degree of hypoxia is sufficient to enforce persistent angiogenesis, particularly in human AT.”

In the paper

“Blood vessels facilitate the physical infiltration of macrophages and leukocytes into tissues.These cells in turn promote endothelial cell proliferation and new blood vessel formation by secreting pro-angiogenic factors (54)(55)(56).”

What the sources say

• Not checked yetcites (54)(55)(56)

In the paper

“Bona fide fibrosis, defined as excessive ECM protein deposition, is a pathological consequence of long-term obesity, but acute ECM remodeling is essential for early healthy AT expansion.”

In the paper

“Interestingly, unlike acute AT expansion, the hypoxia response of obese ob/ob mice fails to induce VEGF expression, and instead a decrease in vascular density is observed (4).”

What the sources say

• Not checked yetcites [4] source

In the paper

“Many ECM molecules, such as hyaluronic acid (HA), signal through direct binding of cell receptors (45).”

What the sources say

• Not checked yetcites [45] source

In the paper

“Other factors produced by inflammatory cells have since been shown to inhibit insulin signaling in the adipocyte including IL-6, IFN-γ and CCL2 (72,73).”

What the sources say

• Not checked yetcites [72] source
• Not checked yetcites [73] source

In the paper

“As in obese AT, tumor vasculature is significantly more permeable than that of normal tissue (87), a characteristic that promotes immune cell extravasation and fibrosis.”

What the sources say

• Not checked yetcites [87] source

In the paper

“For example collagen VI is cleaved at the C5 domain of the α3 subunit and the resulting peptide induces multiple processes including increasing collagen deposition, endothelial cell migration and macrophage infiltration (46,47).”

What the sources say

• Not checked yetcites [46] source
• Not checked yetcites [47] Sun, 2014, Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction, Nat Commun source

In the paper

“It downregulates the major insulin-responsive glucose transporter GLUT4 and inhibits insulin-dependent tyrosine phosphorylation of the insulin receptor and IRS-1 through ceramide production (70,71).”

What the sources say

• Not checked yetcites [70] Lumeng, 2007, Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins, Am J Physiol Endocrinol Metab source
• Not checked yetcites [71] source

In the paper

“In mice, the chronology of oxidative stress and inflammation onset is not known; however, treatment of mice with antioxidants can attenuate diet-induced inflammation and insulin resistance, suggesting a strong influence of oxidative stress on obesity-associated disease (78)(79)(80).”

What the sources say

• Not checked yetcites (78)(79)(80)

In the paper

“Under the persistent metabolic challenge of chronic HFF, the demand for oxygen is great but the capacity to form new blood vessels is poor.The consequence is disorganized and pathologic angiogenesis; however, the underlying mechanisms are not fully understood.”

In the paper

“The prevention of cellular senescence through inhibition of the major senescence regulator p53 attenuates metabolic abnormalities (102, 103).”

What the sources say

• Not checked yetcites [102] source
• Not checked yetcites [103] source

In the paper

“Additionally, a recent study suggested treatment with docosahexaenoic acid might improve insulin resistance through attenuation of AT angiogenesis (90).”

What the sources say

• Not checked yetcites [90] source

In the paper

“This study established a strong link between cell senescence and obesity by demonstrating that inducing genomic instability through ablation of polymerase η increased the number of senescent AT cells and exacerbated AT dysfunction.”

What the sources say

• Not checked yetcites [102] source

In the paper

“Fibrosis occurs during chronic obesity and has been accepted as a major contributor to obesity-associated AT dysfunction.”

In the paper

“Although growth arrested, senescent cells are highly metabolic and exhibit a senescence-associated secretory phenotype (SASP), producing factors that have profound effects on neighboring cells such as proinflammatory cytokines (IL-6, IL-8, TNF-α, monocyte chemoattractant protein 1 [MCP-1]), VEGF, MMPs, and PDGF-AA (100).”

What the sources say

• Not checked yetcites [100] source

In the paper

“In HFD-challenged mice, VEGF-A significantly increased WAT vascularization and beiging, which augmented energy expenditure and prevented unfavorable metabolic changes, while blockade of VEGF-A/VEGFR2 caused aggravated systemic insulin insensitivity.”

What the sources say

• Not checked yetcites [22] source

In the paper

“Increased AT DNA damage and resulting cellular senescence have been identified in mice fed a HFD for 20 weeks (102).”

What the sources say

• Not checked yetcites [102] source

In the paper

“Additionally, HA accumulates in insulin-resistant AT in obese mice and is thought to negatively regulate adipocyte insulin signaling (96).”

What the sources say

• Not checked yetcites [96] source

In the paper

“In this model, the loss of senescent cells blunted age-related fat loss and enhanced adipogenic transcription factor expression within three weeks.”

What the sources say

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

In the paper

“Weisberg et al. demonstrated that subcutaneous AT macrophage infiltration was increased in obese patients, similar to that observed in obese mice (10).”

What the sources say

• Not checked yetcites [10] source

In the paper

“SASP has recently been shown to have a beneficial effect on wound healing by recruiting immune cells to clear dead cells, promote angiogenesis, limit fibrosis, and stimulate wound closure (100, 111, 112).”

What the sources say

• Not checked yetcites [100] source
• Not checked yetcites [111] source
• Not checked yetcites [112] source

In the paper

“In contrast, in ob/ob mice with pre-existing obesity, inhibiting the VEGF-A/ VEGFR2 signaling pathway resulted in improved insulin sensitivity and decreased body weight.”

What the sources say

• Not checked yetcites [22] source

In the paper

“Cells undergo so-called replicative senescence during natural aging when they have reached the genetically determined limit of division.”

In the paper

“Systemically, the circulating endothelial cell precursor population undergoes premature senescence in obese individuals (107), contributing to the impairments in vascular function and repair observed in obesity.”

What the sources say

• Not checked yetcites [107] source

In the paper

“Senescent cells can originate from most cell types and are potent modulators of inflammation, angiogenesis, and fibrosis.”

In the paper

“Mice genetically deficient in interferon regulatory factor 5 display enhanced expansion of subcutaneous AT but limited expansion of visceral AT on a HFD (98).”

What the sources say

• Not checked yetcites [98] source

In the paper

“Although deposition of fibrous collagen proteins is well known to promote metabolic dysfunction in obesity, many other ECM components are dysregulated in obese AT.”

In the paper

“Upregulation of HIF-1α also increases the fibrotic program in AT.”

In the paper

“However, contradictory reports have demonstrated elevated levels of VEGF in obese subjects as well as a positive correlation between VEGF expression and insulin resistance (43).”

What the sources say

• Not checked yetcites [43] Tinahones, 2012, Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels, BMC Physiol source

In the paper

“The integrated responses among those three factors promote significant hypotrophy in adipose tissue, and the consequence is an unhealthy AT expansion as well as obesity-associated metabolic consequences.”

In the paper

“Similar to findings in mice, human studies have reported that VEGF expression is reduced in obese humans (13).”

What the sources say

• Not checked yetcites [13] source

In the paper

“Hypoxia during early AT expansion induces stress signaling that facilitates angiogenesis via upregulation of an array of genes including VEGF, initiates inflammatory cell infiltration, and induces organized ECM remodeling to encourage appropriate AT expansion.”

In the paper

“Less fibrosis was associated with adipocyte hypertrophy, reduced pre-adipocyte hyperplasia, and AT dysfunction (122).”

What the sources say

• Not checked yetcites [122] source

In the paper

“Thus, the role of ECM remodeling and fibrosis in human AT dysfunction is stage dependent and likely fat depot specific.”

In the paper

“This hypoxic condition fails to induce VEGF, resulting in impaired angiogenesis.”

In the paper

“Chronic obesity can cause AT oxidative stress, DNA damage, and increased exposure to high glucose and ceramide concentrations.”