Visceral fat and inflammation -
Resident B-1b lymphocytes secrete natural IgM antibodies and promote adipose physiological functions by suppressing B-2 cells, in mice and humans [ 17 ].
In addition, B-1 cells comprise the major cell type of fat-associated lymphoid clusters which appear to contribute to humoral immune responses to peritoneal antigens [ 18 ]. Lymphoid clusters in mice and humans are also a rich source of Th2-like cytokines released from innate Th2-like lymphoid cells [ 19 , 20 ].
Fat-associated lymphoid clusters such as milky spots on the omentum surface probably serve immune functions of the peritoneal cavity rather than supporting physiological fat tissue functions. Indeed, the numbers of milky spots increase during peritoneal inflammation in response to local TNFα and innate natural killer T cell activity [ 20 , 21 ].
Studies in mice suggest that sympathetic innervation is promoted by γδT cells by signaling via the IL receptor C to induce TGFß1 production by parenchymal cells [ 22 ]. Further, sympathetic neuron-associated macrophages SAMs regulate neuron growth and modulate adrenergic signaling [ 23 ].
Based mostly on animal studies, the continuous release of anti-inflammatory mediators from macrophages, dendritic cells, Th2-cells, γδT cells, eosinophils, mucosa-associated invariant T cells MAIT , and invariant natural killer T cells appears to further help maintain metabolic homeostasis [ 14 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] Fig.
The support of tissue functions by resident immune cells involves interactions with non-immune tissue cells including adipocytes, endothelial cells, neurons, fibroblasts, and other mesenchymal stromal cells [ 3 , 33 , 34 ].
In the absence of immunologic stimuli, immune mediator secretion from resident immune cells and other fat tissue cells is low. The local immune milieu is well buffered, i. Further, pro-inflammatory TNFα and ILA induce counterregulatory IL for the stimulation of anti-inflammatory Tregs and ILC2s [ 15 , 35 , 36 ].
Taken together, in lean visceral adipose tissue, there is a physiological network of adipocytes, stromal cells, and immune cells.
The resident immune system is not dormant but supports overall tissue functions. Cytokines, chemokines, acute phase proteins, and other immune mediators are released in small amounts mostly from resident immune cells but also from mesenchymal stromal cells and adipocytes [ 37 , 38 ].
The primary cause of progression from lean to obese visceral fat tissue is excess calorie intake, including digestible carbohydrates.
Human metabolic control usually is geared in such a way that a calorie surplus is not disposed of by generating additional thermal energy but is stored to a large degree as triglycerides in adipocytes. Excess calorie consumption causes an increase of circulating insulin levels after and between meals.
Being an anabolic hormone, insulin suppresses lipolysis and promotes fat storage in adipocytes already at concentrations that are in the high normal range or which are slightly elevated. Pharmacological or experimental lowering of insulin levels indeed ameliorates obesity which indicates that the support of lipogenesis by insulin is obesogenic reviewed by [ 39 ].
These regulatory effects of insulin do not apply for all adipocytes. In subcutaneous tissue about half of mature adipocytes are insulin responsive, the two other subtypes exhibit little or no increased transcriptional activity when exposed to hyperinsulinemia [ 10 ].
Anabolic activity of visceral fat tissue in response to overnutrition involves adipocyte enlargement and hyperplasia to accommodate for increased requirements of energy storage, i.
Lipogenesis leads to enlargement of mature adipocytes because of more fat stored in one large lipid droplet organelle. There is also differentiation and growth of preadipocytes, but in visceral fat hyperplasia contributes less to the increase of fat mass than adipocyte hypertrophy [ 41 ].
The formation of new fat-laden adipocytes from precursor cells appears to begin when enlarged mature adipocytes reach a critical cell size and release mediators stimulating preadipocyte growth and differentiation [ 42 , 43 ]. Fat cell hyperplasia thus is a second pathway of coping with excess circulating nutrients Fig.
Response of visceral fat tissue to excess calories by adipocyte hypertrophy and hyperplasia. In response to high levels of circulating glucose, triglycerides, and the anabolic hormone insulin mature adipocytes take up increased amounts of nutrients and store excess energy as triglycerides in one large lipid droplet organelle.
The cell size may increase 10—fold in diameter. Enlarged adipocytes secrete factors favoring angiogenesis and remodeling of the extracellular matrix and release of growth factors which is essential for mesenchymal stem cells, adipocyte progenitors, and preadipocytes to differentiate into lipid-storing mature adipocytes.
In parallel, macrophages are stimulated to support angiogenesis and matrix remodeling. ATM, adipocyte tissue macrophages; TGs, triglycerides; Glc, glucose; ECM, extracellular matrix; Pro-inflamm.
Studies in mice indicate that a major obstacle to fat tissue expansion in response to high-fat diet feeding is the collagen network of the extracellular matrix. A major source of collagen is perivascular cells in response to signaling via the platelet-derived growth factor 1α [ 44 ].
Most relevant for limiting fat tissue expansion is the extracellular matrix of niches rich in adipocyte precursors. Interestingly, these niches harbor potentially pro-inflammatory macrophages [ 10 ] and induction of acute local inflammation, for instance by injection of low-dose lipopolysaccharide enhances fibrolysis and remodeling of the extracellular matrix, and promotes angiogenesis to allow for efficient adipocyte hyperplasia.
Enlarged adipocytes initiate fat tissue remodeling by secreting angiogenic factors such as such as fibroblast growth factor-2, vascular endothelial growth factor, human growth factor, and other mediators such as extracellular matrix proteases Fig.
Efficient remodeling requires activation of pro-inflammatory macrophages by hypertrophic adipocytes which appears to be a physiological response needed for fat tissue growth because downregulation of pro-inflammatory reactivity prevents proper adipocyte hyperplasia [ 41 , 45 , 46 ].
Thus, at least initially, inflammation in adipose tissue is a physiological adaptive response which improves fat tissue plasticity and consequently preserves metabolic control and insulin sensitivity [ 47 ].
A similar important role of inflammatory reactions, such as activation of the NLRP3 inflammasome, has been reported to drive postburn white adipose tissue remodeling [ 48 ]. Storage of energy in form of triglycerides also occurs in other fat tissues of the body, notably subcutaneous fat.
The adipogenic activity and the ability to mobilize preadipocytes in response to overeating have been reported to be delayed in subcutaneous fat and therefore may be insufficient to lower the metabolic stress of visceral fat tissue during excess calorie intake [ 43 ].
However, this is different in persons with true metabolic healthy obesity, i. In these persons, the growth of visceral fat and adipocyte enlargement is only moderate, and excess nutrients are primarily handled by enlargement and hyperplasia of adipocytes in subcutaneous fat tissue, primarily in the superficial layer [ 43 , 50 , 51 , 52 ].
In sum, the primary fat tissue response to excess calorie intake includes enlargement of adipocytes, differentiation of new mature cells from pre-adipocytes or stem cells, all supported by remodeling of the extracellular matrix, and of angiogenesis for appropriate blood supply.
Growth of visceral fat tissue is not possible without appropriate remodeling of the vasculature and the extracellular matrix surrounding preadipocytes and small adipocytes. Enlarged adipocytes initiate these changes by secreting factors promoting angiogenesis and matrix remodeling.
These adaptive responses are characteristic of metabolically healthy obesity. A recent overview of inflammatory responses to non-infectious stimuli in various tissues of the body has concluded that there appear to be three types of perturbation causing an inflammatory response which, at least initially, are considered protective [ 2 ] The suggested hierarchy of perturbations is loss of regulation, loss of function and loss of structure.
This concept is applied here to obese fat tissue, and the current section considers loss of regulation. In those visceral adipose regions where the adaptive response to excess energy influx has reached a limit, metabolic homeostasis is lost, and activation of resident immune cells occurs.
In detail, strongly enlarged adipocytes fail to maintain metabolic homeostasis of lipid storage versus lipolysis because the lipid overload leads to endoplasmic reticulum stress, increased expression of the inflammation regulator NF-kB and the production of inflammation-inducing signals such as IL-6 [ 40 , 53 ].
The secretion of pro-inflammatory mediators in response to loss of metabolic homeostasis has been termed metaflammation [ 54 ]. Enlarged adipocytes exhibit additional responses to caloric stress.
For instance, adipocytes respond to high ambient nutrient concentrations with the release of leptin and other hormones which target the brain to limit food intake and increase the sympathetic tone. Adrenaline and noradrenaline are released from nerve endings in adipose tissue and activate lipolysis by signaling via ß-adrenergic receptors of adipocytes.
Sympathetic neuron-associated macrophages may function as rate-limiters by degrading noradrenaline via monoamine oxidase A [ 23 ]. The locally increased concentration of non-esterified fatty acids is expected to activate pro-inflammatory macrophage functions.
This may involve co-secretion of adipocyte fatty acid binding protein FABP4 , induction of FABP4 in macrophages, and signaling via toll-like receptors TLR4 and TLR2.
Free fatty acids do not directly bind to TLR4, but lipid metabolism within macrophages is affected by the influx of free fatty acids which has pro-inflammatory consequences if there is simultaneous activation of TLR4.
The latter may result from increased levels of lipopolysaccharide released from gut microbiota in the context of gut leakiness during an obesogenic diet [ 55 , 56 , 57 , 58 , 59 , 60 ]. Further, recent studies suggest a role of adenine nucleotide translocase 2 in mediating free fatty acid-induced mitochondrial dysfunction, increased oxygen radical production and NF-kB activation in fat tissue macrophages [ 61 ].
The secretion of leptin by enlarged adipocytes not only limits food intake and promotes lipolysis in visceral fat but also engages leptin receptors present on most immune cells. Another pathway of promoting local inflammation in response to adipocyte enlargement is activated by rapid fat tissue growth in the presence of insufficient angiogenesis which lowers capillary density and increases diffusion distance for oxygen eventually resulting in a hypoxic environment of enlarged adipocytes.
Adipose is among the most vascularized tissues with each adipocyte surrounded by capillaries [ 63 ]. Lowering ambient oxygen concentration in adipocyte culture caused a switch from oxidative phosphorylation to anaerobic glycolysis and changed the expression of more than genes [ 64 ].
One major mediator of this response is hypoxia-inducible factor 1α [ 55 ]. Pro-inflammatory mediators secreted by mature adipocytes during hypoxia include chemokines and cytokines such as PAI-1, CCL5, and IL-6 as well as micro RNAs [ 65 , 66 , 67 , 68 ] Fig.
A subset of macrophages is closely associated with the vasculature and characterized by the expression of lymphatic vessel endothelial hyaluronan receptor 1.
These macrophages support angiogenesis by producing tissue remodeling growth factors and metalloproteinases [ 21 , 69 ]. Hypoxia does not homogeneously affect visceral fat tissue but is a regional phenomenon as concluded from immunohistochemical staining for hypoxia-inducible factor 1α.
The colocalization of enhanced numbers of macrophages and T cells supports the pro-inflammatory property of hypoxia [ 70 ]. Local inflammation in response to disturbed adipocyte metabolic homeostasis. When enhanced lipid storage via adipocyte enlargement and differentiation of progenitor cells fails to maintain metabolic homeostasis, local inflammatory changes occur in order to dispose of excess lipid and regain metabolic control.
For one, lipid-laden adipocytes experience endoplasmic reticulum stress and increased expression of NFkB leading to the release of pro-inflammatory mediators such as IL Additional pro-inflammatory signals are delivered by the release of free fatty acids, leptin, lipopolysaccharides, and other products of an unbalanced microbiota in the context of a leaky gut.
Activated resident immune cells release amounts of pro-inflammatory mediators sufficient to promote lipolysis and suppress lipid storage in part via induction of insulin resistance. In addition, there is an uptake of lipids by macrophages and storage in small lipid droplets. Leptin interacts with receptors in the brain to limit food intake and increase the sympathetic tone.
The increased local release of noradrenaline also promotes lipolysis. Another pro-inflammatory condition results from hypoxia due to local enlargement of adipocytes.
The concomitant release of enzymes and factors promoting tissue remodeling and angiogenesis may be considered a healing response. Enlarged adipocytes overexpress MHC class II antigens and appear to present antigens to CD4-positive T cells.
Another pathway of limiting energy storage is the induction of adipocyte beiging by transdifferentiation or growth from progenitors and the disposal of excess energy by thermogenesis. A third pathway of pro-inflammatory activation of resident immune cells is suggested by the finding that hypertrophic adipocytes overexpress major histocompatibility antigens class II MHCII and produce costimulatory molecules for effective antigen presentation to CD4 positive T cells.
Although antigens presented have not been identified, it is remarkable that mice with genetic depletion of MHC II in adipocytes gain weight as control mice but do not develop adipose tissue inflammation and insulin resistance [ 71 ].
An additional pathway of lowering the metabolic stress in obese visceral fat tissue is the transdifferentiation of white adipocytes to beige adipocytes and the formation of new beige adipocytes from precursor cells Fig.
Beige adipocytes contain several smaller lipid droplet organelles and more mitochondria than hypertrophic adipocytes for burning free fatty acids to generate heat. Secretion of IL from macrophages promotes thermogenesis in fat cells [ 8 ], as does the release of enkephalin peptides from ILC2 cells [ 11 , 12 ].
The major mediator of beiging in visceral fat released by adipocytes in obesity is fibronectin type III domain-containing protein 4 FNDC4 which probably targets the receptor GRP There is a positive association between the expression of FNDC4 and obesity-associated inflammation [ 72 ].
In line with a role in regaining normal tissue homeostasis, FNDC4 exhibits anti-inflammatory properties in macrophages [ 73 ]. Taken together, loss of metabolic homeostasis in fat tissue is sufficient to initiate a local pro-inflammatory response. Secretion of pro-inflammatory mediators from macrophages and other immune cells substantially exceeds the release from adipocytes [ 38 ].
This may be viewed as an attempt to restore proper energy balance [ 74 ]. The locally enhanced concentrations of mediators like TNFα, IL-1, and IL-6 act back on adipocytes and suppress further lipid storage by inhibiting lipoprotein lipase, needed for lipid uptake, and by promoting lipolysis and fatty acid release via several pathways.
These include the local induction of insulin resistance in insulin-sensitive adipocytes resulting from engaging TNFα or other pro-inflammatory mediators including microRNAs and subsequent impairment of insulin signaling for lipolysis inhibition [ 26 , 75 ].
Further support comes from increased activation of extracellular signal-regulated kinase ERK stimulating beta3 adrenergic receptor-mediated lipolysis via protein kinase A [ 76 ]. Inflammatory stress induces kinase activity of inositol-requiring protein 1 IRE-1 , a component of the endoplasmic reticulum stress response, which is also followed by enhanced lipolysis [ 77 ].
In addition, there is upregulation of lysosomal biogenesis, increased uptake and turnover of lipids, and increased formation of lipid droplets in macrophages, all of which can be considered an attempt to lower the lipid load of adipocytes [ 78 ].
The interaction between the various cell types in adipose tissue can also be described as crosstalk since there is signaling between cells in both directions. Crosstalk not only involves the secretion of soluble mediators but also of particulate structures such as extracellular vesicles or mitochondria [ 79 , 80 ].
The scenario described relates to observations in animal models. In humans, the direct demonstration an early phase of inflammatory reactions induced by metabolically stressed enlarged adipocytes during overnutrition would require repeated biopsies of visceral fat tissue, but the mechanisms detailed above also apply to human cells.
In mice, high-fat diet feeding studies observed an early period of 4—8 weeks with adipocyte enlargement, limited local immune activation, vasculogenesis, matrix remodeling, and clearance of a low number of dead adipocytes by local macrophages [ 81 ].
A general characteristic of tissue damage is the loss of structural integrity, i. Many of these molecules are immunostimulatory damage-associated molecular patterns DAMPs , they include stress proteins, high mobility group box 1 protein HMGB1 , DNA, some lipids, and mitochondrial structures, among many others.
DAMP receptors also called pattern recognition receptors are present on innate immune cells and in part also on adaptive immune cells and non-immune cells such as epithelial cells, endothelial cells, or fibroblasts.
DAMP receptors include toll-like receptors, C-type lectin receptors, cytoplasmic NLR receptors, and several DNA sensors. Signaling via these receptors leads to the production of pro-inflammatory cytokines and other mediators [ 82 , 83 ].
Dead adipocytes accumulate in obese visceral tissue and attract resident macrophages giving the image of crown-like structures resulting in phagocytic activity and proliferation. Apoptotic adipocytes express surface proteins favoring phagocytosis by M2-type macrophages [ 84 ].
Treg cells also associate with crown-like structures and probably support non-inflammatory macrophage functions [ 14 ]. However, probably because of the size difference of macrophages and hypertrophic dying adipocytes, there is also lysosomal exocytosis, and the released DAMPs stimulate pro-inflammatory immune activities which are more M1- than M2-like [ 85 ].
Immune activation by DAMPs appears to exceed pro-inflammatory signaling caused by metabolically stressed adipocytes because there is an influx of monocytes and other immune cells which outnumber resident immunocytes [ 55 , 84 ].
In mouse fat tissue, induction of inflammasome and caspase-1 activity for the release of IL-1 and IL is required for the recruitment of circulating immune cells and their pro-inflammatory activation [ 86 ]. Secretion of macrophage chemotactic protein 1 MCP-1 also contributes to monocyte attraction [ 87 , 88 ].
These cells exhibit impaired cell functions and an irreversible proliferative arrest in association with the secretion of a variety of pro-inflammatory cytokines, chemokines, proteases, and vesicles containing microRNAs, DNA, lipids, and protein.
Peptides secreted in the context of the senescence-associated secretory phenotype SASP not only stimulate adipocytes and activate resident immune cells but also help recruit circulating immune cells to fat tissue followed by their activation [ 58 , 89 , 90 , 91 ].
Structural damage also ensues if physiological remodeling of the extracellular matrix of obese visceral fat tissue is insufficient to adapt to tissue growth and enhanced angiogenesis.
Collagen accumulates around adipocytes and in fiber bundles leading to decreased tissue plasticity. This leads to an adipocyte-mediated release of endotrophin, a cleavage product of collagen VI, which enhances local inflammatory responses [ 92 , 93 , 94 ].
The findings described above suggest that the recruitment of immune cells and their accumulation occurs in response to structural damage of visceral fat tissue Fig. The dominant immune cells in the infiltrate are monocytes developing into tissue macrophages.
Concomitantly, there is an influx of other immune cell types, including T and B cells, ILC1s, ILC3s, NK cells, mast cells, and neutrophils [ 25 , 30 , 94 , 95 , 96 , 97 , 98 , 99 ]. Since the fat tissue is not homogeneous with regard to vascularization, hypoxia, and adipocyte death, there is regional diversity of the inflammatory state.
Severe visceral fat tissue inflammation in response to structural disruption. Excessive enlargement of adipocytes in response to chronic overnutrition eventually causes structural damage with dying adipocytes and cell senescence as hallmarks. The phagocytotic capacity of macrophages is overwhelmed and released DAMPS strongly activate resident immune and endothelial cells resulting in the attraction of virtually all types of immune cells.
Their pro-inflammatory activation also stimulates anti-inflammatory activities. Another structural change is the accumulation of senescent cells, mostly macrophages, pre-adipocytes, mature adipocytes, and endothelial cells.
Senescent cells secrete pro-inflammatory mediators and enhance the accumulation of immune cells from circulation.
DAMPs and free fatty acids do not exhibit the same strong immunostimulatory activity as seen for bacterial or viral components. In inflamed obese visceral tissue infiltrated by immune cells, there is an overall dominance of pro-inflammatory activity. This situation is best researched for macrophages, which remain the prominent immune cell type in inflamed obese visceral tissue with structural damage, largely due to the recruitment of monocytes from circulation.
Most infiltrated macrophages are polarized towards a pro-inflammatory phenotype which only partially resembles classic M1-like activity characterized by the secretion of IL-1ß, IL, TNFα, chemokines, and proteases [ ]. As discussed above, pro-inflammatory cytokines such as TNFα elicit the production of anti-inflammatory cytokines such as IL or of prostaglandin E2.
There is regional diversity between macrophages within and outside crown-like structures, and in other human obese visceral adipose tissue [ 85 ].
For instance, macrophages with adipogenic and angiogenic gene expression patterns are distributed more evenly in the visceral fat tissue while lipid-laden pro-inflammatory macrophages are associated with dead adipocytes [ 85 ].
Obesity induced by long-term feeding of a high-fat diet in mice also changes the major phenotype of dendritic cells in visceral fat towards a pro-inflammatory profile. There is secretion of IFNα from plasmacytoid dendritic cells [ 58 ].
In parallel, the number of regulatory T cells, supporting the maintenance function of immune cells, is decreasing. The loss of Treg lymphocytes from obese visceral tissue appears to be a direct consequence of IFNα action [ 58 ].
The lower number of regulatory T cells may be the major reason accounting for a pro-inflammatory shift in several other immunocytes. Early changes include an influx of pro-inflammatory T cells and of B lymphocytes.
In high-fat diet-induced obesity of mice both cell types appear to precede peak macrophage infiltration [ , ]. IFN γ secretion by CD4- and CD8-positive T lymphocytes as well as of NK cells and ILC1s probably is a strong activator of pro-inflammatory macrophage activity.
Stimulation of T-cells for IFN γ production probably is supported by the pro-inflammatory B2 subset of B lymphocytes while the percentage of anti-inflammatory B1 cells is decreased [ 55 , 97 , , , , , , ].
There is also activation of MAIT cells which promotes macrophage activation by secretion of TNFα and IL [ ]. In the context of visceral obese fat tissue inflammation, there is also an increase of activated neutrophils.
These cells release extracellular traps which interact with other immune cells to promote pro-inflammatory responses and possibly contribute to remodeling of the matrix because of the protease content of traps, in addition to promoting insulin resistance [ , ].
Obese visceral fat tissue also harbors increased numbers of mast cells [ ] but it is not clear whether these cells promote or dampen inflammation [ ]. The immune cell influx in response to structural damage of fat tissue appears to exhibit tissue-protective and also detrimental properties.
Fat tissue repair such as elimination of dying adipocytes, enhanced lipolysis, tissue remodeling, and angiogenesis represent beneficial functions of infiltrated and resident immune cells.
However, animal studies indicate that matrix remodeling during chronic inflammation eventually may lead to fibrosis, i. An alternative view suggests that a rigid extracellular membrane prevents excessive enlargement of adipocytes and supports metabolic homeostasis [ ].
Senescent cells in inflamed tissue probably also have beneficial and as well as detrimental effects. In animal models, beneficial effects include the orchestration of tissue remodeling through the secretion of pro-inflammatory factors.
Senescent cells positively impact health span, liver, and vascular tissue fibrosis, and wound healing [ , ]. However, if senescent cells are not cleared within days or weeks by innate immune cells, they accumulate and spread senescence to neighboring and distant cells, mostly via secretion of microRNA-containing vesicles with the consequence of a pro-fibrotic state and deficient tissue function in hypertrophic obesity mice [ 46 , , , ].
Obesity and hyperinsulinemia also drive the senescence of adipocytes or visceral fat macrophages in humans [ 91 , ]. In obese mice, genetic or pharmacological elimination of senescent cells promoted adipogenesis and decreased the influx of monocytes into abdominal fat [ 89 , ].
When human obese visceral tissue containing senescent cells was transplanted into immunodeficient mice, lower glucose tolerance and increased insulin resistance were observed.
These detrimental effects were suppressed by clearing the human fat tissue from senescent cells by treatment with a selenolytic cocktail prior to transplantation [ 90 ]. Severe visceral obesity often is accompanied by systemic low-grade inflammation, insulin resistance, glucose intolerance, and other measures of metabolic disturbances.
This does not simply appear to be a spill-over effect because there seem to be contributions of other organs such as the liver, the hypothalamus, and the gut microbiota [ , , ]. Overnutrition and excess systemic nutrients cause changes in the liver related to those described for visceral fat.
There is enhanced lipid uptake by several cell types followed by disturbed metabolic homeostasis as evident from endoplasmic reticulum stress in hepatocytes.
Eventually, this leads to structural tissue damage such as death of hepatocytes and fibrosis. Loss of metabolic homeostasis and tissue damage is accompanied by activation of the resident immune system.
Pro-inflammatory responses are carried by Kupffer cells, stellate cells, many infiltrated immune cell types, other stromal cell types, and also by hepatocytes [ , , , , , , , ]. In animal models, immune intervention trials often have led to improved metabolic control with or without decreased adiposity indicating a pathogenic role of inflammatory immune reactivity [ , , ].
However, most studies do not allow to distinguish between effects mediated at the level of the liver, pancreas, vasculature, gut, brain, or adipose tissue. A detailed discussion of diet-induced inflammatory changes outside the visceral fat tissue and of immune intervention studies is outside the scope of this paper.
Inflammation of tissues in the absence of infectious, toxic or allergenic agents in general is caused by the local expression of immunostimulatory molecules in the context of metabolic or physical tissue damage.
The activation of resident immune cells as well as the influx of immune cells from circulation into stressed tissue can be interpreted as an attempt to regain the previous physiological balance [ 2 , 74 ]. Loss of structure tissue damage elicits a more intense form of inflammation with influx of circulating immune cells, again primarily supporting tissue functions [ 2 ].
In obese visceral fat tissue, adaptive or repair functions of macrophages and other activated immune cells include support of matrix remodeling and angiogenesis by secretion of proteases and growth factors to accommodate for adipocyte enlargement and hyperplasia, lipid uptake and catabolism to lower lipid load, stimulation of thermogenesis for lipid burning, promotion of lipolysis and local insulin resistance to reduce lipid storage, and clearance from dead adipocytes and senescent cells.
Concomitant fibrosis may be regarded as protective or detrimental, and a low density of senescent cells may favor matrix remodeling.
The increase of crown-like structures and the accumulation of senescent cells suggest that repair functions become overwhelmed. Whether pro-inflammatory activities carried by the immune cell infiltrate from circulation eventually contribute to tissue damage remains to be analyzed.
Finally, subtypes of visceral obesity remain to be defined, and not all of them may be represented by animal models. Subtypes may differ with respect to metabolic characteristics, age, sex or genetic background.
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Moon JS, da Cunha FF, Huh JY, Andreyev AY, Lee J, Mahata SK, et al. ANT2 drives proinflammatory macrophage activation in obesity. Kiernan K, MacIver NJ.
The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease. Cao Y. Angiogenesis modulates adipogenesis and obesity. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, et al.
Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Skurk T, Mack I, Kempf K, Kolb H, Hauner H, Herder C. Expression and secretion of RANTES CCL5 in human adipocytes in response to immunological stimuli and hypoxia. Horm Metab Res. Trayhurn P, Alomar SY.
Oxygen deprivation and the cellular response to hypoxia in adipocytes - perspectives on white and brown adipose tissues in obesity. Front Endocrinol Lausanne. Mori MA, Ludwig RG, Garcia-Martin R, Brandao BB, Kahn CR.
Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease. Cho CH, Koh YJ, Han J, Sung HK, Jong LH, Morisada T, et al. Angiogenic role of LYVEpositive macrophages in adipose tissue. Circ Res.
Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Int J Obes Lond. Song J, Deng T. The Adipocyte and Adaptive Immunity. Fruhbeck G, Fernandez-Quintana B, Paniagua M, Hernandez-Pardos AW, Valenti V, Moncada R, et al. FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes.
Bosma M, Gerling M, Pasto J, Georgiadi A, Graham E, Shilkova O, et al. FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.
Nat Commun. Meizlish ML, Franklin RA, Zhou X, Medzhitov R. High CRP levels are related to inflammation, and chronic inflammation is associated with insulin resistance, hypertension, type 2 diabetes and atherosclerosis, among other things. Klein, Fontana and J.
Christopher Eagon, M. All were extremely obese, and all were undergoing gastric bypass surgery. They took blood from the portal vein and from the radial artery in the arm and found differences in levels of IL-6 between the samples.
Fontana believes the findings help explain how visceral fat can lead to inflammation, insulin resistance and other metabolic problems. And he says by contributing to inflammation, visceral fat cells in the abdomen may be doing even more than that.
There also is evidence that inflammation plays a role in cancer, and there is even evidence that it plays a role in aging.
Someday we may learn that visceral fat is involved in those things, too. Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.
Diabetes , published online Feb. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.
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Visceral fat and inflammation fat is a lot Increases mental concentration dangerous than you might Viscwral. When your waistline grows, imflammation health risks do too. That's because the larger your waist size, the more abdominal fat you have. That belly fat comes in two forms: visceral and subcutaneous. Buchinsky says.Visceral fat and inflammation -
Difference range. Radial artery. Portal vein. Data are means ± SD. Significantly different from corresponding radial artery value,.
View Large. The authors thank Jennifer McCrea and Jennifer Shew for technical assistance. Montague CT, O'Rahilly S: The perils of portliness: causes and consequences of visceral adiposity.
Despres JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C: Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Pouliot MC, Despres JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, Nadeau A, Lupien PJ: Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women.
Am J Cardiol. Zhu S, Wang Z, Heshka S, Heo M, Faith MS, Heymsfield SB: Waist circumference and obesity-associated risk factors among whites in the third National Health and Nutrition Examination Survey: clinical action thresholds. Am J Clin Nutr. Boden G: Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.
Nielsen S, Guo ZK, Johnson CM, Hensrud DD, Jensen MD: Splanchnic lipolysis in human obesity. J Clin Invest. Klein S: The case of visceral fat: argument for the defense. Lafontan M: Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
Park KG, Park KS, Kim MJ, Kim HS, Suh YS, Ahn JD, Park KK, Chang YC, Lee IK: Relationship between serum adiponectin and leptin concentrations and body fat distribution.
Diabetes Res Clin Pract. Trujillo ME, Scherer PE: Adiponectin: journey from an adipocyte secretory protein to biomarker of the metabolic syndrome.
J Intern Med. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. J Biol Chem. Schenk WG Jr, Mcdonald JC, Mcdonald K, Drapanas T: Direct measurement of hepatic blood flow in surgical patients: with related observations on hepatic flow dynamics in experimental animals.
Ann Surg. Fried SK, Bunkin DA, Greenberg AS: Omental and subcutaneous adipose tissues of obese subjects release interleukin depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW: Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans.
Heinrich PC, Castell JV, Andus T: Interleukin-6 and the acute phase response. Biochem J. Senn JJ, Klover PJ, Nowak IA, Mooney RA: Interleukin-6 induces cellular insulin resistance in hepatocytes. Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP: Dose dependent effects of recombinant human interleukin-6 on glucose regulation.
Pickup JC, Mattock MB, Chusney GD, Burt D: NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
Plutzky J: Inflammatory pathways in atherosclerosis and acute coronary syndromes. Bisoendial RJ, Kastelein JJ, Levels JH, Zwaginga JJ, van den Bogaard B, Reitsma PH, Meijers JC, Hartman D, Levi M, Stroes ES: Activation of inflammation and coagulation after infusion of C-reactive protein in humans.
Circ Res. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE: Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
Nat Med. Mohamed-Ali V, Goodrick SJ, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW: Subcutaneous adipose tissue releases interleukin-6 but not tumor necrosis factor-alpha in vivo. Ramis JM, Bibiloni B, Moreiro J, Garcia-Sanz JM, Salinas R, Proenza AM, Llado I: Tissue leptin and plasma insulin are associated with lipoprotein lipase activity in severely obese patients.
J Nutr Biochem. Van Harmelen V, Reynisdottir S, Eriksson P, Thorne A, Hoffstedt J, Lonnqvist F, Arner P: Leptin secretion from subcutaneous and visceral adipose tissue in women. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH, Smith SA: Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators.
Biochem Biophys Res Commun. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE: Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.
Cote M, Mauriege P, Bergeron J, Almeras N, Tremblay A, Lemieux I, Despres JP: Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men.
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Xu A, Wang Y, Keshaw H, Xu LY, Lam KSL, Cooper GJS: The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver disease in mice.
Horwitz DL, Starr JI, Mako ME, Blackard WG, Rubenstein AH: Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood. Gelman S: General anesthesia and hepatic circulation.
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org ADA Professional Books Clinical Compendia Clinical Compendia Home News Latest News DiabetesPro SmartBrief. Resources ADA Professional Membership ADA Member Directory Diabetes. X Twitter Facebook LinkedIn. Strikingly, we observed an anti-inflammatory phenotype in the old mice, consisting of higher accumulation of M2 macrophages and IL expression, compared to the adult mice.
In concordance, old mice also had less VAT mass and smaller adipocytes compared to adult mice. In both age groups, exercise training enhanced the anti-inflammatory phenotype and increased PGC1-α mRNA expression. Intriguingly, the brown adipose tissue marker UCP1 was modestly higher in old mice, while remained unchanged by the intervention.
In conclusion, in the absence of obesity, visceral adipose tissue possesses a pronounced anti-inflammatory phenotype during aging which is further enhanced by exercise.
Adipose tissue is host to various immune cells and it is well established that during obesity, the amount of inflammatory macrophages increase in adipose tissue 1 , 2.
Moreover, due to its anatomical location, VAT directly supplies the liver with venous blood via the portal vein, rendering a prominent role in directing whole body metabolism. Thus, it is possible that visceral fat is the source of circulating low grade inflammation, which might be important for the development of life-style related chronic diseases 8 , 9 , It is, however, unclear to what extent these age-related changes are a result of ageing per se or rather the result of changes in life-style with e.
reduced levels of physical activity without a corresponding reduction in caloric intake. A human cross sectional study reported that whereas ageing is associated with increased inflammation, life-long endurance training resulted in lower circulating levels of inflammatory markers in both young and elderly individuals Although endurance exercise has been demonstrated to counteract pathological changes in visceral adipose tissue by reducing the amount of total and visceral adipose tissue under conditions of excess fat 17 , 18 , the effects of exercise training on VAT during ageing under lean conditions currently remains elusive.
Indicators of WAT browning, besides UCP-1 upregulation, include increase in mitochondrial enzymes and involvement of macrophages 20 , 21 , Finally, the mode of exercise might be of importance as some human studies show that endurance but not strength training can reduce the amount of adipose tissue and thereby inflammation In the current study, we wanted to investigate the inflammatory status and tissue integrity of VAT in an exercise-training model of lean adult and old mice.
Experiments were conducted in accordance with Danish guidelines Amendment of November 23, as approved by the Danish Animal Inspectorate, Ministry of Justice permit For characteristics and randomization see Table 1. The running wheels were available to the mice day and night. The resistance was determined as the weight required to maintain motion in the wheel.
In the ET wheels the resistance was fixed at 1. Voluntary running in wheels with high resistance has previously been reported to induce a hypertrophic response in contrast to low resistance wheels Running wheel activity was continuously monitored by recording wheel turning speed with a custom build sensor system, recorded via by Arduino boards Arduino Uno and Ethernet SD Shield , and analyzed in MatLab.
After the intervention, the mice were euthanized with cervical dislocation and visceral fat pads from the epididymal region were carefully dissected All tissue was weighed, right-hand-side tissue was snap-frozen in liquid nitrogen for mRNA analysis, and the left-hand-side tissue was submerged in formalin for subsequent paraffin embedding and immunohistochemistry.
The tissue samples were embedded in paraffin and cut into sections. Samples were then washed 3 times in distilled water, and a hydrophobic barrier pen was used to encircle the sections.
Samples were washed in 0. Afterwards samples were allowed to cool to room temperature and washed in TBS. From this point, 2 protocols were used to stain for either 1 perilipin or 2 CD Samples were washed in TBS and subsequently mounted in Prolong Gold Antifade Molecular Probes ProLong Gold anti-fade reagent, cat.
Finally, samples were mounted in aquamount Merck, Germany. The fluorescent images of the perilipin-stained tissue were blinded, so that the investigator was blinded to age- and training groups.
Using ImageJ Fiji, ImageJ 1. Area with damaged adipocytes cells or non-AT was excluded from the analysis. Finally, we calculated the average adipocyte size in µm 2. Bright-field images of the CDstained tissue were acquired by blinded assessor. Image analysis was conducted using ImageJ software Fiji, ImageJ 1.
Great care was also taken to remove blood vessels from the image analysis. Afterwards the snapshots were converted to 8-bit grayscale and pixel intensity thresholding was performed. In order to make sure that the all images were thresholded with the same relative intensity, the lowest possible pixel value for CD staining was selected.
The upper thresholding border was determined as the addition of pixel intensity values to the lowest detectable value. The area covered by CD was then calculated as measured stained area pr.
total adipose tissue area. Melting point analysis for each reaction was done, confirming primer specificity. Quantitative real-time PCR that was carried out in a ViiA 7 real time PCR system Applied Biosystems.
Standard curves were made with diluted cDNA and used for calculation of Ct values. GAPDH was chosen as reference gene. For primers used, see Table s1. Data were analyzed by using SigmaPlot All data were analyzed using 2-way ANOVA to deduct a possible effect of age and intervention. Whenever significant effects were found a Holm Sidak post hoc analysis was performed.
However, to obtain Gaussian distributed values, visceral fat mass, adipocyte size, CD area fraction and all mRNA analysis were log transformed.
mRNA results are shown as relative change, compared to the AS group. We wanted to assess the effect of exercise training on visceral adipose tissue and thus randomized the mice to resistance training RT , endurance training ET or to a sedentary control group S.
This was despite no differences in total body weight Table 1. The differences in visceral adipose tissue phenotype between old and adult mice seemed more pronounced in old mice following endurance exercise training, possibly suggesting higher lipolytic response in the visceral adipose tissue of the old mice compared to the adult.
Interestingly, previous reports have discussed the relation between local lipid fluxes and adipose tissue macrophage ATM accumulation 26 , Characteristics of visceral adipose tissue in adult and old mice following exercise training interventions. We characterized the epididymal adipose depot of adult and old mice that were sedentary S or had performed either resistance training RT or endurance training ET.
A Representative pictures of perilipin-stained epididymal adipose of adult top and old bottom mice divided by intervention, 20x objective.
B Average adipocyte area µm2 measured from adipocytes, based on the perilipin staining. C Total weight of epididymal adipose depot mg. B , C Y-axis given as log2. To address potential differences in ATM accumulation between adult and old mice, we stained tissue sections for the ATM marker CD, which is described as a reliable marker of alternatively activated macrophages M2 28 , However, we here found an opposing regulation pattern with an increased area positive for CD staining in the old vs.
Furthermore, a trend for significantly more CD staining in ET vs. Immunogenic phenotype of visceral adipose tissue in adult and old mice following exercise training interventions. Epididymal adipose from the groups depicted in Fig. B Quantification of the percentage of total area staining positive for CD from 4 snapshots from each mouse.
C Relative gene expression levels of the anti-inflammatory markers, IL and adiponectin. D Relative gene expression levels of the pro-inflammatory markers, TNF-α and IL Y-axis for all figures given as log2.
To further address the inflammatory status of the visceral adipose tissue samples, we measured the relative gene expression levels of anti-inflammatory and pro-inflammatory markers.
In fact, opposite of what would be expected, there was even a trend for interaction of TNF-α, with adult trained mice exhibiting more TNF-α expression compared to trained old mice Fig. Increased amounts of M2 macrophages, have been found by other studies to be a hallmark of adipose tissue, peritoneal and pancreatic fibrosis 30 , 31 , Increased TGF-beta is thought to be a central mediator in this process 32 , We therefore measured the gene expression of TGF-β1.
However, from the histology analysis in Figs 1A and 2A , we did observe that the visceral adipose tissue from old mice appeared disorganized, with adipocytes varying greatly in shape and size.
To further evaluate whether this phenotype could be related to increased fibrosis, despite not indicated by the TGF-β1 gene expression levels, we applied an exploratory picrosirius red staining on the tissue section of one old mouse, to detect any apparent fibrotic connective tissue in the visceral adipose tissue.
However, no histological signs of fibrosis were observed Fig. Thus, we do not think that the reduced size of visceral adipose tissue and adipocytes in old mice is due to development of classic fibrosis. Markers of fibrosis. Y-axis given as log2.
B Picrosirius red staining of VAT in old sedentary mouse revealed no apparent fibrosis in between adipocytes. Brightfield, 20x objective. To further characterize the visceral adipose tissue from the different groups, we measured the relative gene expression of the master regulator of mitochondria, Pgc-1α, as a marker of oxidative capacity.
Pgc-1α is a co-transcription factor of the brown fat transcriptional program 34 , and browning of white adipose tissue in response to exercise training has been previously reported to occur in mice 19 , 20 , These observations raised the idea that the disorganization and variation of adipocyte size might be related to adipose tissue browning.
Therefore, we measured the gene expression of the mitochondrial thermogenic marker, Uncoupling protein 1 Ucp As previously observed in humans 36 , the Ucp-1 gene expression varied greatly between individuals and we detected no effect of the exercise training intervention.
Oxidative markers. Relative gene expression levels in the epididymal adipose tissue from the groups depicted in Fig. Y-axis given as log2 for both figures. This phenotype was accompanied by less visceral fat, smaller adipocytes, as well as higher Ucp-1 and IL mRNA expression while Tgf-β1 mRNA expression was lower compared to the younger counterparts.
When interpreting our data in the light of the literature, it is important to bear in mind that we utilized a model of very old 23 months mice, which we compared to adult mice.
This could explain why our results conflicted with previous reports on increased visceral fat in old mice 12 , 13 , 37 , as a bimodal pattern with decreased visceral fat has been observed 38 , 39 , In accordance with our study, Donato and colleagues found that 30 months old ancient mice exhibited less visceral fat and smaller adipocytes compared to adult mice 6 months However, in sharp contrast to our findings, that study reported a decrease in Ucp-1 and an increase in fibrosis, while we demonstrate the opposite phenotype.
Certainly, the present study has limitations. Further, we are aware that CD is not a marker exclusively reserved for alternatively activated macrophages 41 , but is a generally accepted M2 marker. Importantly, a previous study applying the M2 macrophage markers CD and Mrc1, support our findings of an increase in M2 macrophages in mice with ageing, although in this study, mice were only aged for 30 weeks Furthermore, the fact that no circulating blood samples were available, limits the ability to conclude regarding the coupling between local adipose tissue changes and alterations in circulating levels of inflammatory markers.
Nevertheless, we here describe an anti-inflammatory phenotype of visceral adipose tissue in old mice, whereas ageing and obesity -induced changes in adipose tissue is originally presumed to be based upon an increasingly inflammatory, and not anti-inflammatory, skewing 43 , Therefore, our data represent an important contribution to the literature, indicating that pronounced aging per se, does not generate a pro-inflammatory phenotype or visceral fat accumulation in mice.
Interestingly, a cross sectional study on human ageing found that from around the 8 th to the 9 th decade, a reduction in waist circumference surrogate marker for abdominal obesity was observed 45 , supporting the notion of decreased visceral fat with pronounced ageing. However, whether the immunological phenotype of visceral adipose tissue in very old humans is indeed dominated by anti-inflammatory processes as our data would suggest, remains unanswered.
In our study, the visceral adipose tissue of the old mice seemed either more lipolytic or had lost lipid storage capacity. This was observed at rest and was accentuated following exercise training as epidydimal fat mass was reduced in combination with smaller adipocytes Fig.
The interaction between adipose tissue macrophages and lipolysis has been previously discussed 27 , and it has been shown that local lipid fluxes is a potent mediator of macrophage recruitment to adipose tissue Indeed, exercise is a powerful mediator of lipolysis, and it has been shown in vivo in humans that the lipolytic activity is higher in abdominal depot represented by both visceral and subcutaneous adipose tissue than in the gluteal depot consisting of subcutaneous adipose tissue This is in line with our finding in which ET decreased visceral adipocyte size in both age groups, a phenomenon already touched upon by other researchers 47 , Moreover, our finding that only ET seemed to reduce visceral fat mass is consistent with one of the few available meta-analysis on the subject Interestingly, in concordance with our observations, exercise has previously been established to generate an anti-inflammatory response, by increasing the expression and release of anti-inflammatory mediators such as IL, arginase-1 and IL-6 acute release without TNF-α from human leukocytes and skeletal muscles 49 , It has also been suggested that exercise might confer a shift from M1 to M2 macrophage phenotype in adipose tissue 51 , As endurance training promote browning of white adipose tissue in mice 20 , 35 , it is interesting to note that pre-adipocytes obtained from epididymal fat tissue have the ability to acquire a brown-like phenotype regulated by PPAR-γ, PGC1-α and norepinephrine, which are all known to be involved in response to exercise Interestingly, some studies advocate that M2 macrophages, through norepinephrine release, can increase UCP-1 expression and mediate browning of white adipose tissue 21 , 54 , which was later questioned by other groups, discarding this idea Here, we report a modestly elevated expression of UCP-1 Fig.
Importantly, our results support an increased oxidative phenotype of VAT generated by exercise, as PGC1-α expression was increased Fig. This is consistent with existing literature where PGC1-α is seen upregulated in both muscle and adipose tissue following an intense exercise protocol 56 , supporting the concept that exercise training can convey a beneficial metabolically effect on visceral adipose tissue In conclusion, our study emphasizes the dynamics of adipose tissue and describe the visceral adipose tissue of lean old mice as an anti-inflammatory and highly lipolytic tissue with endurance exercise further enhancing these characteristics.
Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Article CAS Google Scholar. Weisberg, S. Obesity is associated with macrophage accumulation in adipose tissue. Hotamisligil, G. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
Science , 87—91 Article ADS CAS Google Scholar. Fontana, L. Visceral Fat Adipokine Secretion Is Associated With Systemic Inflammation in Obese Humans. Diabetes 56 , — Nishida, M.
Abdominal obesity exhibits distinct effect on inflammatory and anti-inflammatory proteins in apparently healthy Japanese men. Article Google Scholar. El-Wakkad, A. Proinflammatory, anti-inflammatory cytokines and adiponkines in students with central obesity. Cytokine 61 , — Heilbronn, L.
can cause fatty liver and pancreas, which then further affects insulin regulation. This can ultimately lead to type 2 diabetes and metabolic disease due to excess glucose in our bloodstream.
It has been established that abdominal visceral fat may play a more important pathogenetic role or better reflect an underlying metabolic disorder than subcutaneous fat in the development of diabetes mellitus or hyperlipidemia high level of fats or lipids in the blood.
The accumulation of visceral fat in obesity is associated with metabolic syndrome and an increased risk for clinical cardiovascular disease. One study demonstrates that caloric restriction can delay many age-related diseases and extend lifespan, while an increase in adiposity is associated with enhanced disease risk and accelerated ageing.
Among the various fat depots, the accumulation of visceral fat is a common feature of ageing, and has been shown to be the most detrimental on the metabolic syndrome of ageing in humans.
Visceral fat increases with age in both women and men. Apart from the dietary causes of visceral fat, such as arising from the consumption of highly refined carbohydrates and sugar which leads to excess calories, other potential contributors to visceral adiposity include chronic stress, lack of physical exercise and inadequate sleep.
It has been seen that stress also leads to excess amounts of visceral fat being stored. One study looks at how visceral adiposity may be a physiological adaptation to stress. Under chronic stress, our body releases cortisol which in turn activates the HPA axis, which has been shown to exert hyperphagic related to overeating and anti-thermogenic no-heat-producing effects.
There is also other evidence which shows that abdominal obesity is linked to increased cortisol clearance. Both cortisol and insulin, on the one hand, tend to cause an increase in visceral fat, while growth hormones and sex hormones may prevent it.
Adiponectin is a fat regulator, and if we do not have enough of it circulating in our systems, it could cause our body to accumulate more fat than necessary. Studies have demonstrated that visceral fat and adiponectin were independently associated with the clustering of metabolic risk factors such as high cholesterol, higher triglycerides and lower LDL low-density lipoprotein and HDL high-density lipoprotein.
Yet another effect of accumulated and increased visceral fat seems to be on cognition. One study demonstrated how visceral fat is harmful to the brain because it allows the inflammatory cytokine interleukin-1 beta to heavily infiltrate the brain The interleukin-1 beta cytokine is produced by visceral fat, which then travels through the bloodstream, passes through the blood—brain barrier and enters the brain, where it causes the microglia to become dysfunctional and hampers cognition.
Microglia are the immune cells in the brain which regulate neuronal function indirectly by clearing dead cells and extracellular debris, and directly by releasing signalling molecules that support or suppress neuroplasticity. Inflammation is our immune response to a threat, injury or infection.
During the process of inflammation, inflammatory cells and cytokines are released. Acute or temporary inflammation occurs when there is a sudden body change, or damage or injury to our system. For example, if we cut ourselves, if we have an infection or if we work out. Chronic inflammation, on the other hand, is when the body continues to send out inflammatory cells and there is a continuous inflammatory response.
Major sources of inflammation also include environmental stressors, environmental toxins as well as psychological stress.
Shifts in the inflammatory response from short- to long-lived can cause a breakdown of immune tolerance, which leads to oxidative stress and damage to tissues and cells.
It has been seen that chronic inflammation also contributes to the pathophysiology of a number of metabolic diseases. Systemic chronic inflammation can lead to a number of conditions such as metabolic syndrome a triad of hypertension, hyperglycemia and dyslipidemia , cancer, diabetes, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders.
It is established that the levels of cortisol in the blood increase with age. This is mainly considered to be on account of the HPA axis getting activated by many non-specific stressors. Over time, the phenomenon of anti-inflammaging, mainly exerted by cortisol, gives rise to a tangible decrease in immunological functions.
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They sampled blood from the portal vein in obese patients undergoing gastric bypass surgery and found that visceral fat in the abdomen was secreting high levels of an important inflammatory molecule called interleukin-6 IL-6 into portal vein blood.
Louis and an investigator at the Istituto Superiore di Sanita, Rome, Italy. Increased IL-6 levels in the portal vein correlated with concentrations of an inflammatory substance called C-reactive protein CRP in the body.
High CRP levels are related to inflammation, and chronic inflammation is associated with insulin resistance, hypertension, type 2 diabetes and atherosclerosis, among other things.
Klein, Fontana and J. Christopher Eagon, M. All were extremely obese, and all were undergoing gastric bypass surgery. They took blood from the portal vein and from the radial artery in the arm and found differences in levels of IL-6 between the samples. Fontana believes the findings help explain how visceral fat can lead to inflammation, insulin resistance and other metabolic problems.
And he says by contributing to inflammation, visceral fat cells in the abdomen may be doing even more than that. There also is evidence that inflammation plays a role in cancer, and there is even evidence that it plays a role in aging.
Someday we may learn that visceral fat is involved in those things, too. Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.
Diabetespublished online Feb. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.
Through its affiliations with Barnes-Jewish and St. CSD research informs Senate proposal. Expanded child tax credit would ultimately save money, reduce poverty. Replacing Chevron would have far-reaching implications. The importance of higher purpose, culture in banking.
Brumation and torpor: How animals survive cold snaps by playing dead-ish. Proteins may predict who will get dementia 10 years later, study finds.
NEWS ROOM. Sections Find an Expert Media Resources Newsroom Stories Perspectives WashU Experts WashU in the News. In this abdominal MRI scan, it is possible to see subcutaneous fat around the abdomen, surrounding abdominal muscles.
Visceral fat is deeper inside the abdomen, surrounding internal organs. It is the visceral fat that secretes IL-6, strongly suggesting a mechanistic link to systemic inflammation. Samuel Klein. Luigi Fontana. You Might Also Like. WashU Experts Expanded child tax credit would ultimately save money, reduce poverty Replacing Chevron would have far-reaching implications The importance of higher purpose, culture in banking.
: Visceral fat and inflammation| RESEARCH DESIGN AND METHODS | To reduce your health risks and improve your quality of life, you have to find a way to manage stress at work and home. For some people, that might mean taking a stress-reduction course, practicing yoga or mindfulness, or increasing their exercise and activity level. Quit smoking. Smoking causes inflammation in your body, and swearing off tobacco can improve your health within days. Roy Buchinsky, MD is an internal medicine specialist and the director of wellness at University Hospitals Cleveland Medical Center. UH allows you to schedule an appointment online for select UH physicians and specialties, including primary care. Or use our easy online tool to find a doctor and book an appointment at a time that is convenient for you. Tags: Heart Disease , Heart Attack Risk , Heart Health , Weight Loss Management. Skip to main content. Find Doctors Services Locations. Medical Professionals. Research Community. Medical Learners. Job Seekers. Quick Links Make An Appointment Our Services UH MyChart Price Estimate Price Transparency Pay Your Bill Patient Experience Locations About UH Give to UH Careers at UH. We have updated our Online Services Terms of Use and Privacy Policy. Mice with the interleukin-1 receptor knocked out, could find it just fine, Stranahan says. The high-fat diet, transplant mice also had weaker connections, or synapses, between neurons involved in learning and memory. Mice on a high-fat diet but missing NLRP3 were spared these changes, like mice on a low-fat diet. Also, like many of us, mice tend to prefer new toys and those on a low-fat diet or with NLRP3 removed were better at recognizing novel objects to play with and their synapses were stronger. The high-fat diet transplant mice seemed not to remember so well which toy they'd already played with. There is already potential protection out there from brain effects, Stranahan says, noting biologics in use in humans for problems like rheumatoid arthritis and Crohn's disease, that target interleukin-1 beta. There is also emerging evidence that bariatric surgery, which sometimes includes removing visceral fat, can improve attention, mood and executive function. There are many hypotheses about why visceral fat is so inflamed, including its proximity to the gut microbiota, a centerpiece of our immune response, which is programmed to attack invaders. Increased rates of cognitive decline have been linked to obesity in humans, including shrinkage of key brain areas like the hippocampus, although there also have been contradicting reports about the overall health impact of obesity, the scientists report. The contradiction in impact may relate to where the fat is found, says Stranahan, whose next goals include studying the apparent protective effects of fat deposited under the skin, called subcutaneous fat, whose benefits may include allowing you to store energy away from the highly inflammatory abdominal area. Waist to hip ratio is a better indicator of visceral adiposity than the standard body mass index, or BMI, that divides weight by height. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! Cell Metab 19 1 — Oh HJ, Park EJ, Lee SY, Soh JW, Kong IS, Choi SW, et al. Comparison of cell proliferation and epigenetic modification of gene expression patterns in canine foetal fibroblasts and adipose tissue-derived mesenchymal stem cells. Cell Prolif 45 5 — Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. 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Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 87 12 —7. Freedland ES. Role of a critical visceral adipose tissue threshold CVATT in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutr Metab 1 1 Dusserre E, Moulin P, Vidal H. Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 1 — Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation 11 — Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 83 11 —9. Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue AT : implication of macrophages resident in the AT. J Clin Endocrinol Metab 90 4 —9. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 11 1 —8. Ferrer-Lorente R, Bejar MT, Badimon L. Notch signaling pathway activation in normal and hyperglycemic rats differs in the stem cells of visceral and subcutaneous adipose tissue. Stem Cells Dev Citation: Kredel LI and Siegmund B Adipose-tissue and intestinal inflammation — visceral obesity and creeping fat. Received: 06 August ; Accepted: 10 September ; Published online: 24 September Copyright: © Kredel and Siegmund. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. siegmund charite. |
| Tips For a Healthier Lifestyle | Strength training exercising with weights may Visceral fat and inflammation help fight VVisceral fat. Exp Sustainable energy source. That belly fat comes in Vusceral Visceral fat and inflammation visceral and subcutaneous. Article CAS PubMed PubMed Niflammation Google Scholar Schneider JL, Rowe JH, Garcia-de-Alba C, Kim CF, Sharpe AH, Haigis MC. However, from the histology analysis in Figs 1A and 2Awe did observe that the visceral adipose tissue from old mice appeared disorganized, with adipocytes varying greatly in shape and size. Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. |
| You Might Also Like | Article PubMed PubMed Central Google Scholar. Ilan Y, Maron R, Tukpah AM, Maioli TU, Murugaiyan G, Yang K, et al. Martin-Murphy BV, You Q, Wang H, De La Houssaye BA, Reilly TP, Friedman JE, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Barbarroja N, Lopez-Pedrera R, Mayas MD, Garcia-Fuentes E, Garrido-Sanchez L, Macias-Gonzalez M, et al. outlined the association between pre-diagnosis dietary intake and the risk of developing IBD |
| How to Get Rid of Visceral Fat | J Nutr Biochem. It suggests that visceral fat Visceral fat and inflammation ijflammation markers lnflammation free inflammatiion acids Visceral fat and inflammation travel through the portal vein to the liver. ILC2, Indulgent yet nourishing recipes called infllammation helper cells, are defined by their production of type-2 cytokines such as IL-4, IL-5, and IL and by the transcription factor GATA3 92 — Immunol Lett 2 —7. Added sugar is unhealthy and may increase visceral fat. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician. Eosinophils in fat: pink is the new brown. |
Obesity Visceral fat and inflammation become one Viscwral the main threats to health worldwide inflammattion therefore gained increasing clinical and economic significance as Increasing thermogenesis naturally as scientific Oats and sustainable farming. General fqt accumulation ahd Visceral fat and inflammation inflammatiln associated with systemically increased pro-inflammatory mediators inflammtion humoral and cellular changes within this Viscsral. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases.
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