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Adipose tissue

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"Adipose" redirects here. For the fictional creature from Doctor Who, seeList of Doctor Who universe creatures and aliens (0–9, A–G) § Adipose.
See also:Fat
Adipose tissue
Pigbelly fat (white)
Adipose tissue is one of the main types ofconnective tissue.
Pronunciation/ˈædɪˌpoʊs/ⓘ
Identifiers
MeSHD000273
FMA20110
Anatomical terminology

Adipose tissue(also known asbody fator simplyfat) is a looseconnective tissuecomposed mostly ofadipocytes.[1][2]It also contains thestromal vascular fraction(SVF) of cells includingpreadipocytes,fibroblasts,vascularendothelial cellsand a variety ofimmune cellssuch asadipose tissue macrophages.Its main role is to storeenergyin the form oflipids,although it also cushions andinsulatesthe body.

Previously treated as being hormonally inert, in recent years adipose tissue has been recognized as a majorendocrineorgan,[3]as it produceshormonessuch asleptin,estrogen,resistin,andcytokines(especiallyTNFα).[2]In obesity, adipose tissue is implicated in the chronic release of pro-inflammatory markers known asadipokines,which are responsible for the development ofmetabolic syndrome—a constellation of diseases includingtype 2 diabetes,cardiovascular diseaseandatherosclerosis.[2][4]

Adipose tissue is derived from preadipocytes and its formation appears to be controlled in part by theadipose gene.The two types of adipose tissue arewhite adipose tissue(WAT), which stores energy, andbrown adipose tissue(BAT), which generates body heat. Adipose tissue—more specifically brown adipose tissue—was first identified by the Swiss naturalistConrad Gessnerin 1551.[5]

Anatomical features

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Distribution of white adipose in the human body

In humans, adipose tissue is located: beneath theskin(subcutaneous fat), around internalorgans(visceral fat), in bone marrow (yellow bone marrow), intermuscular (Muscular system) and in the breast (breast tissue). Adipose tissue is found in specific locations, which are referred to asadipose depots.Apart from adipocytes, which comprise the highest percentage of cells within adipose tissue, other cell types are present, collectively termed stromal vascular fraction (SVF) of cells. SVF includespreadipocytes,fibroblasts,adipose tissuemacrophages,andendothelial cells.

Adipose tissue contains many smallblood vessels.In theintegumentary system,which includes the skin, it accumulates in the deepest level, thesubcutaneouslayer, providing insulation from heat and cold. Around organs, it provides protective padding. However, its main function is to be a reserve of lipids, which can be oxidised to meet the energy needs of the body and to protect it from excess glucose by storing triglycerides produced by the liver from sugars, although some evidence suggests that most lipid synthesis from carbohydrates occurs in the adipose tissue itself.[6]Adipose depots in different parts of the body have different biochemical profiles. Under normal conditions, it provides feedback for hunger and diet to the brain.

Mice

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Theobesemouse on the left has large stores of adipose tissue. It is unable to produce the hormoneleptin.This causes the mouse to be hungry and eat more, which results in obesity. For comparison, a mouse with a normal amount of adipose tissue is shown on the right.

Mice have eight major adipose depots, four of which are within theabdominal cavity.[1]The paired gonadal depots are attached to theuterusandovariesin females and theepididymisandtestesin males; the paired retroperitoneal depots are found along thedorsalwall of theabdomen,surrounding the kidney, and, when massive, extend into the pelvis. The mesenteric depot forms a glue-like web that supports theintestinesand the omental depot (which originates near thestomachandspleen) and - when massive - extends into the ventral abdomen. Both the mesenteric and omental depots incorporate muchlymphoid tissueas lymph nodes andmilky spots,respectively.

The two superficial depots are the paired inguinal depots, which are found anterior to the upper segment of the hind limbs (underneath the skin) and the subscapular depots, paired medial mixtures of brown adipose tissue adjacent to regions of white adipose tissue, which are found under theskinbetween the dorsal crests of the scapulae. The layer of brown adipose tissue in this depot is often covered by a "frosting" of white adipose tissue; sometimes these two types of fat (brown and white) are hard to distinguish. The inguinal depots enclose the inguinal group of lymph nodes. Minor depots include thepericardial,which surrounds the heart, and the paired popliteal depots, between the major muscles behind the knees, each containing one largelymph node.[7]Of all the depots in the mouse, the gonadal depots are the largest and the most easily dissected,[8]comprising about 30% of dissectible fat.[9]

Obesity

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In anobeseperson, excess adipose tissue hanging downward from the abdomen is referred to as apanniculus.A panniculus complicates surgery of the morbidly obese individual. It may remain as a literal "apron of skin" if a severely obese person loses large amounts of fat (a common result ofgastric bypass surgery). Obesity is treated through exercise, diet, and behavioral therapy. Reconstructive surgery is one aspect of treatment.[10]

Visceral fat

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See also:Abdominal obesity
Abdominal obesityin a man ( "beer belly" )

Visceral fat or abdominal fat[11](also known as organ fat or intra-abdominal fat) is located inside theabdominal cavity,packed between the organs (stomach, liver, intestines, kidneys, etc.). Visceral fat is different fromsubcutaneous fatunderneath theskin,andintramuscular fatinterspersed inskeletal muscles.Fat in the lower body, as in thighs and buttocks, is subcutaneous and is not consistently spaced tissue, whereas fat in theabdomenis mostly visceral and semi-fluid.[12]Visceral fat is composed of several adipose depots, includingmesenteric,epididymalwhite adipose tissue(EWAT), andperirenaldepots. Visceral fat is often expressed in terms of its area in cm2(VFA, visceral fat area).[13]

An excess of visceral fat is known asabdominal obesity,or "belly fat", in which the abdomen protrudes excessively. New developments such as theBody Volume Index(BVI) are specifically designed to measure abdominal volume and abdominal fat. Excess visceral fat is also linked totype 2 diabetes,[14]insulin resistance,[15]inflammatory diseases,[16]and other obesity-related diseases.[17]Likewise, the accumulation of neck fat (or cervical adipose tissue) has been shown to be associated with mortality.[18]Several studies have suggested that visceral fat can be predicted from simple anthropometric measures,[19]and predicts mortality more accurately than body mass index or waist circumference.[20]

Men are more likely to have fat stored in the abdomen due tosex hormone differences.Estrogen(female sex hormone) causes fat to be stored in the buttocks, thighs, and hips in women.[21][22]When women reachmenopauseand the estrogen produced by the ovaries declines, fat migrates from the buttocks, hips and thighs to the waist;[23]later fat is stored in the abdomen.[12]

Visceral fat can be caused by excesscortisollevels.[24]At least 10MET-hours per week ofaerobic exerciseleads to visceral fat reduction in those without metabolic-related disorders.[25]Resistance training and caloric restriction also reduce visceral fat, although their effect may not be cumulative.[26]Both exercise and hypocaloric diet cause loss of visceral fat, but exercise has a larger effect on visceral fat versus total fat.[27]High-intensity exercise is one way to effectively reduce total abdominal fat.[28][29]An energy restricted diet combined with exercise will reduce total body fat and the ratio of visceral adipose tissue to subcutaneous adipose tissue, suggesting a preferential mobilization for visceral fat over subcutaneous fat.[30]

Epicardial fat

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Epicardialadipose tissue (EAT) is a particular form of visceral fat deposited around the heart and found to be a metabolically active organ that generates various bioactive molecules, which might significantly affectcardiacfunction.[31][32][33]Marked component differences have been observed in comparing EAT withsubcutaneous fat,suggesting a location-specific impact of stored fatty acids on adipocyte function and metabolism.[34]

Subcutaneous fat

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See also:Body fat percentage
Micro-anatomy of subcutaneous fat

Most of the remaining nonvisceral fat is found just below the skin in a region called thehypodermis.[35]This subcutaneous fat is not related to many of the classic obesity-related pathologies, such asheart disease,cancer, andstroke,and some evidence even suggests it might be protective.[36]The typically female (or gynecoid) pattern of body fat distribution around the hips, thighs, and buttocks is subcutaneous fat, and therefore poses less of a health risk compared to visceral fat.[37][38]

Like all other fat organs, subcutaneous fat is an active part of the endocrine system, secreting the hormonesleptinandresistin.[35]

The relationship between the subcutaneous adipose layer and total body fat in a person is often modelled by using regression equations. The most popular of these equations was formed by Durnin and Wormersley, who rigorously tested many types of skinfold, and, as a result, created two formulae to calculate the body density of both men and women. These equations present an inverse correlation between skinfolds and body density—as the sum of skinfolds increases, the body density decreases.[39]

Factors such as sex, age, population size or other variables may make the equations invalid and unusable, and, as of 2012,Durnin and Wormersley's equations remain only estimates of a person's true level of fatness. New formulae are still being created.[39]

Marrow fat

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Marrow fat, also known asmarrow adipose tissue(MAT), is a poorly understood adipose depot that resides in the bone and is interspersed with hematopoietic cells as well as bony elements. The adipocytes in this depot are derived frommesenchymal stem cells (MSC)which can give rise to fat cells, bone cells as well as other cell types. The fact that MAT increases in the setting of calorie restriction/ anorexia is a feature that distinguishes this depot from other fat depots.[40][41][42]Exercise regulates MAT, decreasing MAT quantity and diminishing the size of marrow adipocytes.[43][44][45]The exercise regulation of marrow fat suggests that it bears some physiologic similarity to other white adipose depots. Moreover, increased MAT in obesity further suggests a similarity to white fat depots.[43]

Ectopic fat

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Ectopic fat is the storage oftriglyceridesin tissues other than adipose tissue, that are supposed to contain only small amounts of fat, such as theliver,skeletal muscle,heart,andpancreas.[1]This can interfere with cellular functions and hence organ function and is associated with insulin resistance in type-2 diabetes.[46]It is stored in relatively high amounts around the organs of theabdominal cavity,but is not to be confused with visceral fat.

The specific cause for the accumulation of ectopic fat is unknown. The cause is likely a combination of genetic, environmental, and behavioral factors that are involved in excess energy intake and decreased physical activity. Substantial weight loss can reduce ectopic fat stores in all organs and this is associated with an improvement of the function of those organs.[46]

In the latter case, non-invasive weight loss interventions like diet or exercise can decrease ectopic fat (particularly in heart and liver) in overweight or obese children and adults.[47][48]

Physiology

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Free fatty acids(FFAs) are liberated fromlipoproteinsbylipoprotein lipase(LPL) and enter the adipocyte, where they are reassembled intotriglyceridesbyesterifyingthem ontoglycerol.[2]Human fat tissue contains about 87%lipids.[49]

There is a constant flux of FFAs entering and leaving adipose tissue.[2]The net direction of this flux is controlled by insulin and leptin—if insulin is elevated, then there is a net inward flux of FFA, and only when insulin is low can FFA leave adipose tissue. Insulin secretion is stimulated by high blood sugar, which results from consuming carbohydrates.[50]

In humans, lipolysis (hydrolysis of triglycerides into free fatty acids) is controlled through the balanced control of lipolyticB-adrenergic receptorsand a2A-adrenergic receptor-mediated antilipolysis.

Fat cells have an importantphysiologicalrole in maintaining triglyceride and free fatty acid levels, as well as determininginsulin resistance.[2]Abdominalfat has a differentmetabolicprofile—being more prone to induce insulin resistance. This explains to a large degree whycentral obesityis a marker of impaired glucose tolerance and is an independent risk factor forcardiovascular disease(even in the absence ofdiabetes mellitusandhypertension).[51]Studies of female monkeys atWake Forest University(2009) discovered that individuals with higherstresshave higher levels of visceral fat in their bodies. This suggests a possible cause-and-effect link between the two, wherein stress promotes the accumulation of visceral fat, which in turn causes hormonal and metabolic changes that contribute to heart disease and other health problems.[52]

Recent advances in biotechnology have allowed for the harvesting ofadult stem cellsfrom adipose tissue, allowing stimulation of tissue regrowth using a patient's own cells. In addition, adipose-derived stem cells from both human and animals reportedly can be efficiently reprogrammed intoinduced pluripotent stem cellswithout the need forfeeder cells.[53]The use of a patient's own cells reduces the chance of tissue rejection and avoids ethical issues associated with the use of humanembryonic stem cells.[54]A growing body of evidence also suggests that different fat depots (i.e. abdominal, omental, pericardial) yield adipose-derived stem cells with different characteristics.[54][55]These depot-dependent features includeproliferation rate,immunophenotype,differentiation potential,gene expression,as well as sensitivity to hypoxic culture conditions.[56]Oxygen levels seem to play an important role on the metabolism and in general the function of adipose-derived stem cells.[57]

Adipose tissue is a major peripheral source ofaromatasein both males and females, contributing to the production ofestradiol.[58]

Adipose derived hormonesinclude:

Adipose tissues also secrete a type ofcytokines(cell-to-cell signalling proteins) calledadipokines(adipose cytokines), which play a role in obesity-associated complications. Perivascular adipose tissue releases adipokines such as adiponectin that affect the contractile function of the vessels that they surround.[1][59]

Brown fat

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Brown fat cell
Main article:Brown adipose tissue

Brown fat orbrown adipose tissue(BAT) is a specialized form of adipose tissue important for adaptivethermogenesisin humans and other mammals. BAT can generate heat by "uncoupling" therespiratory chainofoxidative phosphorylationwithinmitochondriathrough tissue-specific expression ofuncoupling protein 1(UCP1).[60]BAT is primarily located around the neck and large blood vessels of thethorax,where it may effectively act in heat exchange. BAT is robustly activated upon cold exposure by the release ofcatecholaminesfromsympathetic nervesthat results in UCP1 activation. Nearly half of the nerves present in adipose tissue are sensory neurons connected to thedorsal root ganglia.[61]

BAT activation may also occur in response to overfeeding.[62]UCP1 activity is stimulated by long chain fatty acids that are produced subsequent toβ-adrenergic receptoractivation.[60]UCP1 is proposed to function as a fatty acid protonsymporter,although the exact mechanism has yet to be elucidated.[63]In contrast, UCP1 is inhibited byATP,ADP,andGTP.[64]

Attempts to simulate this processpharmacologicallyhave so far been unsuccessful. Techniques to manipulate the differentiation of "brown fat" could become a mechanism forweight losstherapy in the future, encouraging the growth of tissue with this specialized metabolism without inducing it in other organs. A review on the eventual therapeutic targeting ofbrown fatto treat human obesity was published by Samuelson andVidal-Puigin 2020.[65]

Until recently, brown adipose tissue in humans was thought to be primarily limited to infants, but new evidence has overturned that belief. Metabolically active tissue with temperature responses similar to brown adipose was first reported in the neck and trunk of some human adults in 2007,[66]and the presence of brown adipose in human adults was later verifiedhistologicallyin the same anatomical regions.[67][68][69]

Beige fat and WAT browning

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Browning of WAT, also referred to as "beiging", occurs when adipocytes within WAT depots develop features of BAT.Beige adipocytestake on a multilocular appearance (containing several lipid droplets) and increase expression ofuncoupling protein 1(UCP1).[70]In doing so, these normally energy-storing adipocytes become energy-releasing adipocytes.

The calorie-burning capacity of brown and beige fat has been extensively studied as research efforts focus on therapies targeted to treat obesity and diabetes. The drug2,4-dinitrophenol,which also acts as a chemicaluncouplersimilarly to UCP1, was used for weight loss in the 1930s. However, it was quickly discontinued when excessive dosing led to adverse side effects includinghyperthermiaand death.[70]β3-adrenergic agonists,like CL316,243, have also been developed and tested in humans. However, the use of such drugs has proven largely unsuccessful due to several challenges, including varying species receptor specificity and poor oralbioavailability.[71]

Cold is a primary regulator of BAT processes and induces WAT browning. Browning in response to chronic cold exposure has been well documented and is a reversible process. A study in mice demonstrated that cold-induced browning can be completely reversed in 21 days, with measurable decreases in UCP1 seen within a 24-hour period.[72]A study by Rosenwald et al. revealed that when the animals are re-exposed to a cold environment, the same adipocytes will adopt a beige phenotype, suggesting that beige adipocytes are retained.[73]

Transcriptional regulators, as well as a growing number of other factors, regulate the induction of beige fat. Four regulators of transcription are central to WAT browning and serve as targets for many of the molecules known to influence this process.[74]These include peroxisome proliferator-activated receptor gamma(PPARγ),PRDM16,[75]peroxisome proliferator-activated receptor gamma coactivator 1 alpha(PGC-1α),and Early B-Cell Factor-2 (EBF2).[76][77][78]

The list of molecules that influence browning has grown in direct proportion to the popularity of this topic and is constantly evolving as more knowledge is acquired. Among these molecules areirisinand fibroblast growth factor 21 (FGF21), which have been well-studied and are believed to be important regulators of browning. Irisin is secreted from muscle in response to exercise and has been shown to increase browning by acting on beige preadipocytes.[79]FGF21, a hormone secreted mainly by the liver, has garnered a great deal of interest after being identified as a potent stimulator of glucose uptake and a browning regulator through its effects on PGC-1α.[70]It is increased in BAT during cold exposure and is thought to aid in resistance to diet-induced obesity[80]FGF21 may also be secreted in response to exercise and a low protein diet, although the latter has not been thoroughly investigated.[81][82]Data from these studies suggest that environmental factors like diet and exercise may be important mediators of browning. In mice, it was found that beiging can occur through the production ofmethionine-enkephalin peptidesbytype 2 innate lymphoid cellsin response tointerleukin 33.[83]

Genomics and bioinformatics tools to study browning

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Due to the complex nature of adipose tissue and a growing list of browning regulatory molecules, great potential exists for the use ofbioinformaticstools to improve study within this field. Studies of WAT browning have greatly benefited from advances in these techniques, as beige fat is rapidly gaining popularity as a therapeutic target for the treatment of obesity and diabetes.

DNA microarrayis a bioinformatics tool used to quantify expression levels of various genes simultaneously, and has been used extensively in the study of adipose tissue. One such study used microarray analysis in conjunction with Ingenuity IPA software to look at changes in WAT and BAT gene expression when mice were exposed to temperatures of 28 and 6 °C.[84]The most significantly up- and downregulated genes were then identified and used for analysis of differentially expressed pathways. It was discovered that many of the pathways upregulated in WAT after cold exposure are also highly expressed in BAT, such asoxidative phosphorylation,fatty acid metabolism,and pyruvate metabolism.[84]This suggests that some of the adipocytes switched to a beige phenotype at 6 °C. Mössenböck et al. also used microarray analysis to demonstrate thatinsulindeficiency inhibits the differentiation of beige adipocytes but does not disturb their capacity for browning.[85]These two studies demonstrate the potential for the use of microarray in the study of WAT browning.

RNA sequencing (RNA-Seq) is a powerful computational tool that allows for the quantification of RNA expression for all genes within a sample. Incorporating RNA-Seq into browning studies is of great value, as it offers better specificity, sensitivity, and a more comprehensive overview of gene expression than other methods. RNA-Seq has been used in both human and mouse studies in an attempt characterize beige adipocytes according to their gene expression profiles and to identify potential therapeutic molecules that may induce the beige phenotype. One such study used RNA-Seq to compare gene expression profiles of WAT from wild-type(WT)mice and those overexpressing Early B-Cell Factor-2 (EBF2). WAT from the transgenic animals exhibited a brown fat gene program and had decreased WAT specific gene expression compared to the WT mice.[86]Thus, EBF2 has been identified as a potential therapeutic molecule to induce beiging.

Chromatin immunoprecipitation with sequencing(ChIP-seq)is a method used to identify protein binding sites on DNA and assesshistonemodifications. This tool has enabled examination ofepigeneticregulation of browning and helps elucidate the mechanisms by which protein-DNA interactions stimulate the differentiation of beige adipocytes. Studies observing the chromatin landscapes of beige adipocytes have found that adipogenesis of these cells results from the formation of cell specific chromatin landscapes, which regulate the transcriptional program and, ultimately, control differentiation. Using ChIP-seq in conjunction with other tools, recent studies have identified over 30 transcriptional and epigenetic factors that influence beige adipocyte development.[86]

Genetics

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Main article:Genetics of obesity § Genes

Thethrifty gene hypothesis(also called the famine hypothesis) states that in some populations the body would be more efficient at retaining fat in times of plenty, thereby endowing greater resistance to starvation in times of food scarcity. This hypothesis, originally advanced in the context of glucose metabolism and insulin resistance, has been discredited by physical anthropologists, physiologists, and theoriginal proponent of the ideahimself with respect to that context, although according to its developer it remains "as viable as when [it was] first advanced" in other contexts.[87][88]

In 1995,Jeffrey Friedman,in his residency at theRockefeller University,together withRudolph Leibel,Douglas Colemanet al. discovered the proteinleptinthat the genetically obese mouse lacked.[89][90][91]Leptin is produced in the white adipose tissue and signals to thehypothalamus.When leptin levels drop, the body interprets this as a loss of energy, and hunger increases. Mice lacking this protein eat until they are four times their normal size.

Leptin, however, plays a different role in diet-induced obesity in rodents and humans. Because adipocytes produce leptin, leptin levels are elevated in the obese. However, hunger remains, and—when leptin levels drop due to weight loss—hunger increases. The drop of leptin is better viewed as a starvation signal than the rise of leptin as asatietysignal.[92]However, elevated leptin in obesity is known asleptin resistance.The changes that occur in the hypothalamus to result in leptin resistance in obesity are currently the focus of obesity research.[93]

Gene defects in the leptin gene (ob) are rare in human obesity.[94]As of July 2010,only 14 individuals from five families have been identified worldwide who carry a mutatedobgene (one of which was the first ever identified cause of genetic obesity in humans)—two families of Pakistani origin living in the UK, one family living in Turkey, one in Egypt, and one in Austria[95][96][97][98][99]—and two other families have been found that carry a mutatedobreceptor.[100][101]Others have been identified as genetically partially deficient in leptin, and, in these individuals, leptin levels on the low end of the normal range can predict obesity.[102]

Severalmutationsof genes involving themelanocortins(used in brain signaling associated with appetite) and theirreceptorshave also been identified as causing obesity in a larger portion of the population than leptin mutations.[103]

Physical properties

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Adipose tissue has a density of ~0.9 g/ml.[104]Thus, a person with more adipose tissue will float more easily than a person of the same weight with moremuscular tissue,since muscular tissue has a density of 1.06 g/ml.[105]

Body fat meter

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See also:Bioelectrical impedance analysis

Abody fat meteris a tool used to measure thebody fat to weight ratioin the human body. Different meters use various methods to determine the ratio. They tend to under-read body fat percentage.

In contrast with clinical tools likeDXAandunderwater weighing,one relatively inexpensive type of body fat meter uses the principle ofbioelectrical impedance analysis(BIA) in order to determine an individual's body fat percentage. To achieve this, the meter passes a small, harmless,electric currentthrough the body and measures theresistance,then uses information on the person's weight, height, age, and sex to calculate an approximate value for the person's body fat percentage. The calculation measures the total volume of water in the body (lean tissue and muscle contain a higher percentage of water than fat), and estimates the percentage of fat based on this information. The result can fluctuate several percentage points depending on what has been eaten and how much water has been drunk before the analysis. This method is quick and readily accessible, but imprecise. Alternative methods are:skin fold methodsusingcalipers,underwater weighing,whole bodyair displacement plethysmography(ADP) andDXA.

Animal studies

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Within the fat (adipose) tissue ofCCR2deficientmice,there is an increased number ofeosinophils,greater alternativeMacrophageactivation, and a propensity towards type 2cytokineexpression. Furthermore, this effect was exaggerated when the mice becameobesefrom a high fat diet.[106]

[edit]
  • Diagrammatic sectional view of the skin (magnified)
    Diagrammatic sectional view of the skin (magnified)
  • White adipose tissue in paraffin section
    White adipose tissue in paraffin section
  • Electronic instrument of body fat meter
    Electronic instrument of body fat meter

See also

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References

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