Adipose tissue

Source: Wikipedia, the free encyclopedia.
"Adipose" redirects here. For the fictional creature from Doctor Who, see
List of Doctor Who universe creatures and aliens (0–9, A–G) § Adipose
.
See also: Fat
Adipose tissue
Pig belly fat (white)
Adipose tissue is one of the main types of connective tissue.
Pronunciation/ˈædɪˌpoʊs/ ⓘ
Identifiers
MeSHD000273
FMA20110
Anatomical terminology

Adipose tissue (also known as body fat or simply fat) is a loose

endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates
the body.

Previously treated as being hormonally inert, in recent years adipose tissue has been recognized as a major

adipokines, which are responsible for the development of metabolic syndrome—a constellation of diseases including type 2 diabetes, cardiovascular disease and atherosclerosis.[2][4]

Adipose tissue is derived from preadipocytes and its formation appears to be controlled in part by the

adipose gene. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. Adipose tissue—more specifically brown adipose tissue—was first identified by the Swiss naturalist Conrad Gessner in 1551.[5]

Anatomical features

Distribution of white adipose in the human body

In humans, adipose tissue is located: beneath the

endothelial cells
.

Adipose tissue contains many small blood vessels. In the integumentary system, which includes the skin, it accumulates in the deepest level, the subcutaneous layer, 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

The obese mouse on the left has large stores of adipose tissue. It is unable to produce the hormone leptin. 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 the

lymphoid tissue as lymph nodes and milky 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 the skin between 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 the pericardial, which surrounds the heart, and the paired popliteal depots, between the major muscles behind the knees, each containing one large lymph 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

In an

obese person, excess adipose tissue hanging downward from the abdomen is referred to as a panniculus. 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 of gastric bypass surgery). Obesity is treated through exercise, diet, and behavioral therapy. Reconstructive surgery is one aspect of treatment.[10]

Visceral fat

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

Visceral fat or abdominal fat

perirenal depots. Visceral fat is often expressed in terms of its area in cm2 (VFA, visceral fat area).[13]

An excess of visceral fat is known as

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 to sex hormone differences. Estrogen (female sex hormone) causes fat to be stored in the buttocks, thighs, and hips in women.[21][22] When women reach menopause and 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 excess cortisol levels.

MET-hours per week of aerobic exercise leads 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

subcutaneous fat, suggesting a location-specific impact of stored fatty acids on adipocyte function and metabolism.[34]

Subcutaneous fat

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 the

heart disease, cancer, and stroke, 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 hormones leptin and resistin.[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

Marrow fat, also known as

marrow 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 from mesenchymal 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

Ectopic fat is the storage of

triglycerides in tissues other than adipose tissue, that are supposed to contain only small amounts of fat, such as the liver, skeletal muscle, heart, and pancreas.[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 the abdominal 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

Free fatty acids (FFAs) are liberated from lipoproteins by lipoprotein lipase (LPL) and enter the adipocyte, where they are reassembled into triglycerides by esterifying them onto glycerol.[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 lipolytic

B-adrenergic receptors
and a2A-adrenergic receptor-mediated antilipolysis.

Fat cells have an important

stress have 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 of

feeder 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 human embryonic 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 include proliferation 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 of aromatase in both males and females, contributing to the production of estradiol.[58]

Adipose derived hormones
include:

Adipose tissues also secrete a type of cytokines (cell-to-cell signalling proteins) called adipokines (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

Brown fat cell
Main article: Brown adipose tissue

Brown fat or

uncoupling protein 1 (UCP1).[60] BAT is primarily located around the neck and large blood vessels of the thorax, where it may effectively act in heat exchange. BAT is robustly activated upon cold exposure by the release of catecholamines from sympathetic nerves
that results in UCP1 activation. Nearly half of the nerves present in adipose tissue are sensory neurons connected to the dorsal 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 to β-adrenergic receptor activation.[60] UCP1 is proposed to function as a fatty acid proton symporter, although the exact mechanism has yet to be elucidated.[63] In contrast, UCP1 is inhibited by ATP, ADP, and GTP.[64]

Attempts to simulate this process pharmacologically have so far been unsuccessful. Techniques to manipulate the differentiation of "brown fat" could become a mechanism for weight loss therapy 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 of brown fat to treat human obesity was published by Samuelson and Vidal-Puig in 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,

histologically in the same anatomical regions.[67][68][69]

Beige fat and WAT browning

Browning of WAT, also referred to as "beiging", occurs when adipocytes within WAT depots develop features of BAT. Beige adipocytes take on a multilocular appearance (containing several lipid droplets) and increase expression of uncoupling 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 drug

2,4-dinitrophenol, which also acts as a chemical uncoupler similarly to UCP1, was used for weight loss in the 1930s. However, it was quickly discontinued when excessive dosing led to adverse side effects including hyperthermia and death.[70] β3 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 oral bioavailability.[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 are

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 of methionine-enkephalin peptides by type 2 innate lymphoid cells in response to interleukin 33.[83]

Genomics and bioinformatics tools to study browning

Due to the complex nature of adipose tissue and a growing list of browning regulatory molecules, great potential exists for the use of bioinformatics tools 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 microarray is 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 as oxidative 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 that insulin deficiency 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 assess histone modifications. This tool has enabled examination of epigenetic regulation 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

Main article: Genetics of obesity § Genes

The thrifty 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 the original proponent of the idea himself 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,

Douglas Coleman et al. discovered the protein leptin that the genetically obese mouse lacked.[89][90][91] Leptin is produced in the white adipose tissue and signals to the hypothalamus
. 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 a satiety signal.[92] However, elevated leptin in obesity is known as leptin 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 mutated ob gene (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 mutated ob receptor.[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]

Several mutations of genes involving the melanocortins (used in brain signaling associated with appetite) and their receptors have also been identified as causing obesity in a larger portion of the population than leptin mutations.[103]

Physical properties

Adipose tissue has a density of ~0.9 g/ml.

muscular tissue, since muscular tissue has a density of 1.06 g/ml.[105]

Body fat meter

See also: Bioelectrical impedance analysis

A body fat meter is a tool used to measure the body fat to weight ratio in 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 like

DXA
.

Animal studies

Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative Macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.[106]

Gallery

  • 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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Further reading

External links

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