Brown adipose tissue

Last updated
Brown adipose tissue
Brownfat PETCT.jpg
Brown adipose tissue in a woman shown in a FDG PET/CT exam
Details
Identifiers
Latin textus adiposus fuscus
Acronym(s)BAT
MeSH D002001
TH H2.00.03.4.00004
FMA 20118
Anatomical terminology

Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). [1] Brown adipose tissue is found in almost all mammals.

Contents

Classification of brown fat refers to two distinct cell populations with similar functions. The first shares a common embryological origin with muscle cells, found in larger "classic" deposits. The second develops from white adipocytes that are stimulated by the sympathetic nervous system. These adipocytes are found interspersed in white adipose tissue and are also named 'beige' or 'brite' (for "brown in white" [2] ). [3] [4] [5]

Brown adipose tissue is especially abundant in newborns and in hibernating mammals. [6] It is also present and metabolically active in adult humans, [7] [8] but its prevalence decreases as humans age. [9] Its primary function is thermoregulation. In addition to heat produced by shivering muscle, brown adipose tissue produces heat by non-shivering thermogenesis. The therapeutic targeting of brown fat for the treatment of human obesity is an active research field. [10] [11]

In contrast to white adipocytes, which contain a single lipid droplet, brown adipocytes contain numerous smaller droplets and a much higher number of (iron-containing) mitochondria, which gives the tissue its color. [3] Brown fat also contains more capillaries than white fat. These supply the tissue with oxygen and nutrients and distribute the produced heat throughout the body.

Location and classification

The presence of brown adipose tissue in adult humans was discovered in 2003 during FDG-PET scans to detect metastatic cancers. [12] [13] Using these scans and data from human autopsies, several brown adipose tissue deposits have been identified. In infants, brown adipose tissue deposits include, but are not limited to: interscapular, supraclavicular, suprarenal, pericardial, para-aortic and around the pancreas, kidney and trachea. [14] These deposits gradually get more white fat-like during adulthood. In adults, the deposits that are most often detected in FDG-PET scans are the supraclavicular, paravertebral, mediastinal, para-aortic and suprarenal ones. [15] [7] It remains to be determined whether these deposits are 'classical' brown adipose tissue or beige/brite fat. [16] [17]

Brown fat in humans in the scientific and popular literature refers to two cell populations defined by both anatomical location and cellular morphology. Both share the presence of small lipid droplets and numerous iron-rich mitochondria, giving the brown appearance.

Development

Brown fat cells come from the middle embryo layer, mesoderm, also the source of myocytes (muscle cells), adipocytes, and chondrocytes (cartilage cells).

The classic population of brown fat cells and muscle cells both seem to be derived from the same population of stem cells in the mesoderm, paraxial mesoderm. Both have the intrinsic capacity to activate the myogenic factor 5 (Myf5) promoter, a trait only associated with myocytes and this population of brown fat. Progenitors of traditional white fat cells and adrenergically induced brown fat do not have the capacity to activate the Myf5 promoter. Both adipocytes and brown adipocyte may be derived from pericytes, the cells which surround the blood vessels that run through white fat tissue. [3] [19] Notably, this is not the same as the presence of Myf5 protein, which is involved in the development of many tissues.

Additionally, muscle cells that were cultured with the transcription factor PRDM16 were converted into brown fat cells, and brown fat cells without PRDM16 were converted into muscle cells. [3]

Function

The mitochondria in a eukaryotic cell utilize fuels to produce adenosine triphosphate (ATP). This process involves storing energy as a proton gradient, also known as the proton motive force (PMF), across the mitochondrial inner membrane. This energy is used to synthesize ATP when the protons flow across the membrane (down their concentration gradient) through the ATP synthase complex; this is known as chemiosmosis.

In endotherms, body heat is maintained by signaling the mitochondria to allow protons to run back along the gradient without producing ATP (proton leak). This can occur since an alternative return route for the protons exists through an uncoupling protein in the inner membrane. This protein, known as uncoupling protein 1 (thermogenin), facilitates the return of the protons after they have been actively pumped out of the mitochondrial matrix by the electron transport chain. This alternative route for protons uncouples oxidative phosphorylation and the energy in the PMF is instead released as heat.

To some degree, all cells of endotherms give off heat, especially when body temperature is below a regulatory threshold. However, brown adipose tissue is highly specialized for this non-shivering thermogenesis. First, each cell has a higher number of mitochondria compared to more typical cells. Second, these mitochondria have a higher-than-normal concentration of thermogenin in the inner membrane.

Infants

In neonates (newborn infants), brown fat makes up about 5% of the body mass and is located on the back, along the upper half of the spine and toward the shoulders. It is of great importance to avoid hypothermia, as lethal cold is a major death risk for premature neonates. Numerous factors make infants more susceptible to cold than adults:

Heat production in brown fat provides an infant with an alternative means of heat regulation.

Adults

Micrograph of a hibernoma, a benign tumour thought to arise from brown fat (haematoxylin and eosin stain) Hibernoma2.jpg
Micrograph of a hibernoma, a benign tumour thought to arise from brown fat (haematoxylin and eosin stain)

It was believed that after infants grow up, most of the mitochondria (which are responsible for the brown color) in brown adipose tissue disappear, and the tissue becomes similar in function and appearance to white fat. In rare cases, brown fat continues to grow, rather than involuting; this leads to a tumour known as a hibernoma. It is now known that brown fat is related not to white fat, but to skeletal muscle. [20] [21] [22]

Studies using positron emission tomography scanning of adult humans have shown that brown adipose tissue is still present in most adults in the upper chest and neck (especially paravertebrally). The remaining deposits become more visible (increasing tracer uptake, meaning more metabolically active) with cold exposure, and less visible if an adrenergic beta blocker is given before the scan. These discoveries could lead to new methods of weight loss, since brown fat takes calories from normal fat and burns it. Scientists have been able to stimulate brown fat growth in mice. [23] [24] [25] [26] One study of APOE knock out mice showed cold exposure could promote atherosclerotic plaque growth and instability. [27] The study mice were subjected to sustained low temperatures of 4 °C for 8 weeks which may have caused a stress condition, due to rapid forced change rather than a safe acclimatisation, that can be used to understand the effect on adult humans of modest reductions of ambient temperature of just 5 to 10 °C. Furthermore, several newer studies have documented the substantial benefits of cold exposure in multiple species including humans, for example researchers concluded that "activation of brown adipose tissue is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis" [28] and that brown fat activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. [29]

Long-term studies of adult humans are needed to establish a balance of benefit and risk, in combination with historical research of living conditions of recent human generations prior to the current increase of poor health related to excessive accumulation of white fat. Pharmacological approaches using β3-adrenoceptor agonists have been shown to enhance glucose metabolic activity of brown adipose tissue in rodents. [30] [31] [32]

Additionally research has shown:

Other animals

The interscapular brown adipose tissue is commonly and inappropriately referred to as the hibernating gland. [55] Whilst believed by many to be a type of gland, it is actually a collection of adipose tissues lying between the scapulae of rodentine mammals. [56] Composed of brown adipose tissue and divided into two lobes, it resembles a primitive gland, regulating the output of a variety of hormones. [57] [58] [59] The function of the tissue appears to be involved in the storage of medium to small lipid chains for consumption during hibernation, the smaller lipid structure allowing for a more rapid path of energy production than glycolysis.

In studies where the interscapular brown adipose tissue of rats were lesioned, it was demonstrated that the rats had difficulty regulating their normal body-weight. [59]

The longest-lived small mammals, bats (30 years) and naked mole rats (32 years), all have remarkably high levels of brown adipose tissue and brown adipose tissue activity. [60] [61] [62] [63] [64] However, brown fat is unlikely to play a role in body temperature regulation of many large-bodied mammals as the UCP1 gene, encoding for the key thermogenic protein of the tissue, has been inactivated in several lineages (e.g. horses, elephants, sea cows, whales and hyraxes). A reduced surface area to volume ratio among large-bodied species decreases heat loss in the cold, diminishing thermogenic demands required to defend body temperatures. UCP1 loss in other species (e.g. pangolins, armadillos, sloths and anteaters) may be linked to selection pressures favouring low metabolic rates. [65]

See also

Related Research Articles

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue (also known as body fat, or simply fat) is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction(SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and cytokines (especially TNFα). In obesity, adipose tissue is also implicated in the chronic release of pro-inflammatory markers known as adipokines, which are responsible for the development of metabolic syndrome, a constellation of diseases, including type 2 diabetes, cardiovascular disease and atherosclerosis. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue – more specifically brown adipose tissue – was first identified by the Swiss naturalist Conrad Gessner in 1551.

<span class="mw-page-title-main">Thermogenin</span> Mammalian protein found in Homo sapiens

Thermogenin is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

<span class="mw-page-title-main">Resistin</span> Mammalian protein found in Homo sapiens

Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.

<span class="mw-page-title-main">Hyperinsulinemia</span> Abnormal increase in insulin in the bloodstream relative to glucose

Hyperinsulinemia is a condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose. While it is often mistaken for diabetes or hyperglycaemia, hyperinsulinemia can result from a variety of metabolic diseases and conditions, as well as non-nutritive sugars in the diet. While hyperinsulinemia is often seen in people with early stage type 2 diabetes mellitus, it is not the cause of the condition and is only one symptom of the disease. Type 1 diabetes only occurs when pancreatic beta-cell function is impaired. Hyperinsulinemia can be seen in a variety of conditions including diabetes mellitus type 2, in neonates and in drug-induced hyperinsulinemia. It can also occur in congenital hyperinsulinism, including nesidioblastosis.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

<span class="mw-page-title-main">White adipose tissue</span> Fatty tissue composed of white adipocytes

White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor gamma</span> Nuclear receptor protein found in humans

Peroxisome proliferator-activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.

<span class="mw-page-title-main">Free fatty acid receptor 4</span> Protein-coding gene in the species Homo sapiens

Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded by the FFAR4 gene. This gene is located on the long arm of chromosome 10 at position 23.33. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1, FFAR2, and FFAR3. These four FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">PRDM16</span> Protein-coding gene in the species Homo sapiens

PR domain containing 16, also known as PRDM16, is a protein which in humans is encoded by the PRDM16 gene.

<span class="mw-page-title-main">FGF21</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the FGF21 gene. Together with FGF19 and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth factor (FGF) family. FGF21 is a potent, extracellularly acting metabolic regulator, whose action was discovered through in vitro phenotypic screening and diet manipulation studies in rodents., unlike canonical growth-stimulating FGFs known to stimulate mitosis, differentiation and angiogenesis in their target tissues, FGF21 exerts its action by activating FGF21 receptors located in the cell membrane of target cells. Each FGF21 receptor is composed of a transmembrane FGF receptor protein, and its complexing co-receptor β-Klotho. Loss of β-Klotho abolishes all effects of FGF21 in vitro and in vivo. In addition to its action as a hormone, FGF21 may be able to act in an autocrine fashion, or possibly also in a paracrine manner in the pancreas.

<span class="mw-page-title-main">Chemerin</span> Protein-coding gene in the species Homo sapiens

Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.

<span class="mw-page-title-main">FNDC5</span>

Fibronectin type III domain-containing protein 5, the precursor of irisin, is a type I transmembrane glycoprotein that is encoded by the FNDC5 gene. Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris.

<span class="mw-page-title-main">Adipogenesis</span>

Adipogenesis is the formation of adipocytes from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as preadipocytes which lose the potential to differentiate to other types of cells such as chondrocytes, myocytes, and osteoblasts. Terminal differentiation is that preadipocytes differentiate into mature adipocytes. Adipocytes can arise either from preadipocytes resident in adipose tissue, or from bone-marrow derived progenitor cells that migrate to adipose tissue.

<span class="mw-page-title-main">KLF15</span> Protein-coding gene in the species Homo sapiens

Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.

Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. Lipotoxicity is believed to have a role in heart failure, obesity, and diabetes, and is estimated to affect approximately 25% of the adult American population.

<span class="mw-page-title-main">Bone marrow adipose tissue</span>

Bone marrow adipose tissue (BMAT), sometimes referred to as marrow adipose tissue (MAT), is a type of fat deposit in bone marrow. It increases in states of low bone density -osteoporosis, anorexia nervosa/ caloric restriction, skeletal unweighting such as that which occurs in space travel, and anti-diabetes therapies. BMAT decreases in anaemia, leukaemia, and hypertensive heart failure; in response to hormones such as oestrogen, leptin, and growth hormone; with exercise-induced weight loss or bariatric surgery; in response to chronic cold exposure; and in response to pharmacological agents such as bisphosphonates, teriparatide, and metformin.

<span class="mw-page-title-main">Perilipin-5</span> Mammalian protein found in Homo sapiens

Perilipin 5, also known as Oxpatperilipin 5 or PLIN5, is a protein that belongs to perilipin family. This protein group has been shown to be responsible for lipid droplet's biogenesis, structure and degradation. In particular, Perilipin 5 is a lipid droplet-associated protein whose function is to keep the balance between lipolysis and lipogenesis, as well as maintaining lipid droplet homeostasis. For example, in oxidative tissues, muscular tissues and cardiac tissues, PLIN5 promotes association between lipid droplets and mitochondria.

References

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