|Year : 2019 | Volume
| Issue : 1 | Page : 24-28
Brown adipose tissue in adult humans: A mini review
VS Kiranmayi1, KM Bhargav2
1 Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
|Date of Web Publication||6-Nov-2019|
V S Kiranmayi
Associate Professor, Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Adipose tissue is of two types: white adipose tissue (WAT) and brown adipose tissue (BAT). For a long time, it was considered that BAT is present only in hibernating animals and newborns, conferring them a protection from the cold environment. However, radionuclide imaging studies have shown that BAT is also present in adult human beings and plays an important role in energy metabolism. This has resulted in a resurgence of interest on BAT in the researchers. The molecular mechanisms underlying the thermogenic role of BAT and various factors that can induce the formation and activity of BAT are being explored. The thermogenic effect of BAT is mediated by uncoupling protein 1, also known as thermogenin. Several factors such as exposure to cold, stimulation by sympathetic nervous system, thyroid hormones and other endocrine factors induce brown adipogenesis and its activity. An inverse relationship exists between BAT and body weight. The increasing prevalence of obesity globally and its association with various complications makes it essential to search for therapeutic strategies to prevent and treat obesity. In this regard, BAT with its ability to dissipate energy in the form of heat appears to be a potential therapeutic target for the management of obesity.
Keywords: Adipocytes, brown adipose tissue, thermogenesis, uncoupling protein 1
|How to cite this article:|
Kiranmayi V S, Bhargav K M. Brown adipose tissue in adult humans: A mini review. J Clin Sci Res 2019;8:24-8
| Introduction|| |
It is well known that adipose tissue plays an important role in health as well as disease. Two types of adipose tissues exist in mammals. These include the white adipose tissue (WAT) and the brown adipose tissue (BAT). These tissues differ completely with respect to their metabolic role. The WAT stores excess energy as fat, whereas the BAT is involved in the dissipation of energy as heat by thermogenesis due to the presence of a unique protein known as uncoupling protein 1 (UCP1), also called thermogenin. The cells of the WATs and BATs also differ with respect to their morphology. White adipocytes are spherical and of varied size with a single large lipid droplet that mainly contains triglycerides. The mitochondria in white adipocytes are varied in number. On the other hand, the brown adipocytes consist of multiple small vacuoles containing triglycerides and have an abundance of mitochondria. The BAT is richly supplied with blood vessels owing to its increased demand for oxygen. The high mitochondrial content and the rich vascularity impart brown colour to the BAT.
| Rediscovery of Brown Adipose Tissue|| |
BAT was first identified in hibernating mammals in 1551 by Gesner. The role of BAT in the maintenance of warmth during exposure to cold was first provided by Silverman et al. in the year 1964. Although described since long time, in contrast to other organs, the BAT remains scientifically a new organ. BAT is considered to be abundantly present in neonates and small mammals, helping them to overcome the cold temperatures. The tissue was thought to be absent or minimally present in adult human beings. However, the traditional concept that BAT is absent from adult human tissues has been challenged by radionuclide imaging findings. It has been identified that BAT is present in adult humans and plays an important functional role, especially in energy metabolism. Further evidence for the presence of BAT in adults resulted in a resurgence of interest in this tissue.
The presence of BAT was observed during radiological studies done on cancer patients using fluorodeoxyglucose (FDG)-positron emission tomography (PET), a technique used for the detection of metabolically active tumour tissues. Positron emission tomography scan using radioactive fluorodeoxyglucose can identify tissues with high glucose uptake such as brown adipocytes. While PET imaging determines physiological aspects of a tissue, computerised tomography (CT) helps in defining the anatomy. For a long time, it was thought that false-positive results were obtained on imaging studies as the tissues identified mainly in the parasternal or supraclavicular regions were negative for malignant cells. However, simultaneous examination of these sites using FDG-PET and CT enabled identification of them to be BAT. Initially, no histological confirmation of the identified tissue was performed. Subsequently, histological evidence of the presence of BAT in the biopsy specimens of tissues obtained from adipose tissue has been reported.
| Development of Brown Adipose Tissue|| |
Earlier, it was considered that WATs and BATs arise from common origin; however, recent studies have provided a clear concept on the development of adipocytes. In the mouse models, BAT was first identified on or after 15.5 days of embryonic development. In human beings, BAT develops earlier than WAT, around midgestation, and attains maximum size relative to body weight at birth. The adipocytes share a common developmental origin with other mesodermal tissue cells such as chondrocytes, osteoblasts and myocytes. All these cells originate from the mesenchymal stem cells which are multipotent cells.
Adipogenesis occurs in two stages: initial development of mesenchymal stem cells into preadipocytes under appropriate stimulation and subsequent differentiation into mature adipocytes. The myocyte factor 5 (Myf5) expressing preadipocytes develop into either brown adipocytes or myoblasts. On the other hand, Myf5-negative precursor cells differentiate into white adipocyte or beige/brite adipocytes [Figure 1]. After the terminal differentiation, the different types of adipocytes can be identified by their marker gene expression. Several transcription factors including peroxisome proliferator-activated receptor γ (PPAR-γ), steroid response element-binding protein1c, CCAAT/enhancer-binding proteins α, β and δ direct the differentiation of brown and white adipocytes. Of these, PPAR-γ is considered to be the most important factor and is highly expressed in both mature brown and white adipocytes. Another factor which is PPAR-γ-interacting protein and is known as PPAR-γ coactivator-1α (PGC-1α) has been described. PGC-1α is involved in the regulation of mitochondrial development, synthesis of UCP1 by inducing its promoter and is highly expressed in BAT. The specific development of brown adipocytes is regulated by PGC-1α and another transcription factor PR-domain-containing-16, which interacts with C/EBPβ. In addition to these factors, transcriptional regulation of brown adipogenesis is also mediated by zinc finger proteins: Zfp423 and Zfp521. PGC-1α also controls the development of BAT within WAT; similarly, several other nuclear receptor coregulators including steroid receptor coactivator-1, transcriptional intermediary factor-2 and Twist-1 also regulate brown adipocyte development from white adipocytes. Thus, it can be understood that brown adipocytes have more than one source of origin, differentiation from brown preadipocytes and the transdifferentiation (direct transformation) of white adipocytes. The brown adipocytes developing within WAT are described as brite (brown-in-white) cells or beige adipocytes.
| Regulation of Brown Adipogenesis|| |
The BAT activity in human beings could be studied with the help of PET-CT imaging as well as byin vitro studies employing immortalised multipotent stem cell-derived brown adipocytes and primary cultures. Several factors that contribute to the regulation of BAT activity in human beings have been identified, the environmental temperature being the most widely investigated factor [Table 1].
Effect of temperature
Studies have shown that exposure of an individual to cold stimulates BAT activity., Acute exposure to cold was shown to enhance the mRNA expression of and prolonged exposure resulted in hypertrophy and hyperplasia of brown adipocytes. Cold-induced brown adipogenesis was further supported by studies involving cooling protocols and also by using tracers that could detect increased metabolic activity in BAT.,, Consistent with the finding that BAT activity is induced by cold exposure, it was further shown that BAT detection rates were higher in winter than in summer season.,
Effect of sympathetic stimulation
In addition to rich vascularity, BAT is densely innervated by sympathetic nerves. The sympathetic nervous system (SNS) stimulates the activity of BAT. Exposure to cold causes activation of sympathetic nerves through a pathway involving the thermoregulatory hypothalamus. Sympathetic stimulation results in the increased levels of circulating noradrenaline. Further studies evaluated the effects of central nervous system (CNS) depressants on FDG uptake and reported that CNS depressants reduced BAT activity.,
Effect of noradrenaline
Noradrenaline is the hormone of SNS. Noradrenaline positively influences BAT in that it induces the proliferation and differentiation of BAT. Long-term administration of noradrenaline resulted in an increase in the cellularity as well as overall mass of BAT., Although noradrenaline acts through α and β receptors, the effects of noradrenaline on BAT were shown to be mediated through β receptors, mainly the β3 receptors that are abundantly expressed on adipocytes.
Effect of thyroid hormones
Thyroid hormones also form important positive regulators of BAT activity. Triiodothyronine (T3) is especially important in this regard. The precursor of T3, which is T4, is taken up by brown adipocytes and is converted to T3 by type 2 deiodinase (DIO2). T3 upregulates the expression of UCP1 through its effects on the thyroid hormone responsive elements present on UCP1 promoter.
The amount and activity of BAT decreases with increasing age and is inversely related to body mass index and body fat. Insulin, which is a pancreatic hormone, is a major regulator of brown adipogenesis. Fibroblast growth factor 21 (FGF21), another hormone synthesised and secreted by liver, is involved in the browning of white fat through its effects on PGC-1α.In vitro studies have shown that cardiac natriuretic peptides, including atrial natriuretic peptide and brain-type natriuretic peptide, also induce browning of WAT. Irisin, another recently identified hormone, secreted from skeletal muscle also has been shown to modulate brown and WAT composition in animals.
| Thermogenic Role of Brown Adipose Tissue|| |
Tissue studies have shown that BAT in human beings is mainly located in the fat tissues of the neck, thorax, abdomen, around the deep viscera and along great vessels. Adenosine triphosphate (ATP), which is the chief cellular source of energy, is synthesised from adenosine diphosphate (ADP) and inorganic phosphate by oxidative phosphorylation, occurring in the mitochondrial respiratory chain comprising four complexes (I–IV), located on the inner mitochondrial membrane. Oxidation of principal nutrients by cellular enzymes results in the generation of reducing equivalents (NADH and FADH2). These reducing equivalents donate their electrons to the mitochondrial respiratory chain, and the electrons move across the complexes, driven by redox potential. The movement of electrons is coupled with the pumping out of proteins across the inner mitochondrial membrane, at complexes I, III and IV. The movement of protons results in the generation of an electrochemical gradient, known as proton motive force across the inner mitochondrial membrane. The energy that is released when the protons are transported back from the intermembrane space into the mitochondrial matrix is utilised by ATP synthase for the synthesis of ATP from ADP. The final step in the mitochondrial respiratory chain is the reduction of molecular oxygen by complex IV to water.
Uncoupling protein 1
UCPs located on the inner mitochondrial membrane belong to anion carrier protein family. Five types of UCPs (UCP1, UCP2, UCP3, UCP4 and UCP5) have been described in humans. UCP1, also known as thermogenin, is a 33-kDa dimeric protein that is mainly expressed in brown adipocytes., The gene for UCP1 is present on chromosome 4. UCPs are known to decrease metabolic efficiency by uncoupling oxidation in mitochondria from phosphorylation, thereby decreasing ATP synthesis. The UCP1 acts as membrane transporter, and the uncoupling effect is brought about by causing translocation or backleaking of protons from the intermembrane space across the inner mitochondrial membrane into the mitochondrial matrix. The resulting potential energy instead of being used for ATP synthesis is dissipated in the form of heat, leading to thermogenesis. Thus, BAT is chiefly concerned with dissipation of energy in the form of heat.
| Anti-Obesity Role of Brown Adipose Tissue|| |
Obesity, which is a worldwide public health problem, occurs mainly as a result of increased intake of energy-dense foods, decreased physical activity and is associated with various complications. The increasing prevalence of obesity indicates the need for the development of therapeutic strategies to prevent and treat obesity. The ultimate goal of the knowledge gained on BAT is to apply it for therapeutic benefits. Increased BAT activity can be obtained by measures that can enhance its mass or its activity. Pharmacological β-adrenergic stimulation to cause the release of noradrenaline, a potent inducer of BAT, is one of the mechanisms that can be used for stimulating BAT proliferation and activity. Studies conducted to evaluate the efficacy of β-adrenergic stimulation in causing brown adipogenesis reported that the noradrenaline concentration attained by β-agonist stimulation could not match with that attained by cold-induced β-adrenergic stimulation., Increasing the dosage of β-agonists may be associated with adverse side effects. In this context, naturally occurring compounds such as capsinoids have been observed to induce recruitment of BAT. Another therapeutic strategy is to induce browning of WAT. Among the various transcriptional factors that are involved in the browning of white adipocytes, the hormones – FGF21 and irisin appear to be promising owing to their availability in injectable forms. However, human studies need to be conducted to further explore their usefulness.
In conclusion, it is now well established that functional BAT is present in adult human beings and plays an active role in energy metabolism. Understanding the factors that determine the ultimate differentiation of adipocytes into fat-storing WAT or thermogenic BAT may help to understand the mechanisms underlying the development of obesity. Moreover, BAT-induced thermogenesis can reduce obesity. The inducible nature of BAT by various factors paves the way for developing effective therapeutic strategies that can enhance brown adipogenesis. Although certain therapies have been developed, their safety needs to be confirmed before they can be applied for human benefit.
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Conflicts of interest
There are no conflicts of interest.
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