Brown Adipose Tissue

Brown adipose tissue (BAT) is a type of fat that burns lipids and glucose in order to generate heat. This is a remarkable function when compared to white adipose tissue (WAT), which stores energy in the form of lipids and forms the vast majority of human adipose tissue. BAT was described for the first time in 1551 by the Swiss naturalist Conrad Gessner. For a long time it was thought that BAT was only present in hibernating mammals and human babies, as they depend on the heat generating function of BAT to maintain a stable core temperature. It was not until 2009 that functional brown fat is shown in human adults.

Figure 1 A and B. Fig 1A shows the relation between BAT activity and BMI. Fig 1B shows the relation between BAT activity and Body Fat percentage (picture from van Marken Lichtenbelt et al., 2009) Click to enlarge.
Figure 1 A and B. Fig 1A shows the relation between BAT activity and BMI. Fig 1B shows the relation between BAT activity and Body Fat percentage (picture from van Marken Lichtenbelt et al., 2009) Click to enlarge.
In adult humans, BAT is mainly detected in the cervical-supraclaviculair and paravertebral area. The amount depends on several factors, such as body fat percentage, body mass index (BMI) (Figure 1 A and B) , age and environmental temperature [1][2][3]. Its brown/reddish colour is the effect of numerous iron containing mitochondria and high vascularization. It can be easily dissected in rodents, because they have very distinct BAT depots. Human WAT and BAT is more difficult to distinguish by the naked eye. However under the microscope differences are more evident. Brown adipocytes contain multilocular lipid droplets and high numbers of mitochondria (Figure 2). Very specific for brown adipocytes is the presence of uncoupling protein 1 (UCP1). UCP1 is located in the inner membrane of the mitochondria and contributes to heat generation. For an overview of characteristics of both types of adipose tissue see table 1.

Table 1. Overview of the characterisics of brown and white adipose tissue

Brown adipose tissue White adipose tissue
Function Uses energy when activated to generate heat Stores energy
Location Cervical-supraclaviculair area and paravertebral area Ubiquitous
Characteristics tissue Fleshy like appearance Yellowish colour
High vascularization Low vascularization
Characteristics cells Polygonal shape Generally rounded shape
Nucleus located in the centre Nucleus compressed to the cell membrane
Multiple lipid droplets of varying size Single large lipid droplet
High number of mitochondria Few small mitochondria
UCP1 present No UCP1

Figure 2 A. Adipose tissue is stained with hematoxylin and eosin. BAT contains multiple lipid droplets (white areas) and mitochondria (purple lining) (picture from van Marken Lichtenbelt et al.,2009) Click to enlarge.
Figure 2 A. Adipose tissue is stained with hematoxylin and eosin. BAT contains multiple lipid droplets (white areas) and mitochondria (purple lining) (picture from van Marken Lichtenbelt et al.,2009) Click to enlarge.

BAT is innervated by the sympathetic nervous system. Stimulation of this system, for example by cold exposure, results in release of norepinephrine at the nerve endings. Norepinephrine binds to beta-adrenergic receptor located at the cell membrane of brown adipocytes. The beta-adrenergic receptor is a G-protein coupled receptor, which upon activation results in production of second messenger cAMP and subsequent activation of protein kinase A. Activation of the beta-adrenergic receptor ultimately results in activation of UCP1 in the mitochondria. UCP1 activity is crucial for heat production by the mitochondria. To understand the underlying mechanism, more detailed information regarding energy production in mitochondria is necessary (figure 3). Cellular energy/fuel, called ATP, is produced by the electron transport chain due to a proton electrochemical gradient across the inner mitochondrial membrane. For this, protons (H+) are transferred from the matrix across the inner membrane to the intermembrane space by the complexes of the electron transport chain. This results in a proton gradient across the inner membrane. For ATP production, protons are transported into the matrix again via ATP synthase. The energy released from the proton flow through ATP synthase is used to couple phosphate to ADP resulting in ATP. For this process it is Figure 3. Schematic illustration of a mitochondrion in brown adipose tissue. Protons (H+) are transferred from the matrix via de electron transport chain to the inter membrane space. A proton gradient across the inner membrane arises. Proton flow via ATPase leads to production of ATP. Proton flow via UCP1 results in extra heat generation. Click to enlarge.
Figure 3. Schematic illustration of a mitochondrion in brown adipose tissue. Protons (H+) are transferred from the matrix via de electron transport chain to the inter membrane space. A proton gradient across the inner membrane arises. Proton flow via ATPase leads to production of ATP. Proton flow via UCP1 results in extra heat generation. Click to enlarge.
important that the inner membrane is intact, thus resulting in an efficient build up of the proton gradient. UCP1 provides BAT with an additional route for protons to go into the matrix. When stimulated by the sympathetic nervous system, protons pass through UCP1 thereby not resulting in ATP production. This, together with an increased activity of the electron transport chain results in extra heat production. This way of generating heat is called non-shivering thermogenesis and is a way of maintaining core body temperature in the cold. Prolonged cold exposure not only activates BAT, but can also increase the amount of BAT and its activity [4].

Thus, the energy from glucose and lipids is used to build up a proton gradient that in turn is used for ATP production. Due to the presence of UCP1 in BAT, ATP synthesis is uncoupled resulting in extra heat production. Stimulation of BAT increases consumption of glucose and lipids by BAT because of the augmented electron transport chain’s activity. As a result BAT stimulation increases resting metabolic rate [1][4].

Brown like adipocytes

Besides classical brown adipocytes, also brown-like adipocytes have been described to reside in WAT depots. These adipocytes are also known as brite adipocytes (brown-in-white) or beige adipocytes. Cold acclimation and beta adrenergic receptor stimulation increase the amount of brite cells in rodents [5]. This process is also called browning. So far, in humans browning has only been demonstrated in conditions that provoke extreme adrenergic stress [6]. The exact mechanism underlying recruitment of beige fat cells is not completely elucidated. Several lines of research have indicated that white adipocytes can become brown-like adipocytes and vice versa [7]. This process is referred to as transdifferentiation. On the other hand, it has also been demonstrated that beige adipocytes are differentiated from their own precursor cells [8].

Detection methods in Humans

PET-CT scan

Figure 4. PET/CT scans. Black areas depict uptake of 18F-FDG. Left: PET/CT scan performed after cold exposure. Brown adipose tissue is activated in the supraclaviculair area, paravertebral area and in the axilla. Right: PET/CT scan during thermoneutral  condition. In this case no activated BAT is detected. (Picture from van Marken Lichtenbelt et al., 2009) Click to enlarge.
Figure 4. PET/CT scans. Black areas depict uptake of 18F-FDG. Left: PET/CT scan performed after cold exposure. Brown adipose tissue is activated in the supraclaviculair area, paravertebral area and in the axilla. Right: PET/CT scan during thermoneutral condition. In this case no activated BAT is detected. (Picture from van Marken Lichtenbelt et al., 2009) Click to enlarge.
The gold standard for detection of BAT in humans is to visualize the uptake of a radioactive glucose tracer by positron emission tomography (PET) combined with computed tomography (CT). To this end, a person is exposed to cold resulting in activation of his/her BAT. Following, radioactive labeled glucose (2-deoxy-2-(18F)fluoro-D-glucose or 18F-FDG) is administered. Due to the cold exposure, the 18F-FDG will be taken up by brown adipocytes. Via PET the uptake of 18F-FDG can be visualized and via CT the location within the body is determined. Combining the information of both scans provides information on what tissue has taken up the 18F-FDG (fig 4). Apart from BAT also other glucose consuming organs like brain and heart will be detected by this technique. In addition, skeletal muscle will take up the radioactive glucose if a person shivers or moves. Therefore, the severity of cold exposure should be enough to induce non shivering thermogenesis, but shivering should be avoided. Once BAT is determined, the mass and the activity of BAT can be calculated from the image related data.

UCP1

Given the fact that expression of UCP1 occurs almost exclusively in BAT and brown-like adipocytes, detection of UCP1 is a way to distinguish brown/beige fat from white fat. Gene expression of UCP1 can be measured via qPCR analysis and protein expression can be measured via Western Blotting. Further techniques include immunofluorescence where a combination is made of morphology and localization of UCP1. However invasive procedures are necessary to use the discussed techniques because a BAT biopsy needs to be collected from a human subject.

Role of BAT in type 2 diabetes

Due to the possibility of BAT to modulate energy expenditure, and glucose and lipid handling, it can be conceptually linked to the pathogenesis of diabetes.

Animals

Rodents lacking UCP1 in BAT are obese and have a diabetic phenotype [9]. Transgenic mice overexpressing UCP1 in skeletal muscle (in wild type mice, UCP1 is mainly present in BAT, so these transgenic mice have a lot more UCP1) are protected from obesity [10]. Expression of UCP1 could thus be a positive thing when combating metabolic disease. Several rodent studies have indicated that cold acclimation recruits BAT and that this is associated with a full reversal of a diabetic phenotype. More specifically, the activity or mass of BAT has a positive effect on whole body insulin resistance [11], plasma glucose levels [12], plasma triglyceride and cholesterol levels [13]. These results emphasize the possible role of BAT in the pathophysiology in type 2 diabetes.

Humans

As aforementioned BAT activity is inversely associated with BMI and body fat percentage [1]. Indeed, morbid obese subjects have hardly any detectable BAT [14]. This could suggest that low BAT activity might be a result of obesity, due to increased insulation by an increased subcutaneous fat mass, or inversely: low BAT activity might increase the susceptibility to develop obesity. However the negative association between BMI and BAT activity is independent of diabetic status (2). Brown fat activity by cold exposure in young healthy men improves insulin sensitivity [15][16]. It is not clear whether this improvement is owing to activated brown adipose tissue only. Recently a large increase in insulin sensitivity was shown in type 2 diabetes patients after cold acclimation. In this study, the activity of the brown adipose tissue also increased significantly, but not to large amounts. Therefore the change in insulin sensitivity could not completely be explained by BAT in this study [17].

In addition to information discussed before, it has been suggested that BAT has an endocrine function, but up to date little is known as BAT functioning as a secreting organ. Although the exact role of BAT in diabetes is not completely understood, it might be a target for treatment or prevention of type 2 diabetes. Currently, many research is still being performed on human BAT activity and its relation to T2D.(link naar andere manieren om bruin vet te stimuleren ter behandeling diabetes)

References

  1. ^ van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. The New England journal of medicine. 2009 Apr 9;360(15):1500-8. PubMed PMID: 19357405.

  2. ^ Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier AC, et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. The Journal of clinical endocrinology and metabolism. 2011 Jan;96(1):192-9. PubMed PMID: 20943785.

  3. ^ Huttunen P, Hirvonen J, Kinnula V. The occurrence of brown adipose tissue in outdoor workers. European journal of applied physiology and occupational physiology. 1981;46(4):339-45. PubMed PMID: 6266825.

  4. ^ van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. The Journal of clinical investigation. 2013 Aug;123(8):3395-403. PubMed PMID: 23867626. Pubmed Central PMCID: 3726172.

  5. ^ Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. Journal of cell science. 1992 Dec;103 ( Pt 4):931-42. PubMed PMID: 1362571.

  6. ^ Sidossis LS, Porter C, Saraf MK, Borsheim E, Radhakrishnan RS, Chao T, et al. Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress. Cell metabolism. 2015 Aug 4;22(2):219-27. PubMed PMID: 26244931. Pubmed Central PMCID: 4541608.

  7. ^ Kajimura S, Saito M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annual review of physiology. 2014;76:225-49. PubMed PMID: 24188710. Pubmed Central PMCID: 4090362.

  8. ^ Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nature medicine. 2013 Oct;19(10):1338-44. PubMed PMID: 23995282. Pubmed Central PMCID: 4075943.

  9. ^ Guerra C, Navarro P, Valverde AM, Arribas M, Bruning J, Kozak LP, et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. The Journal of clinical investigation. 2001 Oct;108(8):1205-13. PubMed PMID: 11602628. Pubmed Central PMCID: 209529.

  10. ^ Li B, Nolte LA, Ju JS, Han DH, Coleman T, Holloszy JO, et al. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nature medicine. 2000 Oct;6(10):1115-20. PubMed PMID: 11017142.

  11. ^ Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. The Journal of clinical investigation. 2013 Jan;123(1):215-23. PubMed PMID: 23221344. Pubmed Central PMCID: 3533266.

  12. ^ Wu C, Cheng W, Sun Y, Dang Y, Gong F, Zhu H, et al. Activating brown adipose tissue for weight loss and lowering of blood glucose levels: a microPET study using obese and diabetic model mice. PloS one. 2014;9(12):e113742. PubMed PMID: 25462854. Pubmed Central PMCID: 4252055.

  13. ^ Berbee JF, Boon MR, Khedoe PP, Bartelt A, Schlein C, Worthmann A, et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nature communications. 2015;6:6356. PubMed PMID: 25754609. Pubmed Central PMCID: 4366535.

  14. ^ Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One.6(2):e17247. PubMed PMID: 21390318. Pubmed Central PMCID: 3044745. Epub 2011/03/11. eng.

  15. ^ Chondronikola M, Volpi E, Borsheim E, Porter C, Annamalai P, Enerback S, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014 Dec;63(12):4089-99. PubMed PMID: 25056438. Pubmed Central PMCID: 4238005.

  16. ^ Lee P, Smith S, Linderman J, Courville AB, Brychta RJ, Dieckmann W, et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes. 2014 Nov;63(11):3686-98. PubMed PMID: 24954193. Pubmed Central PMCID: 4207391.

  17. ^ Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ, et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nature medicine. 2015 Aug;21(8):863-5. PubMed PMID: 26147760.

Comments

  1. Gauranga Dhar
    Gauranga Dhar added a compliment on 9 September 2016 at 01:43PM
    Excellent detail about fat tissue
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