Brown adipose tissue and the concept of uncoupling

Brown adipose tissue has a unique metabolic feature. Like most other tissues, it can oxidise substrates, via the tricarboxylic acid cycle, in its mitochondria; unlike in any other tissue, this process can be 'uncoupled' from the generation of ATP when the tissue is stimulated by the sympathetic nervous system (Fig. 4.14).

In all tissues that have mitochondria, the electron transport chain pumps hydrogen ions (protons) out of the mitochondrial matrix (the inside of the mitochondrion) into the space between the two mitochondrial membranes, creating a 'proton gradient' across the mitochondrial inner membrane. This is a way of temporarily storing the energy released in oxidation of substrates. The proton gradient is discharged by a flow of protons back into the mitochondral matrix through an enzyme complex known as ATP synthase, which, as its name suggests, synthesises ATP from ADP and inorganic phosphate. In brown adipose tissue mitochondria this process is uncoupled by a specific uncoupling protein (UCP) (formerly known as thermogenin), which allows the proton gradient across the mitochondrial inner membrane to be dissipated or 'short-circuited'. UCP is related to other proteins that transport substrates across the inner mitochondrial membrane but has become specialised as a 'proton channel'. Discharge of the proton gradient results in the liberation of heat from oxidation of substrates without trapping the free energy in high-energy compounds, and indeed the role of brown adipose tissue is specifically to generate heat. It does not do this all the time; it can be activated via the sympathetic nervous system,

Fig. 4.13 Appearance of brown and white adipose tissue. Top, white adipose tissue under the light microscope. Each cell consists of a large lipid droplet (white) surrounded by a narrow layer of cytoplasm. The nucleus (N) can be seen in some cells, and some of the capillaries are marked (C). The picture represents a width of 0.2 mm although large human fat cells can themselves approach 0.1 mm diameter. From Burkitt, H.G., Young, B. & Heath, J.W. (1993) Wheater's Functional Histology, 3rd edn. Edinburgh: Churchill Livingstone. With permission of the publisher. Bottom, an electron micrograph of brown adipose tissue. In this high-powered view, one adipocyte nearly fills the picture. Unlike the white adipocytes shown above, it has multiple lipid droplets (white areas) and many mitochondria (white adipocytes also have mitochondria, but not so densely packed). CAP is a capillary adjacent to the cell, Go the Golgi apparatus. The picture represents a width of about 14 ^m (i.e. it is about 14 times more enlarged than the upper picture). From Cinti (2001) with permission of the author.

Fig. 4.13 Appearance of brown and white adipose tissue. Top, white adipose tissue under the light microscope. Each cell consists of a large lipid droplet (white) surrounded by a narrow layer of cytoplasm. The nucleus (N) can be seen in some cells, and some of the capillaries are marked (C). The picture represents a width of 0.2 mm although large human fat cells can themselves approach 0.1 mm diameter. From Burkitt, H.G., Young, B. & Heath, J.W. (1993) Wheater's Functional Histology, 3rd edn. Edinburgh: Churchill Livingstone. With permission of the publisher. Bottom, an electron micrograph of brown adipose tissue. In this high-powered view, one adipocyte nearly fills the picture. Unlike the white adipocytes shown above, it has multiple lipid droplets (white areas) and many mitochondria (white adipocytes also have mitochondria, but not so densely packed). CAP is a capillary adjacent to the cell, Go the Golgi apparatus. The picture represents a width of about 14 ^m (i.e. it is about 14 times more enlarged than the upper picture). From Cinti (2001) with permission of the author.

bringing about both an increase in the liberation of fatty acids from the stored triacylglycerol, and a large increase in the flow of blood through the tissue. It is very highly vascularised; that is, it has many capillaries per unit cross-sectional area. The increased blood flow on stimulation brings an increased supply of oxygen, and carries away the heat produced to the rest of the body.

Outer mitochondrial membrane

Electron Micrograph Adipocytes

Fig. 4.14 Uncoupling of respiration in brown adipose tissue, and potentially other tissues. The electron transport chain (proteins and other molecules associated with the inner mitochondrial membrane) transfers reducing equivalents (which can be envisaged either as electrons, shown as e, or as hydrogen atoms, shown as {H}) to molecular oxygen. In the process hydrogen ions (protons) are pumped from the mitochondrial matrix to the space between the inner and outer mitochondrial membranes. The proton gradient is usually discharged by a flow of protons through the ATP synthase complex, which synthesises ATP from ADP. Thus, the free energy available from oxidation of the substrate is trapped in ATP. In brown adipose tissue, uncoupling protein-1 (UCP1) allows the proton gradient to dissipate without synthesis of ATP: therefore metabolic energy is lost as heat. UCP1, like other putative uncoupling proteins, is a member of the family of mitochondrial transporters and has six trans-membrane domains. The right-hand scheme shows how an uncoupling protein may actually facilitate the transfer of a fatty acid anion (Fatty acid-) out of the mitochondrial matrix. Because the anion has the possibility of combining with a proton on either side, the net effect is the same as the inward transfer of a proton. This may be the real physiological function of the 'novel' UCPs expressed outside brown adipose tissue.

Brown adipose tissue is important in animals that have a particular need to generate heat, for instance hibernating mammals. During hibernation the body temperature falls and metabolism slows, to preserve fuel stores. Awakening from hibernation is helped by the generation of heat in brown adipose tissue. Large adult mammals such as humans do not usually have a problem in generating heat, since the ratio of body mass (in which heat is generated) to body surface area (through which heat is lost) is in favour of generating too much heat, and instead adult humans have a variety of means of losing excess heat - sweating and dilation of blood vessels in the skin, for example. Correspondingly, there is no good evidence that adult humans have signi ficant amounts of brown adipose tissue. In contrast, infants have a different surface area to body mass ratio and have a need for a mechanism to generate heat, and in infant humans brown adipose tissue has a clear role. It is lost during development. There is considerable controversy over whether it can be 'reawakened' in adults, or whether white adipose tissue can ever be converted into brown.

Since the process of uncoupling dissipates metabolic energy, there has been great interest in this process in relation to regulation of body weight: if we could

Table 4.2 'Uncoupling' proteins (UCPs).

Name

Tissue distribution

Comments

UCP1 (thermogenin)

Brown adipose tissue

Function is definitely to generate heat

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Responses

  • lavinia
    How does thermogenin generate heat?
    2 years ago

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