Functional Anatomy of Brown Adipose Tissue

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In the 1990s, advances were also made in the study of brown adipose tissue. Especially following the studies by Stock et al. reported above, a rising num ber of laboratories began to focus on BAT, soon leading to the description of the main mechanisms of action of brown adipocytes.

An uncoupling protein (UCP1) expressed solely in brown adipocyte mitochondria was identified [23-25], as an atypical p-adrenergic receptor (p3-AR), which appeared to be prevalently expressed by adipose tissue [26, 27]. Therefore, brown adipocytes are activated by adrenergic stimulation of these receptors, leading to triglyceride lipolysis and new synthesis of UCP1. The fatty acids thus released are burnt by p oxidation, which gives rise to a hydrogenionic gradient between the two mito-chondrial membranes. This gradient, commonly used by adenosinetriphosphatase to produce ATP, is abrogated by the abundance of UCP1 in the inner mitochondrial membrane, UCP1 being a protonophore [28].

All this allows for a fast and highly regulated transformation of the potential energy contained in triglycerides into heat, also accounting for brown adipocyte anatomy: given the enormous demand for oxidisable substrate (the lipid vacuoles), and that lipolysis can take place only on the surface of the vacuoles, a multilocular organisation is essential to increase the contact surface between lipids and hyaloplasm. Such ready substrate availability would be useless without a large number of mitochondria - which large size and abundance of cristae make very efficient - ready to carry out the oxidation process.

The presence of the protonophore UCP1 is thus the final step in a series of events beginning with the adrenergic stimulus and proceeding through lipolysis and fatty acid oxidation to the formation of an electrochemical gradient that is dissipated. These cells therefore represent a unique phenomenon in the mammalian organism because, unlike all the other cell types, which pursue optimal efficiency, they work via a loss of efficiency.

The enormous amount of heat produced requires a vascular bed capable of ensuring a large oxygen supply and the rapid transport of the heat from the tissue to the rest of the organism, not least to prevent the high temperature from damaging the tissue itself. This accounts for the impressive vascularity of BAT.

The obvious physiological stimulus capable of activating BAT is cold, and virtually all facultative non-shivering thermogenesis is to be ascribed to this tissue. As mentioned above, food intake is also capable of activating it [1], and several synthetic molecules, called specific |33-AR agonists, have been manufactured industrially. Pharmacological utilisation demonstrated their effectiveness in treating obesity and the consequent diabetes in both genetically and diet-induced rodent obesity [29, 30], whereas the drugs developed in the hope of treating human obesity gave disappointing results [31] commonly attributed to the scarce presence of BAT in adult humans.

For this reason, the work published in 1997 by Fleury et al. [32] has had the merit of rekindling the hope for a pharmacological intervention aimed at dissipating the excess energy accumulated by obese subjects. These researchers identified a new protein, homologous to UCP1 and also expressed in man, which they denominated UCP2, and demonstrated that UCP2 is not only expressed in BAT, but that it is widely distributed in all tissues and is thus well represented in adult human tissues [32].

Shortly after the publication of this paper, two different teams [33, 34] independently described a protein highly homologous to UCP1 and UCP2, hence designated UCP3. UCP3 is expressed in mice and human BAT and skeletal muscle. The enthusiasm generated by these findings was chilled by subsequent research showing the absence of any specific phenotype in transgenic mice lacking this protein [35, 36] and the absence of alternative non-shivering thermogenesis in cold-acclimatised transgenic mice lacking UCP1 [37]. Nonetheless, these studies opened new avenues of research in cell physiology, and the group of Lowell went on to discover the important role of UCP2 in pancreatic insulin secretion [38].

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