Its shape and location is very complex: the more consistent and large part of it is localized in a deep fossa between the two scapulae (interscapular area). From this central core several elongated bilateral projections reach the neck and the upper limbs. Those projecting to the neck reach superficial and deep levels (cervical fat). The superficial parts can be subdivided into anterior and posterior. These last are located under nuchal muscles.

Two bilateral projections reach the upper limbs. Two are superficial and two are deeply located among the dorsal muscles. These last deep projections reach the axillae (axillary fat) and are continuous with thin and large dorso-lateral prolongments.

This depot can be considered as a fascia that wraps around the origin of posterior limbs. Thus this fascia starts at the dorso-lumbar area and runs at the inguinal level to end at contralateral dorso-lumbar area. While passing at the pubis level, a large projection reaches the gluteal area. This depot is easy to distinguish as three bilateral areas: dorso-lumbar, inguinal, and gluteal areas. A large lymph node is usually found in a point that can be considered as the boundary between the inguinal and the dorsal area. In some cases, a second bilateral lymph node can be found at the level of the dorso-lumbar area.

The limb fat depots are always small. They are located under the fascia that surround the limb, thus even if they can be considered subcutaneous depots it must be outlined that they have a close connection with muscles. In this respect their localization can be considered quite similar to those deep parts of the anterior subcutaneous depot described above (see below for histology implications). Two small depots are located per each limb: at the level of shoulder and elbow in the anterior limbs and at the level of tight and popliteal fossa in the posterior limbs.

Brown adipocytes’ main function is thermogenesis. Thus, cold exposure enhances the BAT activity. Looking at the gross anatomy of adipose organ of cold-exposed mice, we observed that most of the depots appearing as white in warm acclimated mice turned to a brownish color and most of brown areas became darker brown when animals were cold acclimated (Fig. 6.1).

Histology, electron microscopy, morphometry, and immunohistochemistry studies comparing the adipose organ of warm acclimated (28 °C per 10 days) with that of cold acclimated (6 °C per 10 days) mice showed that this browning of the adipose organ is mainly due to a direct conversion of mature white adipocytes into metabolic active thermogenetic brown adipocytes [23–25]. Of note, we also found intermediate forms of adipocytes never described before: paucilocular adipocytes. These adipocytes have a morphology similar to that of unilocular white adipocytes, but are smaller and show many small lipid vacuoles surrounding a predominant central lipid droplet. These cells contain numerous mitochondria with a morphology that covers a complete spectrum between classic “white” mitochondria and classic “brown” mitochondria. Furthermore, some of these adipocytes are immunoreactive for the protein marker of brown adipocytes: UCP1 (Fig. 6.6). These cells, that are also present in the adipose organ of warm acclimated mice, always occupy mainly the boundaries between white and brown areas in any fat depot. In summary, we think that under the noradrenergic stimulus due to cold exposure part of the WAT of the adipose organ converts into thermogenetic BAT by direct transition at cellular level from a specific phenotype into a different phenotype [26, 27].

The key target for this phenomenon is the specific β3 adrenoceptor. Mice lacking this receptor have a very blunted phenomenon [28]. Sympathetic nervous system, activated by cold exposure, expands by branching its parenchymal fibers into the adipose organ and this is accompanied by white into brown conversion of adipocytes. In line with this observation, we found a positive correlation between parenchymal noradrenergic nerve fibers and the number of brown adipocytes in the adipose organ of two different strains of mice [3, 5, 29].

This white to brown plasticity of adipose organ is of paramount importance because mice lacking BAT or its function become massively obese in comparison to control mice with identical food intake and physical exercise [30, 31]. Furthermore, mice expressing UCP1 in white fat are obesity-resistant [32] and the obesity prone mice have reduced amount of BAT in comparison with obesity-resistant strains [5, 33].

BAT is also important to prevent diabetes and atherosclerosis. Removing the insulin receptor specifically in BAT induces hyperglycemia [34]. BAT explants regulates insulin sensitivity [35] and BAT activity controls triglycerides clearance [36, 37]. Thus, BAT can be considered as an important organ to fight the metabolic syndrome [37].

The recent re-discovery of BAT in the adipose organ of adult humans [38–42] renewed the attraction of scientists to this tissue in view of the human health care possibilities. We found that adult humans have BAT with most of the characteristics found in mice, including morphology, UCP1 expression, high density of parenchymal noradrenergic fibers, and perivascular adipocyte precursors. In our case series of human adults, as well as in other studies, age, body mass index and insulin resistance correlate inversely with presence of BAT in the classic anatomical site for humans: the supraclavicular area [42]. Age-related disappearance of human BAT seems to spare supraclavicular more than interscapular BAT [43], thus suggesting that supraclavicular BAT in humans correspond to interscapular BAT in mice even if detailed studies of supraclavicular BAT in mice are lacking. On the other hand, PET images showing metabolically active BAT in humans seem to suggest that this depot is tightly connected with subclavian vessels in line with the idea that BAT areas of the adipose organ are linked to heart, aorta and its main branches: carotid, subclavian, intercostals, and renal vessels. This is clearly visible in PET images of cold acclimated humans and corresponds to PET images of patients suffering from pheocromocytomas (benign tumors secreting high levels of epinephrine and norepinephrine) before surgery [44]. Thus, human adipose organ seems to share many characteristics of murine adipose organ and allows the hope we could modulate the browning of human adipose organ in order to pervert or curb the metabolic syndrome affecting a very large percentage of humans in western countries.

Of note, we recently showed that even human omental WAT, that seems to be a pure white fat, can be converted into BAT under the peculiar noradrenergic stimulus of pheocromocytomas. We found that in all 12 adult patients studied, omental WAT undergo a remodeling process: half of them had a significant reduction of the adipocytes’ size and half had a conversion of white adipocytes into UCP1 expressing brown adipocytes. Furthermore, this WAT to BAT transition was accompanied by a significant brown phenotype gene expression, and increased density of vessels and parenchymal noradrenergic fibers. Several UCP1 immunoreactive paucilocular adipocytes (we consider as morphologic-immunohistochemistry marker of direct WAT to BAT conversion, see above) were also found. Electron microscopy of paucilocular cells found in omentum of our case series of pheocromocytomas patients showed similar aspects of those found in fat of cold exposed mice: small lipid droplets at the periphery of a predominant central lipid droplet and numerous mitochondria with the white to brown morphology spectrum. We also found mitochondria with transitional characteristics: i.e. with white-like morphology at one extremity and brown-like morphology at the opposite extremity [45]. Similar mitochondria were described previously in adipocytes developed in vitro from the stroma-vascular fraction obtained from BAT, sampled from the axillary fat of a dead newborn [46]. Electron microscopy can distinguish perivascular adipocyte precursors [47, 48], thus it is possible to make quantitative analysis with this technique. Our quantitative electron microscopy showed that adipocyte precursors were not significantly increased in omentum of pheocromocytomas patients. In line with these results, the proliferative marker Ki67 was absent in nuclei of brown adipocytes confirming our previous murine data showing that noradrenergic stimuli do not induce proliferation of new adipocytes [45], consistent with results from other authors [49, 50]. All together, these data support the idea that brown adipocytes derive from a direct conversion of white adipocytes also in humans.

Beta adrenergic agonists are able to curb murine obesity [51–53] and drugs have been created in order to see if any therapeutic effect can be obtained to curb human obesity, however clinical trials were found to be unsuccessful [54, 55]. Nevertheless, several molecular mechanisms that overcome the beta adrenoceptors have been described recently (reviewed in [56]). Interestingly, physical activity seems to induce BAT activation and browning of WAT both in mice and humans [57–59].

When mice are exposed to warmth, a whitening effect is visible in the gross anatomy of the adipose organ [1]. Classic interscapular BAT changes the morphology of its brown adipocytes. They change gradually into white-like adipocytes. This morphologic transformation is accompanied by suppression of brown genes (such as UCP1) and activation of genes that are inactive in classic multilocular brown adipocytes (such as leptin and S-100b) [60, 61]. This transformation is also evident in beta-less mice (lacking all beta adrenoceptors). Beta-less mice are particularly prone to obesity and related disorders [31]. Genetically, obese mice have similar transformations of the adipose organ including brown to white transdifferentiation of interscapular BAT [62]. Thus, warm acclimation or chronic positivity of energy balance in absence of leptin or its receptor induces the opposite effect of cold exposure probably due to reduction of noradrenergic stimulus as suggested by knockout experiments described above. Chronic positive balance induces proliferation and development of new adipocytes and the adipose organ of obese humans can reach 60–70 % of the body weight (normal 15–20 %) [63, 64]. Thus the obese adipose organ is characterized by hypertrophy and hyperplasia of adipocytes.