Mammals have two types of adipocytes, white and brown, but their anatomy and physiology is different. White adipocytes store lipids, and brown adipocytes burn them to produce heat. Previous descriptions implied their localization in distinct sites, but we demonstrated that they are mixed in many depots, raising the concept of adipose organ. We explain the reason for their cohabitation with the hypothesis of reversible physiological transdifferentiation; they are able to convert one into each other. If needed, the brown component of the organ could increase at the expense of the white component and vice versa. This plasticity is important because the brown phenotype of the organ associates with resistance to obesity and related disorders. Another example of physiological transdifferetiation of adipocytes is offered by the mammary gland; the pregnancy hormonal stimuli seems to trigger a reversible transdifferentiation of adipocytes into milk-secreting epithelial glands. The obese adipose organ is infiltrated by macrophages inducing chronic inflamation that is widely considered as a causative factor for insulin resistance. We showed that the vast majority of macrophages infiltrating the obese organ are arranged around dead adipocytes, forming characteristic crown-like structures. We recently found that visceral fat is more infiltrated than the subcutaneous fat despite a smaller size of visceral adipocytes. This suggests a different susceptibility of visceral and subcutaneous adipocytes to death, raising the concept of smaller critical death size that could be important to explain the key role of visceral fat for the metabolic disorders associated with obesity.
- brown adipose tissue
- white adipose tissue
- mammary gland
the current obesity epidemic and the associated increased incidence of diabetes, hypertension, hyperlipidemia, cancer, and other disorders has heightened the interest in the fat tissues involved in obesity (9). An organ is defined as an anatomically dissectible structure with a discrete gross anatomy comprising at least two different tissues. White adipose tissue (WAT) is made up of cells capable of storing lipids that are then used as fuel for the organism in the intervals between meals. Brown adipose tissue (BAT) has a different function; it burns lipids to produce heat.
Our group has recently proposed a new concept with regard to the adipose tissues of rodents: the adipose organ. Its most innovative part is that it tries to account for the observation that WAT and BAT are intermingled in a dissectible organ formed by multiple subcutaneous and visceral depots. Although the reason for such organization is unclear, the notion of an adipose organ offers an explanation. The two constituent cell types are intermingled because they are capable of transdifferentiating into one another to meet different energy partitioning biological demands. Accordingly, the well-known reversible apparent adipose tissue transformations induced by physiological stimuli, such as exposure to cold (the organ's phenotype switches from white to brown), warm exposure (the phenotype switches from brown to white), and pregnancy/lactation (part of the organ's phenotype changes from WAT to milk-secreting glands), would stem from intrinsic biological properties of the adipocytes, which are capable of reversible transdifferentiation. The notion opens new prospects in cell biology, since it hinges on the ability of differentiated mammalian cells to undergo a physiological reversible transformation process that results in a new phenotype and a different cell morphology and physiology. Here we describe the salient data that support the concept of adipose organ, found in our and other laboratories (21–23, 51), with particular emphasis on those consistent with transdifferentiation as the main process underpinning adipose organ plasticity.
WAT and BAT are Intermingled in the Adipose Organ
The murine adipose organ (Fig. 1) (21–23) consists of two main subcutaneous depots (anterior and posterior) and several visceral depots (mediastinal, omental, mesenteric, perirenal, retroperitoneal, perigonadal, and perivesical). Other fat depots are found in close connection with skeletal muscles and in organs such as bone marrow, parathyroid gland, parotid gland, pancreas, and lymph nodes.
The white parts of the organ are formed predominantly by WAT, whereas the brown parts are prevalently composed of BAT. White and brown adipocytes are often interspersed, with the color of mixed areas depending on the prevalent cell type. The relative amount of white, brown, and mixed areas is genetically programmed and depends on several factors, including age, sex, environmental temperature, and nutritional status.
In most small rodents, brown areas are readily recognizable by gross inspection in the interscapular, axillary, and cervical portions of the anterior subcutaneous depots and in the mediastinal and perirenal visceral depots. White, brown, and mixed areas are found in discrete depots; some subcutaneous (anterior) and visceral (mediastinal and perirenal) depots are clearly partitioned into WAT and BAT.
In recent articles, we reported quantitative anatomical data on the adipose organ of adult Sv129 female mice (76, 78). Calculation of the total number of white and brown adipocytes in the main depots (anterior subcutaneous, posterior subcutaneous, mediastinal, perirenal, perigonadal, perivesical, retroperitoneal, and mesenteric) demonstrated that in this strain white and brown adipocytes are interspersed in all subcutaneous and visceral depots. White adipocytes are more numerous in some depots (posterior subcutaneous, mesenteric, and retroperitoneal), and brown adipocytes are more numerous in others (anterior subcutaneous, mediastinal, and abdominopelvic). The depots on the limbs, which are in close connection with skeletal muscles, are also mixed; in a comparative study of Sv129 and B6 mice, the former were shown to contain a greater amount of BAT (2).
White and Brown Adipocytes Have a Discrete Morphology and Physiology
White adipocytes are spherical cells (Fig. 2) with a fairly variable size that depends mainly on the size of the lipid droplet stored in them. Differentiated white adipocytes are sometimes quite small (<10 μm in diameter) compared with the average adipocytes found in adult mammals (22). Their main feature is a single lipid droplet (unilocular adipocytes) formed by triacylglycerols that accounts for >90% of the cell's volume. Even on electron microscopy there seems to be no distinct structure separating it from the thin rim of cytoplasm, although it is well known that perilipin is found at this level (8, 52). Mitochondria are thin and elongated, with randomly oriented cristae, and variable in amount; in general, they are less numerous in the larger cells. Several caveolae are found on the outer surface. Other organelles are usually poorly represented. A distinct basal membrane surrounds the adipocyte (Fig. 3).
Brown adipocytes store triglycerides in the form of multiple small vacuoles (multilocular adipocytes; Fig. 2). Most brown adipocytes are polygonal with a variable diameter that is usually in the 15- to 50-μm range. The most characteristic organelles of these cells, the mitochondria, are large, spherical, and packed with laminar cristae and are usually numerous in the cytoplasm (Fig. 4).
In our experience, when an adipocyte with the light microscopic appearance of a multilocular cell is viewed under the electron microscope, it will have several mitochondria with a morphology characteristic of brown adipocytes (21, 31). This is independent of the presence of uncoupling protein 1 (UCP1). At variance with those who hold that brown adipocytes are cells expressing UCP1, we believe that expression of this protein merely reflects the cell's thermogenic activity and that a brown adipocyte is a cell with a distinctive morphology, i.e., a multilocular lipid content and several characteristic mitochondria.
We also believe that the multilocular adipocytes found in the adipose organ of adult animals should be considered as thermogenically hypofunctioning brown adipocytes when they are UCP1 negative and as thermogenically active brown adipocytes when they are UCP1 positive on immunohistochemistry. Since most researchers hold UCP1 expression to be the hallmark of brown adipocytes, hereinafter only cells expressing the protein will be designated as brown adipocytes.
The adipose organ is diffused in the organism; its vascular supply is provided predominantly by visceral or parietal regional nerve-vascular bundles. The density of the capillary network is much greater in brown than in white parts.
The nerve supply is also different between brown and white areas and is again denser in the former. In brown areas, numerous noradrenergic fibers are also found in fat lobules running with blood vessels and in direct contact with adipocytes.
Adrenergic receptors are found in the adipose organ (α1 and α2 and β1, β2, and β3) and on adipocytes (mainly β1 and β3) (15).
The density of parenchymal fibers depends on the functional status of the organ. The density of noradrenergic parenchymal fibers grows in BAT during cold exposure (35, 76) and in WAT during fasting (45).
Noradrenergic vascular fibers are immunoreactive for neuropeptide Y. The vast majority also contain noradrenaline (14, 45), suggesting that they belong to the sympathetic nerve supply to WAT blood vessels.
The main function of white adipocytes is to store highly energetic molecules (fatty acids) and to release them as fuel for the organism in the intervals between meals.
Brown adipocytes use these molecules to produce heat (nonshivering thermogenesis) through the action of the mitochondrial protein UCP1, which is found exclusively in brown adipocytes (13, 15, 28, 40, 63, 88, 98).
The signal for brown adipocyte activation is a temperature below thermoneutrality, which induces activation of the sympathetic nervous system (98).
Genetic ablation of BAT or of all β-adrenergic receptors in mice induces obesity (3, 72), although mice lacking UCP1 are cold sensitive but not obese (38). On the other hand, ectopic UCP1 expression in WAT results in resistance to obesity (64). Accordingly, it has recently been shown that obesity-prone mice have less BAT than obesity-resistant ones (2).
Another primary function of white adipocytes, uncovered a few years ago, is the production of leptin, a hormone capable of influencing animal feeding behavior (112). Leptin also induces energy dispersion (via BAT and locomotor activation) and has gonadotropic properties. Classic multilocular brown adipocytes, i.e., those performing thermogenic activity, are not immunoreactive for leptin (12, 26).
A growing body of evidence suggests that the adipose organ produces a large number (>50) of proteins, or adipokines, that control several important functions such as glucose and lipid metabolism, blood coagulation, blood pressure, and steroid hormone modulation. This finding has inspired the recent notion of the adipose organ as an endocrine organ (62, 101). For an extensive description of white and brown adipocyte endocrine production, see Refs. 99 and 15, respectively.
Variable Adipose Organ Phenotype: Plasticity of the Adipose Organ
Acclimatization to different temperatures, pregnancy/lactation, obesity, fasting, and calorie restrictions are the most common physiological and pathological (obesity) conditions in which the plastic nature of the adipose organ is engaged. Here we address some cell biology aspects related to its plasticity.
Adipose Organ Plasticity Related to Temperature Acclimatization
The organ of cold-acclimatized mice is darker in color than that of warm-exposed animals, suggesting a switch to a more brown phenotype (Fig. 1). The phenomenon is reversible and is due to an increase in the amount of brown adipocytes, capillaries, and nerves in the organ (31, 47, 48, 53, 71, 76, 110). It can also be induced by administration of β3-adrenoceptor agonists (16, 29, 43, 44, 51, 57) and is largely suppressed in mice lacking β3-adrenoceptor (61), suggesting that noradrenergic fibers play a central role mainly by acting on β3-adrenoceptors of adipocytes. Accordingly, noradrenergic fiber density increases in all parts of the adipose organ after cold acclimatization (35, 48, 76).
In theory, the newly formed brown adipocytes could derive from existing stem cells in the tissue, from migrating stem cells, from the direct transformation of differentiated white adipocytes (transdifferentiation), or from a combination of these phenomena.
Our data support the view that reversible transdifferentiation is the most significant phenomenon underlying the plasticity of the adipose organ for several reasons.
Several white adipocytes in the white parts of the organ (WAT) are lost after cold acclimatization, and their amount matches the number of new brown adipocytes.
The total number of adipocytes in the adipose organs of adult female Sv129 mice after 10 days of cold acclimatization is not significantly different from that found in mice kept at 28°C (76, 78). However, the number of brown adipocytes in the former mice was significantly increased by roughly the same amount of white adipocytes that were lost. Given the lack of histological evidence of apoptosis or of other forms of white adipocyte degeneration, these data suggest that most of the new brown adipocytes derive from direct transformation of white into brown adipocytes. The absence of signs of necrosis or apoptosis is in line with the fact that the cold-induced adrenergic stimulus protects brown adipocytes (82), which are more subject to apoptosis than white adipocytes (81). Intracerebroventricular injection of leptin can induce white adipocyte apoptosis (54); however, cold acclimatization reduces leptin expression and leptinemia (86), thus probably ruling out leptin-induced apoptosis. These findings agree with earlier data from other laboratories that neither DNA (30) nor the number of adipocytes (17, 74) increases in rodent WAT after cold acclimatization. Recently, an antiproliferative effect of sympathetic nervous system on WAT was also shown (39).
The vast majority (80–95%) of newly formed brown adipocytes arising in WAT after β3-adrenoceptor agonist treatment are BrdU negative.
The retroperitoneal depot of 20-wk-old Sprague-Dawley rats is formed almost entirely by white adipocytes. Treatment with the β3-adrenoceptor agonist CL-316,243 for 7 days results in ∼17% of the adipocytes in this depot being brown like. Electron microscopy and biochemical studies, together with immunohistochemistry, demonstrate that most of these newly formed brown-like adipocytes are not thermogenically active (only 8% are UCP1 positive on immunohistochemistry) and show evidence of intense mitochondrial biogenesis. Importantly, several adipocytes with an intermediate morphology between white and brown adipocytes have been documented by electron microscopy. BrdU experiments have shown that these cells have a very low mitotic index (5%; i.e., 95% are BrdU negative, entailing the absence of a mitotic process) (57). Of note, 80% of the multilocular cells described by Granneman et al. (51) were also BrdU negative.
Adipocyte precursors do not increase in WAT after cold acclimatization despite the striking increase in the number of brown adipocytes.
Adipocyte precursors in the developing adipose organ or in the organ of animals subjected to adrenergic stimulation are easily detected by electron microscopy in both WAT and BAT (6, 22, 24, 92). Although we found rare adipocyte precursors in the WAT of cold-exposed and -acclimatized animals, their number was similar to that seen in control animals kept at room temperature (Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, and Cinti S, unpublished observations). In addition, rats treated with the β3-adrenoceptor agonist CL-316,243 showed no electron microscopic evidence of adipocyte precursor development in WAT (57).
A new form of UCP1-positive brown adipocyte with intermediate features between white and brown adipocytes arises in WAT after cold acclimatization and β3-adrenoceptor agonist treatment.
In a recent study (Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, and Cinti S, unpublished observations), we found that cold acclimatization, or treatment with a β3 agonist, induced the appearance in WAT of numerous UCP1-positive multilocular adipocytes (i.e., cells bearing the hallmarks of the commonly accepted definition of brown adipocytes) with an intermediate morphology between white and brown adipocytes on electron microscopy. The two main characteristics of these cells are a predominant lipid vacuole in the cytoplasm and a mitochondrial population exhibiting several intermediate features between white and brown mitochondria (Figs. 5 and 6).
This type of cell is easily recognized on light microscopy by the characteristic large lipid droplet surrounded by several small droplets. On immunohistochemistry, this cell type is often UCP1 immunoreactive.
Isolated brown adipocytes show intermediate features between white and brown adipocytes.
Early in vitro data from our laboratory showed that adipocytes obtained from the stromal-vascular fraction of the interscapular BAT of young rats and from humans have a morphology intermediate between white and brown adipocytes, including mitochondria with intermediate features (19, 20). Addition of noradrenaline to the culture medium induced a more typical mitochondrial morphology in rats (25). In line with these studies, genetic suppression (knockout) of all types of β-adrenoceptor in mice induces morphological changes in interscapular BAT adipocytes, which become unilocular and express leptin (3). Again, the mitochondria of these cells have intermediate features between those of white and brown adipocytes.
Brown adipocyte morphology and protein expression vary in relation to noradrenaline tissue levels.
Noradrenaline levels in interscapular BAT are lower in warm-acclimatized mice than in their cold-acclimatized counterparts. In these conditions, brown adipocyte morphology changes as follows. In cold-acclimatized animals it is the classic morphology with multilocular lipid droplets and large mitochondria rich in cristae; these cells express UCP1 but neither leptin nor S-100B (a protein expressed in white adipocytes and preadipocytes that could be implicated in cytoskeletal organization) (37). Warm-acclimatized animals show brown adipocytes with a unilocular lipid droplet and mitochondria that have intermediate features between those of white and brown adipocytes; these adipocytes express leptin and S-100B but not UCP1 (5, 12). Genetically obese ob/ob and db/db mice have a reduced noradrenaline flux to interscapular BAT, and brown adipocytes have the same characteristics as the adipocytes of warm-acclimatized mice described above.
White-to-brown transdifferentiation is also suggested by in vitro studies using primary cultures from human subcutaneous adipose tissue. In previous studies, UCP1 expression was induced by treatment with peroxisome proliferator-activated receptor (PPARγ) agonists (85) or by PPARγ coactivator-1α transfection (97).
Recently, new transcriptional control mechanism of brown fat determination has been described; PR domain-containing protein 16 (PRDM16) expressed in white fat cell progenitors activates a robust brown phenotype (91). Bone morphogenetic protein 7 (BMP7) has also been found to be a brown fat molecular determinant (102).
Altogether, these data suggest that the adipose organ is plastic and that the brown phenotype exerts an antiobesity effect. β3-Adrenoceptors seem to play a pivotal role in mediating white-to-brown transdifferentiation, thus supporting a possible role for β3-adrenoceptor agonists in treating obesity. Genetic obesity and diet-induced obesity have successfully been treated with β3-adrenoceptor agonists in animals. Recent data suggesting that adult humans have a metabolically active BAT, coupled with our experimental data showing that human WAT is immunoreactive to highly specific anti-β3-adrenoceptor monoclonal antibodies (34), raise hopes for the treatment of obesity and diabetes. Unfortunately, a β3-adrenoceptor agonist with curative effects on human obesity has not yet been identified (69).
Phenotype Transformation: Pregnancy and Lactation
The mammary gland is composed of branched epithelial ducts infiltrating subcutaneous adipose tissue and connected to a nipple. In adult female mice, three bilateral nipples are connected to epithelial ducts infiltrating the whole anterior subcutaneous fat depot of the adipose organ. Two bilateral nipples are connected to epithelial ducts infiltrating the whole posterior subcutaneous fat depot of the adipose organ. Therefore, adult virgin female mice have five bilateral incomplete mammary glands that are ready to become milk-secreting glands during pregnancy and lactation. The two subcutaneous depots containing the glands differ from those of males only for the presence of the branched epithelial ducts. The adipose component of these depots follows the general rules described above for the adipose organ: intermingled white and brown adipocytes whose relative amount depends mainly on age, strain, and environmental conditions.
Of note, adipocytes of the mammary glands express prolactin receptor (70). Mammary gland anatomy changes during pregnancy and lactation, with a progressive decline in the number of adipocytes and formation of milk-secreting lobulo-alveolar epithelial glands. This plastic phenomenon is reversible since at the end of lactation the milk-secreting components disappear to be replaced by adipocytes, with a complete restoration of prepregnancy anatomy. The phenomenon used to be interpreted as a hiding in the glands of adipocytes, which underwent delipidation during pregnancy and a lipid refilling process in the postlactation period.
Our recent morphological studies, combined with Cre-lox fate-mapping experiments on the mammary gland, suggest that adipocytes undergo a reversible process of adipocytic/epithelial transdifferentiation during pregnancy and lactation (75). During pregnancy, adipocytes seem to transform progressively into epithelial cells, forming the lobulo-alveolar part of the mammary gland responsible for milk production. At the end of lactation the lobulo-alveolar component disappears, and a new adipocyte population restores the prepregnancy anatomy. Our data are in favor of the direct transformation of milk-producing epithelial cells into adipocytes. The morphological data supporting a succession of intermediate steps in the processes of adipocytic/epithelial and epithelial/adipocytic transdifferentiation seem to exclude dedifferentiation and suggest a pure transdifferentiation phenomenon (75).
Phenotype Transformation: Hypertrophy and Hyperplasia (Positive Energy Balance: Overweight and Obesity)
In conditions of positive energy balance, the white part of the adipose organ grows. White adipocytes become hypertrophic and subsequently hyperplasic.
Indeed, adipocytes have been suggested to have a maximum volume that cannot be further expanded. The maximum volume, also referred to as critical cell size, would be genetically determined and specific for each depot (36). Adipocytes with the critical cell size would trigger an increase in cell number (7, 74). The diverse depots seem to have a different tendency to hypertrophy and hyperplasia, the former being more characteristic of epididymal and mesenteric depots and the latter being more characteristic of inguinal and perirenal depots (36).
Adipose tissue expresses numerous factors that may be implicated in the modulation of adipogenesis, including IGF-I, transforming growth factor-β, TNFα, macrophage colony-stimulating factor, angiotensin-2, autotaxin-lysophosphatidic acid, leptin, and resistin (1).
Interestingly, mouse obesity induced by a high-fat diet is hypertrophic, whereas that induced by hypothalamic lesions through administration of monosodium glutamate is hyperplasic (60).
It has been shown that the WAT of obese mice and humans is infiltrated with macrophages and that the level of infiltration correlates with body mass index (BMI) and mean adipocyte size (10, 106, 107). It has been suggested that this infiltration might be an important cause of the insulin resistance associated with obesity (95, 107). We recently noted that macrophages are found mainly at the level of dead adipocytes in the WAT of obese mice and obese humans and in transgenic mice that are lean but have hypertrophic adipocytes (hormone-sensitive lipase-knockout mice) (27). Remnants of dead adipocytes are removed by macrophages, resulting in characteristic crown-like structures (Fig. 7). Thus, adipocytes grow in volume and may reach another critical maximum size that probably induces hypoxia-related stress (99, 100), leading to cell death [“critical death size” (CDS)]. Visceral fat accumulation is important in clinical terms because it is more closely associated with metabolic syndrome (7). Visceral fat is formed by adipocytes smaller than those of subcutaneous fat, but it is more infiltrated by macrophages in both obese mice (95) and humans (11, 56). We recently suggested that visceral adipocytes reach the CDS earlier than subcutaneous adipocytes (77). It is unclear why visceral adipocytes are smaller than their subcutaneous counterparts, but it is well accepted that white adipocytes deriving from the transformation of brown adipocytes are smaller than white adipocytes (26). It is also well established that in some murine strains most mediastinal adipocytes are brown adipocytes (76). Accumulation of epicardial fat (mediastinal fat) strongly correlates with visceral fat accumulation (59). Altogether, and in line with the notion of adipose organ plasticity, these data suggest that the reason for the smaller size of visceral adipocytes and the different resistance to death of visceral and subcutaneous adipocytes is that visceral white adipocytes are brown adipocytes turned white.
In addition, the brown part of the organ also undergoes changes in conditions of a positive energy balance. The rate of brown adipocyte apoptosis is higher in obese mice and much slower in those lacking TNFα receptor (49). Brown adipocytes in obese animals gradually change to cells similar in morphology to white adipocytes, including the transformation of the lipid depot from multilocular into unilocular. Both mitochondrial number and morphology change; a reduction in number is accompanied by a progressive transformation from a characteristic “brown” to a less characteristic “white” morphology. These phenomena correlate with activation of the leptin gene; cells become leptin immunoreactive (12, 26), thus providing further evidence for the reversible transdifferentiation of the two types of adipocytes.
Phenotype Transformation: Hypoplasia (Negative Energy Balance: Calorie Restriction/Fasting)
The morphology of the adipose organ during fasting is distinctive due to a variable amount of slimmed cells in WAT. The slimmed cells are barely visible on light microscopy, but they are easily recognized on electron microscopy by their characteristic ultrastructural morphology with thin, irregular cytoplasmic projections and numerous invaginations rich in pinocytotic vesicles (Fig. 8). The projections are larger in proximity to the nucleus and to the residual lipid droplet. In acute fasting, completely delipidized adipocytes are found near apparently unaffected unilocular cells. Vasculogenesis and neurogenesis are also seen in WAT of fasted animals. Capillaries are often surrounded by thin cytoplasmic projections of the slimmed adipocytes. Neurogenesis is supported mainly by an increase in noradrenergic fibers (45).
In chronic calorie restriction, the size reduction of adipocytes is homogeneous (79).
The Human Adipose Organ
The human adipose organ is composed of subcutaneous and visceral depots. The subcutaneous adipose tissue is continuous with the dermal adipose tissue (whereas in rodents they are separated by a smooth muscle layer) and is not confined to specific areas but forms a continuous layer beneath the skin. The mammary and gluteofemoral subcutaneous adipose tissues are more developed in females.
The visceral depots correspond to those described above for the rodent adipose organ, whereas the omental depot is much more developed in humans. It should be noted that although epididymal fat is considered as a visceral depot by many authors, it is not in fact found in humans.
The human adipose organ in lean adults accounts for ∼8–18% of body weight in males and for 14–28% in females (∼5% in monkeys) (84). The morphology of human adipose tissues is identical to that of murine tissues.
The development of the human adipose organ ends at puberty and is mainly underpinned by a proliferation process (18). A dynamic of fat cell turnover has been described in adult humans (93). Approximately 10% of fat cells are renewed annually at all adult ages and BMI levels. In the massively obese, the adipose organ can increase fourfold to reach 60–70% of body weight (85).
In fasting or calorie-restriction conditions, both the adipose organ and adipocytes shrink. The adipocyte size reduction is important because it correlates with insulin sensitivity (94). Completely delipidized adipocytes can be found in the adipose tissue of subjects with a negative energy balance. Their morphology is quite similar to the one described for the mouse and rat. The fate of delipidized adipocytes is still unclear; some authors suggest that they undergo apoptosis, but the matter has been debated (81).
The lipolytic process has different characteristics in the different depots. Subcutaneous adipose tissue from the gluteofemoral region of premenopausal women is more resistant to lipolysis than subcutaneous abdominal adipose tissue, but the difference disappears after menopause (87). This seems to be due to a combination of increased lipoprotein lipase activity and reduced lipolytic activity in the gluteofemoral adipose tissue. The reduced lipolytic activity seems to be related to a relative preponderance of antilipolytic activity of α2-adrenoceptors over lipolytic β-adrenoceptors (103). In general, α2-adrenoceptors are more abundant in human than in murine adipose tissue. In genetically modified mice with human-like fat (lacking β3 and expressing human α2-adrenoceptor), a high-fat diet induces adipose tissue hyperplasia (but not hypertrophy), and mice are insulin sensitive. These data agree with the importance of α2-adrenoceptor in adipocyte hyperplasia and with the relationship between cell size and insulin sensitivity (103).
Like the murine adipose organ, the human adipose organ contains BAT. Thermal dispersion is obviously much lower in humans than in rodents due to the different surface area-to-volume (S/V) ratio of the human body. This alone explains the reduced need for BAT in adult humans. Newborns have a different S/V ratio and a considerable amount of BAT. Nevertheless, brown adipocytes interspersed among white adipocytes have been described in several histological studies, including investigations showing the presence of UCP1 (41, 65).
Brown adipose tissue has been described in human newborns at almost all of the sites where it is found in rodents, and UCP1 gene expression has been detected in biopsies from visceral adipose tissue of adult lean and obese patients. In the same article, it was calculated that the visceral adipose tissue of adult lean humans contained one brown adipocyte in every 100–200 white adipocytes (83).
An increased amount of BAT has also been described in outdoor workers in northern Europe (58) and in patients with pheochromocytoma (a noradrenaline-secreting tumor) (89). Furthermore, patients with hibernoma, a rare brown adipose tissue tumor arising at several anatomical sites, including subcutaneous and visceral fat, have been described [overall, ∼100 cases have been published (4); we studied a case in which brown adipocytes expressed UCP1 and had the classic electron microscopic appearance with typical mitochondria] (111). Recently, a new case showed the presence of many brown adipocyte precursors (73).
Brown adipocytes are able to incorporate high levels of glucose; fluorodeoxyglucose is used in radiological examinations [positron emission tomography (PET)] to identify tissues with high rates of glucose incorporation, such as tumor metastasis. Extensive use of this technique has recently disclosed large amounts of metabolically active BAT in adult humans (42, 55). Common anatomical sites for human BAT are the neck, the roots of the upper limbs, and the intercostal spaces near the spine (80). Of note, the PET density of human BAT increases after cold exposure, especially in winter (90). Several higher-density areas corresponding to the anatomical sites of BAT were identified by PET in pheochromocytoma patients (68, 108). In human adult biopsies from the perithyroid area of the neck, corresponding to areas seen to harbor BAT on PET, we and other groups detected UCP1-positive brown adipocytes and BAT stem cells by immunohistochemistry and electron microscopy (Fig. 9) (33, 104, 105, 113).
Although the physiological role of BAT in humans has been debated, the possibility to increase it artificially to treat obesity and related disorders cannot be excluded. In this respect, it is interesting to note that human adults with a reduced brown phenotype of abdominal subcutaneous adipose tissue (109) or reduced amount of BAT (33) have reduced insulin sensitivity and that human white adipocyte precursors can be induced to express UCP1 in vitro by drug administration (85, 109). Although the obvious pharmaceutical target (β3-adrenoceptor) has so far produced no encouraging clinical results, even with highly selective β3-adrenoceptor agonists (69), recent discoveries of molecules important for brown adipocyte phenotype development, such as PRDM16 and BMP7 (91, 102), have raised fresh hope for the future treatment of obesity and related disorders.
In conclusion, our data support the concept of the adipose tissue as a true organ endowed with two parenchymal cell types having distinct anatomical and physiological characteristics, with both involved in energy partitioning and interacting because of their specific property: transdifferentiation. This property would entail the ability of adipocytes to undergo a physiological process entailing reversible reprogramming of their genome and enabling differentiated cells to change both phenotype and function. In this regard, it is crucial that the mammary gland of female animals shows adipocytic/epithelial/adipocytic transdifferentiation phenomena during pregnancy, lactation, and postlactation. β3-adrenoceptor-mediated transdifferentiation of white to brown adipocytes could open new prospects for the treatment of obesity and type 2 diabetes in light of recent PET and histology data showing morphological and molecular evidence of metabolically active BAT and BAT stem cells in adult humans.
- Copyright © 2009 the American Physiological Society