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Adipose Organ Development and Remodeling

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ABSTRACT

During the last decades, research on adipose tissues has spread in parallel with the extension of obesity. Several observations converged on the idea that adipose tissues are organized in a large organ with endocrine and plastic properties. Two parenchymal components: white (WATs) and brown adipose tissues (BATs) are contained in subcutaneous and visceral compartments. Although both have endocrine properties, their function differs: WAT store lipids to allow intervals between meals, BAT burns lipids for thermogenesis. In spite of these opposite functions, they share the ability for reciprocal reversible transdifferentiation to tackle special physiologic needs. Thus, chronic need for thermogenesis induces browning and chronic positive energy balance induce whitening. Lineage tracing and data from explant studies strongly suggest other remodeling properties of this organ. During pregnancy and lactation breast WAT transdifferentiates into milk‐secreting glands, composed by cells with abundant cytoplasmic lipids (pink adipocytes) and in the postlactation period pink adipocytes transdifferentiate back into WAT and BAT. The plastic properties of mature adipocytes are supported also by a liposecretion process in vitro where adult cell in culture transdifferentiate to differentiated fibroblast‐like elements able to give rise to different phenotypes (rainbow adipocytes). In addition, the inflammasome system is activated in stressed adipocytes from obese adipose tissue. These adipocytes die and debris are reabsorbed by macrophages inducing a chronic low‐grade inflammation, potentially contributing to insulin resistance and T2 diabetes. Thus, the plastic properties of this organ could open new therapeutic perspectives in the obesity‐related metabolic disease and in breast pathologies. © 2018 American Physiological Society. Compr Physiol 8:1357‐1431, 2018.

Figure 1. Figure 1. Light microscopy (A) and electron microscopy morphology of isolated human adipocyte (A), murine white adipose tissue (B, scanning electron microscopy), human subcutaneous adipocytes (C and D, transmission electron microscopy). Bar: in A, 15 μm; in B, 20 μm; in C, 1.2 μm; and in D, 0.3 μm. B adapted, with permission, from ().
Figure 2. Figure 2. UCP1 immunohistochemistry of mixed (white and brown adipose tissues) areas of murine (A) and human (B) adipose organ. Bar: in A, 35 μm; and in B, 50 μm.
Figure 3. Figure 3. Scanning (A) and Transmission (B) Elecron microscopy of murine brown adipose tissue. Bar: in A, 6.0 μm; and in B, 1.0 μm. A adapted, with permission, from ().
Figure 4. Figure 4. TH Immunohistochemistry (noradrenergic fibers) in murine (A) and human (B) brown adipose tissue. In B (confocal), a double staining UCP1/TH is shown. Bar: in A, 15 μm; and in B, 6.5 μm. B adapted, with permission, from ().
Figure 5. Figure 5. Murine adipose organ gross anatomy of warm and cold acclimated Sv129 adult mice. (A and F) Subcutaneous depots B to E visceral depots. Bar: 1 cm. Adapted, with permission, from ().
Figure 6. Figure 6. Vasculo‐adipocytic islets of epididymal white adipose tissue from a newborn rat. Light microscopy. Bar: 7.0 μm. Adapted, with permission, from ().
Figure 7. Figure 7. Transmission electron microscopy of vasculo‐adipocytic islets shown in Figure 7. Bar: in A, 1.5 μm; and in B, 3.0 μm, in inset 0.5 μm.
Figure 8. Figure 8. Rat brown adipose tissue anlage at E16 (A, light microscopy) and E18 (B, electron microscopy). Inset: enlargement of electron microscopy showing pretypical mitochondria. Bar: in A, 6 μm; and in B, 2 μm, in inset 0.6 μm.
Figure 9. Figure 9. Scheme showing a hypothesis of molecular signaling inducing endothelial‐pericyte‐preadipocyte conversion. Inset adapted, with permission, from (). Red: positive, Blue: negative.
Figure 10. Figure 10. Inguinal adipose tissue from a Ve‐Cad/Cre/R26R mouse showing lineage‐tracing evidence of endothelial origin of adipocytes. Bar: in A, 330 μm; and in B, 15 μm.
Figure 11. Figure 11. UCP1 immunohistochemistry of acutely activated brown adipose tissue show the heterogeneous immunoreactivity (Harlequin phenomenon). Bar: 35 μm.
Figure 12. Figure 12. Potential β3‐adrenoceptor‐dependent molecular mechanisms driving white‐to‐brown adipocyte transdifferentiation. All brown‐colored molecules are inhibitors of brown phenotype and are inhibited by activated β3‐adrenoceptor signaling. Adapted, with permission, from ().
Figure 13. Figure 13. White adipocytes converting to brown adipocytes show a paucilocular morphology and a weak UCP1 immunoreactivity (Beige adipocytes). Bar: 9.0 μm. Adapted, with permission, from ().
Figure 14. Figure 14. Graphical summary of the most important hormone‐like molecules secreted by adipose organ.
Figure 15. Figure 15. Histology of inguinal adipose tissue of virgin (A) and pregnant (B‐D) mice. Epithelial alveolar cells appear only during pregnancy and are immunoreactive for ELF‐5 (C) and WAP (D). This milk‐producing alveolar cells show large cytoplasmic lipid vacuoles (pink adipocytes). Bar: in A and B, 50 μm; and in C and D, 12 μm. Adapted, with permission, from ().
Figure 16. Figure 16. Dorsal view of anterior mammary glands. Note interscapular brown adipose tissue still visible in mouse in A and not visible in mouse in B. Bar: in A, 1.9 cm; and in B, 2.8 cm. Adapted, with permission, from ().
Figure 17. Figure 17. The remodeling properties of adipocytes in the adipose organ. Adapted, with permission, from ().
Figure 18. Figure 18. Electron microscopy of slimming adipocytes. Bar: in A, 1.6 μm; and in B, 0.2 μm.
Figure 19. Figure 19. Morphologic aspects of lipolysis in slimming adipocytes. Electron microscopy (osmium‐tannic acid cytochemistry). Bar: in A, 1.0 μm; and in B, 40 nm.
Figure 20. Figure 20. Critical steps of liposecretion process of mature adipocytes cultivated in primary culture (see also video: Fig. 21). Bar: in A, 2.5 μm; in B, 1.0 μm; in C, 1.5 μm; and in D, 0.5 μm. Adapted, with permission, from ().
Figure 21. Figure 21. Still of time‐lapse video reproducing a record of about 70 h of mature adipocytes in primary culture (see also Fig. 20; see video in 576). Adapted, with permission, from ().
Figure 22. Figure 22. Immunohistochemistry of CLS showing M2 immunoreactivity of macrophages. Bar: in A and B 15 μm. A adapted, with permission, from ().
Figure 23. Figure 23. High‐resolution scanning electron microscopy of a hypertrophic and degenerating adipocyte from an obese db/db mouse. Bar: 2 μm. Adapted, with permission, from ().
Figure 24. Figure 24. TH immunoreactivity of parenchymal noradrenergic fibers in human brown adipose tissue. Bar: 23 μm.
Figure 25. Figure 25. Human subcutaneous white adipose tissue fresh (A) and paraffin embedded (B). Bar: in A, 80 μm; and in B, 30 μm. B adapted, with permission, from ().
Figure 26. Figure 26. Proposed mechanisms for the paradoxical clinical outcome of obesity and lipodystrophy. Adapted, with permission, from ().
Figure 27. Figure 27. Slimmed adipocyte (A) and adipocyte precursors (B) resulted typical features of localized lipodystrophy secondary to insulin injections. Bar: in A, 1.8 μm; and in B, 1.2 μm. Adapted, with permission, from ().


Figure 1. Light microscopy (A) and electron microscopy morphology of isolated human adipocyte (A), murine white adipose tissue (B, scanning electron microscopy), human subcutaneous adipocytes (C and D, transmission electron microscopy). Bar: in A, 15 μm; in B, 20 μm; in C, 1.2 μm; and in D, 0.3 μm. B adapted, with permission, from ().


Figure 2. UCP1 immunohistochemistry of mixed (white and brown adipose tissues) areas of murine (A) and human (B) adipose organ. Bar: in A, 35 μm; and in B, 50 μm.


Figure 3. Scanning (A) and Transmission (B) Elecron microscopy of murine brown adipose tissue. Bar: in A, 6.0 μm; and in B, 1.0 μm. A adapted, with permission, from ().


Figure 4. TH Immunohistochemistry (noradrenergic fibers) in murine (A) and human (B) brown adipose tissue. In B (confocal), a double staining UCP1/TH is shown. Bar: in A, 15 μm; and in B, 6.5 μm. B adapted, with permission, from ().


Figure 5. Murine adipose organ gross anatomy of warm and cold acclimated Sv129 adult mice. (A and F) Subcutaneous depots B to E visceral depots. Bar: 1 cm. Adapted, with permission, from ().


Figure 6. Vasculo‐adipocytic islets of epididymal white adipose tissue from a newborn rat. Light microscopy. Bar: 7.0 μm. Adapted, with permission, from ().


Figure 7. Transmission electron microscopy of vasculo‐adipocytic islets shown in Figure 7. Bar: in A, 1.5 μm; and in B, 3.0 μm, in inset 0.5 μm.


Figure 8. Rat brown adipose tissue anlage at E16 (A, light microscopy) and E18 (B, electron microscopy). Inset: enlargement of electron microscopy showing pretypical mitochondria. Bar: in A, 6 μm; and in B, 2 μm, in inset 0.6 μm.


Figure 9. Scheme showing a hypothesis of molecular signaling inducing endothelial‐pericyte‐preadipocyte conversion. Inset adapted, with permission, from (). Red: positive, Blue: negative.


Figure 10. Inguinal adipose tissue from a Ve‐Cad/Cre/R26R mouse showing lineage‐tracing evidence of endothelial origin of adipocytes. Bar: in A, 330 μm; and in B, 15 μm.


Figure 11. UCP1 immunohistochemistry of acutely activated brown adipose tissue show the heterogeneous immunoreactivity (Harlequin phenomenon). Bar: 35 μm.


Figure 12. Potential β3‐adrenoceptor‐dependent molecular mechanisms driving white‐to‐brown adipocyte transdifferentiation. All brown‐colored molecules are inhibitors of brown phenotype and are inhibited by activated β3‐adrenoceptor signaling. Adapted, with permission, from ().


Figure 13. White adipocytes converting to brown adipocytes show a paucilocular morphology and a weak UCP1 immunoreactivity (Beige adipocytes). Bar: 9.0 μm. Adapted, with permission, from ().


Figure 14. Graphical summary of the most important hormone‐like molecules secreted by adipose organ.


Figure 15. Histology of inguinal adipose tissue of virgin (A) and pregnant (B‐D) mice. Epithelial alveolar cells appear only during pregnancy and are immunoreactive for ELF‐5 (C) and WAP (D). This milk‐producing alveolar cells show large cytoplasmic lipid vacuoles (pink adipocytes). Bar: in A and B, 50 μm; and in C and D, 12 μm. Adapted, with permission, from ().


Figure 16. Dorsal view of anterior mammary glands. Note interscapular brown adipose tissue still visible in mouse in A and not visible in mouse in B. Bar: in A, 1.9 cm; and in B, 2.8 cm. Adapted, with permission, from ().


Figure 17. The remodeling properties of adipocytes in the adipose organ. Adapted, with permission, from ().


Figure 18. Electron microscopy of slimming adipocytes. Bar: in A, 1.6 μm; and in B, 0.2 μm.


Figure 19. Morphologic aspects of lipolysis in slimming adipocytes. Electron microscopy (osmium‐tannic acid cytochemistry). Bar: in A, 1.0 μm; and in B, 40 nm.


Figure 20. Critical steps of liposecretion process of mature adipocytes cultivated in primary culture (see also video: Fig. 21). Bar: in A, 2.5 μm; in B, 1.0 μm; in C, 1.5 μm; and in D, 0.5 μm. Adapted, with permission, from ().


Figure 21. Still of time‐lapse video reproducing a record of about 70 h of mature adipocytes in primary culture (see also Fig. 20; see video in 576). Adapted, with permission, from ().


Figure 22. Immunohistochemistry of CLS showing M2 immunoreactivity of macrophages. Bar: in A and B 15 μm. A adapted, with permission, from ().


Figure 23. High‐resolution scanning electron microscopy of a hypertrophic and degenerating adipocyte from an obese db/db mouse. Bar: 2 μm. Adapted, with permission, from ().


Figure 24. TH immunoreactivity of parenchymal noradrenergic fibers in human brown adipose tissue. Bar: 23 μm.


Figure 25. Human subcutaneous white adipose tissue fresh (A) and paraffin embedded (B). Bar: in A, 80 μm; and in B, 30 μm. B adapted, with permission, from ().


Figure 26. Proposed mechanisms for the paradoxical clinical outcome of obesity and lipodystrophy. Adapted, with permission, from ().


Figure 27. Slimmed adipocyte (A) and adipocyte precursors (B) resulted typical features of localized lipodystrophy secondary to insulin injections. Bar: in A, 1.8 μm; and in B, 1.2 μm. Adapted, with permission, from ().

 

Teaching Material

S. Cinti. Adipose Organ Development and Remodeling. Compr Physiol 8: 2018, 1357-1431.

Didactic Synopsis

Major Teaching Points:

  • Adipocytes are lipid rich cells.
  • White adipocytes, organized in white adipose tissue (WAT), store energy allowing intervals between meals.
  • Brown adipocytes, organized in brown adipose tissue (BAT), burn lipids for thermogenesis.
  • Both WAT and BAT are contained in a dissectible organ.
  • The adipose organ shows a similar composition in all mammals, including humans.
  • The prevalent tissue is WAT, but BAT is present in several depots.
  • The adipose organ is provided with dense vascular and nerve supply especially in BAT.
  • WAT and BAT are interconvertible tissues to satisfy specific physiologic requirements: whitening to allow energy storing when the energy balance is chronically positive and browning when thermogenesis is chronically required.
  • Remodeling is mainly due to plasticity of parenchymal noradrenergic nerve fibers and hormonal factors.
  • During pregnancy-lactation white adipocytes convert reversibly to alveolar cells (pink adipocytes).
  • The plastic properties of adipose organ allow energy repartition among three vital needs: metabolism, thermogenesis, and lactation.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 This figure illustrates the morphologic characteristics of white adipocytes and white adipose tissue. Bar: in A, 15 μm; in B, 20 μm; in C, 1.2 μm; and in D, 0.3 μm.

  1. Isolated human adipocyte. A crescent shaped nucleus is visible on the left side of the cell. Light microscopy.
  2. Murine white adipose tissue. The spherical shape of white adipocytes is easily recognizable by scanning electron microscopy. Collagen fibers and fibrils form a delicate web covering part of the tissue. Scanning electron microscopy. Adapted, with permission, from (154).
  3. Human white adipocyte. Organelles contained into adipocytes are visible by transmission electron microscopy. Part of a white adipocyte including the crescent shaped nucleus is visible. Note the presence of a macrophage on the outer surface of adipocyte. Transmission electron microscopy.
  4. Human white adipocyte. Enlargement of cytoplasm showing several organelles: mitochondria, rough endoplasmic reticulum (RER), external lamina with associated collagen fibrils. At the boundary between hyaloplasm and lipid droplet the typical dense line, site of lipid associated proteins, is visible. Transmission electron microscopy.

 

Figure 2 This figure illustrates the histology and immunohistochemistry characteristics of normal adipose organ. Bar: in A, 35 μm; and in B, 50 μm.

  1. Murine adipose organ (maintained at room temperature). White adipose tissue (WAT) is often mixed with brown adipose tissue (BAT). Only BAT is immunoreactive for the marker functional protein UCP1. Adipocytes with intermediate morphology between white and brown adipocytes are visible (*, some indicated). Light microscopy, immunohistochemistry UCP1 antibodies (1:1500, Avidin-Biotin-Complex method).
  2. Human adipose organ. 73-year-old female, peri-renal fat, surgically treated for peri-adrenal sarcoma. Histology of human adipose organ is very similar to that of murine adipose organ. Also in humans only BAT is immunoreactive for UCP1. White (WAT) and brown (BAT) adipose tissues are mixed and show adipocytes with intermediate morphology (*, some indicated). Light microscopy. Immunohistochemistry UCP1 antibodies (1:300, Avidin-Biotin-Complex method).

Figure 3 This figure illustrates the ultrastructural characteristics of brown adipose tissue and brown adipocytes. Bar: in A, 6.0 μm; and in B, 1.0 μm.

  1. The polygonal shape of brown adipocytes and their multilocular arrangement of cytoplasmic lipid droplets are well recognized by scanning electron microscopy. Scanning electron microscopy. Adapted, with permission, from (154).
  2. The most represented and typical organelles in the cytoplasm of brown adipocytes are mitochondria. In this adipocyte (from a young cold exposed rat), most of cytoplasm is occupied by classic large mitochondria. Note the characteristic abundant and laminar cristae. Lipid droplets (L) are very small and barely visible. Transmission electron microscopy.

 

Figure 4 This figure illustrates some anatomical and immunohistochemistry aspects of innervation of brown adipose tissue. A dense network of parenchymal noradrenergic (Tyrosine Hydroxilase-TH-immunoreactive) nerve fibers surrounds multilocular brown adipocytes. Bar: in A, 15 μm; and in B, 6.5 μm.

  1. Mouse (maintained at room temperature) interscapular brown adipose tissue. Immunohistochemistry (Avidin-Biotin-Complex-method) with anti-TH antibodies (1:300). Note TH immunoreactive fibers in direct contact with brown adipocytes (arrows, some indicated). Light microscopy.
  2. Supraclavicular brown adipose tissue from adult human. Note the direct contact of a noradrenergic (TH-immunoreactive) fiber to a UCP1 (Uncoupling Protein 1) immunoreactive brown adipocyte. A clear synaptic enlargement (“en passant” synaptoid contacts) is also visible (arrow). Confocal microscopy: green TH, red UCP1, blu DAPI (nuclei). Adapted, with permission, from (851).

 

Figure 5 This figure illustrates the gross anatomy of murine adult female Sv129 adipose organ in different environmental conditions: 10 days at 28°C (left) and 10 days at 6°C (right). After cold acclimation, the brown areas of adipose organ are more reddish and more expanded. The white part of the organ apparently almost disappears and change the color from white into brown (browning phenomenon). The scheme illustrates the visceral and subcutaneous depots forming the organ:

  1. Anterior subcutaneous (interscapular, subscapular, deep and superficial cervical, and axillar-thoracic),
  2. visceral mediastinal periaortic,
  3. visceral mesenteric,
  4. visceral retroperitoneal,
  5. visceral abdomino-pelvic (perirenal, periovarian, parametrial, perivesical), and
  6. posterior subcutaneous (dorso-lumbar, inguinal, gluteal). Bar: 1 cm. Adapted, with permission, from (614).

 

Figure 6 This figure illustrates the key step of development of epididymal white adipose tissue. Newborn (6-day-old) rat. Some areas (vasculo-adipocytic islets) are delimited by fibroblast-like cells (arrows, some indicated). Only in vasculo-adipocytic islets adipocyte precursors with variable amount of cytoplasmic lipids (yellow) are visible. Note the numerous, large capillaries inside the islets. The tight anatomical connection of vessels and adipocyte precursors is evident. Resin embedded and toluidine blue stained tissue. Light microscopy. Bar: 7.0 μm. Adapted, with permission, from (164).

Figure 7 This figure illustrates the ultrastructural details of adipocyte precursors observed in the vascuolo-adipocytic islets of Figure 7. Bar: in A, 1.5 μm; and in B, 3.0 μm, in inset 0.5 μm.

  1. A poorly developed white adipocyte precursors (P: nucleus) is visible in contact with the capillary wall (CAP). Note the small and numerous lipid droplets.
  2. Three white adipocyte precursors in intermediate steps of development are visible. Note the predominant central lipid droplets (L) and several small lipid droplets at the periphery of the cell. Compare with the unilocular adipocyte visible at the top panel of panel A (ad) and with Figure 1. Mitochondria are small, elongated, and with randomly oriented cristae (inset), compare with pretypical mitochondria of brown adipocyte precursors in Figure 6 inset. Abundant collagen (COL) is present only inside the islets.

 

Figure 8 This figure illustrates two key steps of rat subscapular brown adipose tissue anlage development. Bar: in A, 6 μm; and in B, 2μm, in inset 0.6 μm. 

  1. At fetal day 16 (E16) the anlage is formed by a loose mesenchymal tissue with large capillaries (CAP) surrounded by poorly differentiated irregularly shaped cells, often in pericyte position (arrows, some indicated). Resin embedded and toluidine blue stained tissue. Light microscopy.
  2. At E18 the anlage assumes a parenchymal epithelioid aspect with a homogeneous population of cells filling the space among the capillaries (CAP). Most of these cells show the characteristic ultrastructure of brown adipocyte precursors with numerous pre-typical mitochondria (inset), small lipid droplets (arrow) and roundish glycogen clusters (G). Frequently these cells are in mitosis. Transmission electron microscopy.

 

Figure 9 This figure illustrates a hypothesis linking proposed molecular mechanisms of white adipocyte precursor determination and morphologic ultrastructural data supporting the endothelial origin of adipocyte progenitors. If the endothelial cell would be the adipose stem cell, it would be necessary several adaptations to maintain the vascular wall integrity while allowing a transition from capillary to interstitial space. The presented molecular events have been claimed to play a role in adipogenesis and could be implicated in the dynamic aspects necessary for the eventual endothelial-pericyte-preadipocyte conversion. Inset: molecular mechanisms proposed, with permission, by (378)

Figure 10 This figure illustrates the lineage tracing technique data supporting the endothelial origin of adipocytes. Double transgenic mice in which the activation of the promoter of Ve-Cad gene induce synthesis of β-galactosidase (Ve-Cad/R26R mice). β-galactosidase is detected by X-Gal staining inducing blue-green crystals in cells expressing or derived from cells that expressed Ve-Cad. In these mice only endothelial cells, bone marrow hematopoietic cells and both brown and white adipocytes resulted X-Gal positive. Bar: in A, 330 μm; and in B, 15 μm.

  1. Inguinal white adipose tissue (WAT) of a newborn (5-day-old) Ve-Cad/R26R mouse. Note the negative skeletal muscle with clearly stained capillaries. Light microscopy, X-Gal staining.
  2. Enlargement of WAT shown in A. Note the intense staining in endothelial cells of capillaries (CAP) and in the cytoplasm of adipocytes. Mesothelial cells are negative (arrows, some indicated). Light microscopy X-Gal staining.

 

Figure 11 This figure illustrates the heterogeneous staining (Harlequin phenomenon) of brown adipocytes of periadrenal fat removed from a patient with pheochromocytoma. Note that the intensity of UCP-1 immunoreactivity parallel the size of cytoplasmic lipid droplets suggesting that the more intensely stained are the more metabolically active. Multilocular cells with large lipid vacuoles are unstained as well as the unilocular adipocytes. The Harlequin phenomenon is quite evident in acutely stimulated brown adipose tissue. Data support the idea that heterogeneous activation of brown adipocytes is necessary to avoid heating damage of the cells. Light microscopy. Immunohistochemistry (Avidin-Biotin-Complex method, UCP1 antibodies dilution 1: 300). Bar: 35μm.

Figure 12 This figure illustrates the molecular signaling promoting the direct conversion of white adipocyte to brown adipocyte upon activation of beta3AR. Several molecules in white adipocytes or in white adipocyte precursors seems to inhibit the nuclear signals necessary to develop a brown phenotype. All these molecules (brown colored) are inhibited by signaling downstream to betaAR activation. Adapted, with permission, from (333).

Figure 13 This figure illustrates peri-renal brown adipocytes of cold exposed mouse with different morphology and UCP1-immunoreactivity. Note that the most intensely stained (four cells in the right upper corner) have the typical aspect of metabolically active brown adipocytes (intense UCP1 immunoreactivity, regular small lipid droplets and central nucleus). In the central part of the figure two weakly UCP1-stained paucilocular (multilocular with predominant central lipid vacuole) adipocytes are visible. These paucilocular adipocytes are bona fide white adipocytes converting to brown adipocytes (early stage of conversion). Their staining is beige (compare with brown of fully differentiated adipocytes in the upper right corner). Bar: 9.0 μm. Adapted, with permission, from (851).

Figure 14 This figure illustrates the main adipokines produced by white and brown adipocytes of adipose organ. The principal target organs are also illustrated. Some adipokines have hormone properties and act also, or mainly, on distal organs such as brain (leptin, asprosin), liver (adiponectin, resistin, asprosin, FGF-21), skeletal muscles (adiponectin), pancreas (adipsin, C3a), and cardiovascular system (adiponectin, visfatin, apelin, vaspin, omentin, RAS, C3, PAI-1, factor B, CETP). Some have paracrine/autocrine properties acting on adipose organ itself or nearby organs (NGF, Nrg4, semaphorins, VEGF, FGF-21, NO, CO, PC1/3, IL-6/33, PM20D1, SLITC2, TNFα, BMPs, TGFβ, AEA, 2-AG, LPL, RBP-4, DPP4).

Figure 15 This figure illustrates inguinal adipose tissue (corresponding to the fourth mammary gland) of virgin (A) and pregnant (B-D) mice. In virgin mice only ducts infiltrating the tissue are present. During pregnancy and lactation, alveoli formed by lipid-rich epithelial cells (pink adipocytes, see C and D) progressively replace the adipose tissue. Pink adipocytes are immunoreactive for ELF-5 (E74-like factor 5: key transcription factor for alveologenesis) in nuclei (C) and for whey acidic protein (WAP) in cytoplasm (D). Light microscopy. Immunohistochemistry (Avidin-Biotin-Complex-method) with ELF-5 (diluted 1:300) and WAP (diluted 1:400) antibodies. Bar: in A and B, 50 μm; and in C and D, 12 μm. Adapted, with permission, from (154).

Figure 16 This figure illustrates the gross anatomy of the first three bilateral mammary gland of mice at day 10 of lactation (dorsal view). It is obvious the anatomical coincidence with anterior subcutaneous depot of virgin mice (compare with Figure 5). In the dorsal extension, the glands form a continuum and include the interscapular brown adipose tissue. Bar: in A, 1.9 cm; and in B, 2.8 cm. Note that the interscapular brown adipose tissue is recognizable in mouse of panel A (dotted line), but not in mouse of panel B. Adapted, with permission, from (164).

Figure 17 This figure schematically illustrates the theory of transdifferentiation triangle of adipose organ. Published papers supporting specific conversions are indicated. Adapted, with permission, from (164).

Figure 18 This figure illustrates typical ultrastructural features of slimming adipocytes of fasted animals. Retroperitoneal fat of adult rat fasted for 3 days at 20°C. Transmission electron microscopy. Bar: in A, 1.6 μm; and in B, 0.2 μm.

  1. The adipocyte on the right upper corner (L, only in part visible) shows early signs of slimming process: that is, cytoplasmic invaginations forming a villous-like appearance of an area of the cell surface (arrows). The adipocyte in the middle of the panel (with more advanced signs of slimming process) shows the residual lipid droplet in the central part of the cell and a thick peripheral cytoplasm rich of invaginations conferring a villous-like appearance to the whole surface of the cell.
  2. Enlargement of the area framed in A. Cytoplasmic invaginations are rich of pinocytotic vesicles (V, denoting high rate of molecular traffic). Note the small peripheral lipid droplets (L) and redundant external lamina (EL) mixed with collagen fibrils (COL).

 

Figure 19 This figure illustrates morphologic aspects of lipolysis. Retroperitoneal fat of adult rat fasted for 3 days at 20°C. Dark whorl-like structures (enlarged in B) formed by membranous-like aggregates of fatty acids are shown by osmium-tannic acid cytochemistry. The adipocyte lost the main lipid droplet and only small residual lipid droplets are contained in the cytoplasm. Note the characteristic villous-like surface, typical of slimming adipocytes (compare with Figure 15). Whorl-like structures are detected at four levels (some indicated): (i) at the surface of lipid droplets (where fatty acids derive from triglycerides), (ii) in the cytoplasm, (iii) at the level of cytoplasmic invaginations (site where fatty acids leave the cell), and (iv) free in the interstitium (through which vessels are reached). Transmission electron microscopy. Osmium-tannic acid cytochemistry. Bar: in A, 1.0 μm; and in B, 40 nm.

Figure 20 This figure illustrates the critical steps of liposecretion process in mature adipocytes cultivated with ceiling culture (see also video of Figure 21). Bar: in A, 2.5 μm; in B, 1.0 μm; and in C, 1.5 μm, in D 0.5 μm.

  1. Two adipocytes in contact with large lipid droplets (L) partially surrounded by cytoplasmic processes (P) and partially extruded from these cells are visible. Resin embedded and toluidine blue stained cells. Light microscopy.
  2. Ultrastructure of a detail similar to that framed in A. A large lipid droplet is still surrounded by a thin cytoplasmic rim as in normal mature adipocytes, but a gap in the cytoplasm (arrow) suggest an imminent secretion. Transmission electron microscopy.
  3. Ultrastructure of a fibroblast-like postliposecretion adipocyte. Transmission electron microscopy.
  4. Enlargement of the framed area in C showing well-differentiated organelles (nucleus N, mitochondria m, Golgi complex G, endoplasmic reticulum ER, and small lipid droplets). Note the well-differentiated morphology of this cell (Rainbow adipocyte) that is able to convert to different phenotypes (adipocyte, muscle cell, chondrocyte, and endothelial cell) under appropriate stimuli. Adapted, with permission, from (576).

 

Figure 21 This is a still of time-lapse video of about 16 s reproducing a record of about 70 h of mature adipocytes in primary culture (see also Figure 20). In the bottom part of the video an adipocyte shows all steps from unilocular morphology to postliposecretion fibroblast-like morphology of rainbow adipocyte (see video in 576). Adapted, with permission, from (576).

Figure 22 This figure illustrates the morphology and immunohistochemistry of crown-like structures (CLS) found in hypertrophic white adipose tissue of HSL -/- (A) and obese (B) mice. Bar: in A and B, 15 μm.

  1. HSL-/- mice are lean but have white adipose tissue composed by hypertrophic adipocytes similar to those found in obese animals. Hypertrophic adipocytes die both in lean (A) and in obese (B) mice. Remnants of dead adipocytes are reabsorbed by macrophages. Perilipin2 (Plin2) is never expressed by normal adipocytes and surrounds lipid droplets in nonadipose cells. Most of the CLS macrophages shown here are immunoreactive for Plin2 and contain lipid droplets. The few negative macrophages of CLS and in the interstitium (arrows) do not contain lipid droplets suggesting that only macrophages reabsorbing lipids from the adipocyte remnants are involved in CLS. Light microscopy. Immunohistochemistry (Avidin-Biotin-Complex-method) with Plin2 (diluted 1:100) antibodies. Adapted, with permission, from (179).
  2. Inguinal white adipose tissue of diet induced obese mouse. All CLS macrophages stain for CD206 (marker of M2 or alternatively activated, macrophages). In line with data shown in A, M2 macrophages are mainly devoted to repair tissue (reabsorption of dead adipocyte remnants in CLS). Confocal microscopy: red CD206, blue DAPI (nuclei).

 

Figure 23 This figure illustrates the high-resolution scanning electron microscopy of a hypertrophic and degenerating adipocyte from the mesenteric depot of an obese db/db mouse releasing differently sized lipid droplets into the extracellular space (arrows, some indicated). Bottom left side: an extruded lipid droplet (L) surrounded by a group of macrophages (M) is visible. Note the numerous collagen fibrils (C, some indicated) on the surface of the degenerating adipocyte. High-resolution scanning electron microscopy. Bar: 2 μm. Adapted, with permission, from (336).

Figure 24 This figure illustrates the parenchymal innervation of human perirenal brown adipose tissue from a newborn male patient (5 months old). Tyrosine hydroxylase (TH) immunoreactive noradrenergic parenchymal fibers are visible in direct contact with brown adipocytes (arrows). Dense innervation is present also at the arteriole (a) and precapillary (p) wall level. Light microscopy. Immunohistochemistry (Avidin-Biotin-Complex-method) with TH (diluted 1:300) antibodies. Bar: 23 μm.

Figure 25 This figure illustrates the morphology of subcutaneous abdominal white adipose tissue from an adult overweight (BMI 27) female patient (see also Figure 1). Light microscopy. Bar: in A, 80 μm; and in B, 30 μm.

  1. Fresh fixed tissue showing the quite regular spherical shape of the cells.
  2. Paraffin embedded tissue. Only a thin rim of cytoplasm is visible in adipocytes. Few capillaries (CAP) are visible among adipocytes. Adapted, with permission, from (155).

 

Figure 26 This figure illustrates the paradoxical clinical similarity between two conditions due to excess or insufficient adipose organ. In both situations, the clinical outcome is the metabolic syndrome due to different mechanisms. Furthermore, the recent discoveries of adipokines with beneficial effects on pancreatic beta cells reinforce the whole picture that obesity and lipodystrophy can induce a confluent metabolic phenotype. Adapted, with permission, from (943).

Figure 27 This figure illustrates the main ultrastructural characteristic of subcutaneous adipose tissue from an adult diabetic patient with local lipoatrophy due to insulin injections. In this tissue, slimmed cells and adipocyte precursors are very common. Transmission electron microscopy. Bar: in A, 1.8 μm; and in B, 1.2 μm. Adapted, with permission, from (588).

  1. Classic slimmyed adipocyte (compare with Figures 18 and 19) showing residual lipid droplets (L) in the wizened central part of the cell containing also an irregular nucleus (N). Note the numerous invaginations giving a villous-like appearance to the surface of the cell (arrows, some indicated). Transmission electron microscopy.
  2. Classic white adipocyte precursor (see also Figure 7) in pericytic position (CAP: capillary). Note the high nucleus/cytoplasm ratio, the poorly differentiated organelles, presence of a distinct external lamina. Transmission electron microscopy.

 

 


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How to Cite

Saverio Cinti. Adipose Organ Development and Remodeling. Compr Physiol 2018, 8: 1357-1431. doi: 10.1002/cphy.c170042