Origin of fat cells

Adipose tissue expansion involves the enlargement of existing adipocytes, the formation of new cells from committed preadipocytes, and the coordinated development of the tissue vascular network. Here we find that murine endothelial cells (ECs) of classic white and brown fat depots share ultrastructural characteristics with pericytes, which are pluripotent and can potentially give rise to preadipocytes. Lineage tracing experiments using the VE-cadherin promoter reveal localization of reporter genes in ECs and also in preadipocytes and adipocytes of white and brown fat depots. Furthermore, capillary sprouts from human adipose tissues, which have predominantly EC characteristics, are found to express Zfp423, a recently identified marker of preadipocyte determination. In response to PPARg activation, endothelial characteristics of sprouting cells are progressively lost, and cells form structurally and biochemically defined adipocytes. Together these data support an endothelial origin of murine and human adipocytes, suggesting a model for how adipogenesis and angiogenesis are coordinated during adipose tissue expansion

The pink adipocytes

Most of white and brown adipocytes, in spite of their well-known different functions: i.e. storing energy (white) and thermogenesis (brown), are contained together in visceral and subcutaneous depots (adipose organ) in all mammals including humans (1, 2). A growing body of evidence suggests that the reason for this anatomical mixture could reside in the fact that adipocytes have peculiar plastic properties allowing them to convert directly each other under appropriate stimuli (3). Under chronic cold exposure white convert into brown to support the need for thermogenesis and under obesogenic diet brown convert into white to satisfy the need of energy storing. Adipocyte population in the mammary gland offers another striking example of adipocyte plasticity: during pregnancy and lactation adipocytes transdifferentiate into milk-producing epithelial cells (we propose to call them: pink adipocytes) and vice versa in the post-lactation period (4, 5, 6). The white into brown transdifferentiation is of great medical interest because the brown phenotype of the adipose organ is associated with obesity resistance and drugs inducing the brown phenotype curb obesity and related disorders (7). We recently showed by transmission electron microscopy that in the post-lactating mammary gland interscapular multilocular adipocytes found close to the mammary alveoli contain milk protein granules. Lineage tracing system allowed showing that the involuting mammary gland of whey acidic protein-Cre/R26R mice, whose secretory alveolar cells express the lacZ gene during pregnancy, contains some X-Gal-stained and uncoupling protein 1 immunoreactive interscapular multilocular adipocytes. These data suggest that during mammary gland involution some milk- secreting epithelial cells in the anterior subcutaneous depot may transdifferentiate to brown adipocytes, highlighting a hitherto unappreciated feature of mouse adipose organ plasticity (8)

White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ

In mammals, the adipocyte is a lipid-laden cell forming the parenchyma of a mul- ti-depot organ, the adipose organ. The white adipocyte stores lipids to release them, in the form of free fatty acids, during fasting, while the brown adipocyte burns glu- cose and lipids to perform thermogenesis. A recently characterized, third type of adi- pocyte does appear in the subcutaneous depot of the adipose organ of female mice during pregnancy and lactation: the pink adipocyte. The pink adipocytes are mam- mary gland alveolar epithelial cells with the essential role of producing and secret- ing milk for pup nourishment. Emerging evidence suggest that they derive from the transdifferentiation of the subcutaneous white adipocytes. Different metabolic and environmental challenges highlight the extraordinary plasticity of the mammalian adipose organ. Cold exposure leads to an increase of the “brown” component of the adipose organ to warrant thermal homeostasis. Under positive energy balance, the “white” component enlarges to a some extent to allow storage of the excess of nutri- ents. Finally, during pregnancy the “pink” component develops in the subcutaneous depots to satisfy pup nutritional needs. At cellular level, the plasticity of the adipose organ appears to occur not only through proliferation and differentiation of stem cells but, distinctively, via a direct transformation of fully-differentiated adipocytes that under proper stimuli by reprogramming their genetic expression change phenotype and, consequently, function. Understanding the transdifferentiation properties of the adipocytes is expected to offer not only new biological insights, but also possible therapeutic strategies to combat the metabolic syndrome (“browning”) and the breast cancer (“pinking”).

Histopathology of the obese adipose organ

Most of white and brown adipocytes, in spite of their well known different functions: i.e. storing energy (white) and thermogenesis (brown), are contained together in visceral and subcutaneous depots (adipose organ) in all mammals including humans. A growing body of evidence suggests that the reason for this anatomical mixture could reside in the fact that adipocytes have peculiar plastic properties allowing them to convert directly each other under appropriate stimuli (1). Under chronic cold exposure white convert into brown to support the need for thermogenesis and under obesogenic diet brown convert into white to satisfy the need of energy storing. Adipocyte population in the mammary gland offers another striking example of adipocyte plasticity: during pregnancy and lactation adipocytes transdifferentiate into milk-producing epithelial glands and vice versa in the post-lactation period. The white into brown transdifferentiation is of great medical interest because the brown phenotype of the adipose organ is associated with obesity resistance and drugs inducing the brown phenotype curb obesity and related disorders. Type 2 (T2) diabetes is the most common disorder associated to visceral obesity. Macrophages infiltrating the adipose organ are responsible for the low-grade chronic inflammation dealing to insulin resistance and T2 diabetes. This inflammation is caused by the need of removal debris deriving from the death of adipocytes (2). Death of adipocytes is tightly related to their hypertrophy up to the critical death size. Visceral adipocytes have a critical death size smaller than subcutaneous adipocytes, thus explaining the higher inflammation and higher morbidity of visceral fat (3). The smaller critical death size of visceral adipocytes could be explained by their origin from brown adipocytes transformed into small white adipocytes less expansible than the constitutive white adipocytes (4). 1) Frontini A and Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 2010 Apr 7;11(4):253-6. 2) Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005 Nov;46(11):2347-55. 3) Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008 Jul;49(7):1562-8. 4) Cinti S. Reversible physiological transdifferentiation in the adipose organ. Proc Nutr Soc. 2009 Nov;68(4):340-9. Epub 2009 Aug 24

Organo endocrino adiposo 2020: stato dell'arte

SommarioI tessuti adiposi bianco e bruno sono organizzati a formare un vero e proprio organo. Essi svolgono funzioni diverse ma collaborano grazie alla loro plasticità che permette la reciproca conversione. Ciò implica una nuova proprietà per le cellule mature. Il sottocutaneo della ghiandola mammaria fornisce un altro esempio perché queste cellule adipose si trasformano in ghiandole durante la gravidanza. L'organo adiposo nell'obesità va incontro a flogosi inducendo insulino-resistenza, patogeneticamente coinvolta nel diabete Tipo 2. L'organo adiposo collabora con quelli della digestione formando un sistema che è in grado di controllare diversi aspetti nutrizionali e quindi denominato sistema nutrizionale

The Nutritional System

AbstractThe white and brown adipose tissues are organized to form a true organ. They have a different anatomy and perform different functions, but they collaborate thanks to their ability to convert mutually and reversibly following physiological stimuli. This implies a new fundamental property for mature cells, which would be able to reversibly reprogram their genome under physiological conditions. The subcutaneous mammary gland provides another example of their plasticity. Here fat cells are reversibly transformed into glands during pregnancy and breastfeeding. The obese adipose organ is inflamed because hypertrophic fat cells, typical of this condition, die and their cellular residues must be reabsorbed by macrophages. The molecules produced by these cells during their reabsorption work interfere with the insulin receptor, and this induces insulin resistance, which ultimately causes type 2 diabetes. The adipose organ collaborates with those of digestion. Both produce hormones that can influence the nutritional behavior of individuals. They produce molecules that mutually influence functional activities including thermogenesis, which contributes to the interruption of the meal. The nutrients are absorbed by the intestine, stored in the adipose organ, and distributed by them to the whole body between meals. Distribution includes offspring during breastfeeding. The system as a whole is therefore called the nutritional system

The Normal, Cryptorchid and Retractile Prepuberal Human Testis: A Comparative Morphometric Ultrastructural Study of 101 Cases

Fifty-two surgical biopsies from retractile testes of patients in pediatric age (3-14 years), of which 25 were treated with hormonal therapy (RT) and 27 did not undergo therapy before orchidopexy (RNT), were compared with the biopsies of 19 normal (N) and 30 cryptorchid or ectopic (E) testes. A light and electron microscopic morphologic and morphometric study was performed. For the quantitative investigation 4 parameters were selected: a) the mean tubular diameter (on 20 cross-sections); b) the mean spermatogonial number per tubular section; c) the mean nucleolar area of the Sertoli cells; and d) the mean thickness of the tubular basal lamina. The 101 biopsies were collected for statistical evaluation into four age groups: 3-6 years, 7-10, 11-13 without spermatogenesis and 10-14 with signs of early spermatogenesis. In the RT category the mean tubular diameter and the mean spermatogonial number were similar to N in the first two age groups, but were significantly reduced in the RNT categories. The morphometric study of the Sertoli cell nucleolar area confirms the delay of maturation observed in the categories of RT, RNT and E. In normal biopsies, the basal lamina shows a progressive reduction of the thickness, with the lowest values around puberty, while constantly higher values were found in the other categories, although this increase is not statistically significant

Tim Bartness, Ph.D. (1953-2015)

Tim Bartness (Fig. 1) was a friend, mentor, collaborator and leader to many scientists, younger and older, across a variety of disciplines. He died September 24, 2015 at the age of 62 after a one-year battle with multiple myeloma. Tim not only helped educate many of us, but also challenged us to think critically and to laugh heartily about both the bad and the good we experienced in life. Tim was dedicated to science and to those around him. He worked diligently on his research right up the very end until he no longer could

Action of the ciliary neurotrophic factor in mouse brainstem

Systemic administration of ciliary neurotrophic factor (CNTF) determines sustained weight loss in rodents and humans. The anorectic effect of CNTF is due, at least in part, to activation of the signal transducer and activator of transcription (STAT) 3, STAT1 and STAT5 in neuronal and glial cells of the tuberal hypothalamus (Severi et al., 2012, 2013 and unpublished data). To assess whether CNTF also exerts an action on the brainstem feeding centres, male Swiss CD-1 mice were intraperitoneally treated with rat recombinant CNTF (0.3 mg/kg of body weight; CNTF-treated mice) or with saline (control mice) for 45 minutes (min) to perform P-STAT3, P-STAT1 and P-STAT5 immunohistochemistry, and for 120 min to detect c-Fos expression. Double staining experiments with neuronal and glial markers and confocal microscopy analyses were performed to assess the phenotype of the CNTF-responsive cells. P-STAT3-, P-STAT1- or P-STAT5-positive cells were not detected in brainstem coronal sections from control mice. In contrast, CNTF administration led to a strong activation of the transcription factors STAT3, STAT1 and STAT5 in CNTF receptor α-bearing glial cells of the area postrema, a circumventricular organ devoid of blood-brain barrier, that allows circulating molecules to gain access to the adjacent brain parenchyma. In 120 min CNTF-treated mice specific nuclear staining for c-Fos was detected not only in cells of the area postrema but also in numerous neurons widely distributed in the nucleus of the solitary tract (Sol), the dorsal motor nucleus of vagus (DMV) and parabrachial nuclei. Ongoing experiments on capsaicin-treated (deafferented) mice will disclose a possible vagal contribution to the Sol and DMV neuronal activation due to a peripheral action of CNTF in the gastro-intestinal tract. Collectively, these data show for the first time that CNTF similarly to other satiety factor, like leptin, has redundant actions on both hypothalamic and brainstem energy balance neuronal networks. Unravelling the phenotype of brainstem neurons responsive to CNTF will clarify its role in distinctive aspects of feeding behaviour