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Cell cycle (Georgetown, Tex.) 08/2012; 11(15):2765-6. · 5.36 Impact Factor
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Roberta Possenti,
Giampiero Muccioli,
Pamela Petrocchi,
Cheryl Cero,
Aderville Cabassi,
Lucy Vulchanova,
Maureen S Riedl,
Monia Manieri,
Andrea Frontini, Antonio Giordano, [......],
Antonio Torsello,
Vittorio Locatelli,
Valentina Sanghez,
Bjarne D Larsen,
Jorgen S Petersen,
Paola Palanza,
Stefano Parmigiani,
Anna Moles,
Andrea Levi,
Alessandro Bartolomucci
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ABSTRACT: The peptides encoded by the VGF gene are gaining biomedical interest and are increasingly being scrutinized as biomarkers for human disease. An endocrine/neuromodulatory role for VGF peptides has been suggested but never demonstrated. Furthermore, no study has demonstrated so far the existence of a receptor-mediated mechanism for any VGF peptide. In the present study, we provide a comprehensive in vitro, ex vivo and in vivo identification of a novel pro-lipolytic pathway mediated by the TLQP-21 peptide. We show for the first time that VGF-immunoreactivity is present within sympathetic fibres in the WAT (white adipose tissue) but not in the adipocytes. Furthermore, we identified a saturable receptor-binding activity for the TLQP-21 peptide. The maximum binding capacity for TLQP-21 was higher in the WAT as compared with other tissues, and selectively up-regulated in the adipose tissue of obese mice. TLQP-21 increases lipolysis in murine adipocytes via a mechanism encompassing the activation of noradrenaline/β-adrenergic receptors pathways and dose-dependently decreases adipocytes diameters in two models of obesity. In conclusion, we demonstrated a novel and previously uncharacterized peripheral lipolytic pathway encompassing the VGF peptide TLQP-21. Targeting the sympathetic nerve-adipocytes interaction might prove to be a novel approach for the treatment of obesity-associated metabolic complications.
Biochemical Journal 08/2011; 441(1):511-22. · 4.90 Impact Factor
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ABSTRACT: Leptin binding to its functional receptor stimulates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway, finally resulting in nuclear translocation of the phosphorylated STAT3 (P-STAT3). Systemic treatment with leptin (3mg/kg; intraperitoneal injection) induced the appearance of P-STAT3-immunoreactive cells in adult mouse preoptic area (POA). Here we show that the vast majority of leptin-responsive cells were located in medial POA (mPOA), followed by the median preoptic nucleus. Rare, scattered and weakly stained cells were found in ventromedial preoptic nucleus and lateral preoptic area. Co-localization studies disclosed that mPOA leptin-responsive cells were neurons, and that a large proportion expressed the alpha(1A)- and/or alpha(2A)-adrenergic receptor (AR) isoforms. Although understanding the functional relevance of leptin-responsive POA neurons requires further investigation, the finding that they bear alpha-ARs suggests that they may be targeted by the ascending noradrenergic system, which densely innervates the mPOA, and thus be involved in thermoregulation, arousal and/or the sleep-wake cycle.
Neuroscience Letters 03/2010; 471(2):83-8. · 2.11 Impact Factor
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Alessandra Valerio,
Marta Dossena,
Paola Bertolotti,
Flora Boroni,
Ilenia Sarnico,
Giuseppe Faraco,
Alberto Chiarugi,
Andrea Frontini, Antonio Giordano,
Hsiou-Chi Liou,
Maria Grazia De Simoni,
Pierfranco Spano,
Michele O Carruba,
Marina Pizzi,
Enzo Nisoli
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ABSTRACT: Leptin is an adipose hormone endowed with angiopoietic, neurotrophic, and neuroprotective properties. We tested the hypothesis that leptin might act as an endogenous mediator of recovery after ischemic stroke and investigated whether nuclear transcription factors kappaB activation is involved in leptin-mediated neuroprotection.
The antiapoptotic effects of leptin were evaluated in cultured mouse cortical neurons from wild-type or NF-kappaB/c-Rel(-/-) mice exposed to oxygen-glucose deprivation. Wild-type, c-Rel(-/-) and leptin-deficient ob/ob mice were subjected to permanent middle cerebral artery occlusion. Leptin production was measured in brains from wild-type mice with quantitative reverse transcriptase-polymerase chain reaction and immunostaining. Mice received a leptin bolus (20 microg/g) intraperitoneally at the onset of ischemia.
Leptin treatment activated the nuclear translocation of nuclear transcription factors kappaB dimers containing the c-Rel subunit, induced the expression of the antiapoptotic c-Rel target gene Bcl-xL in both control and oxygen-glucose deprivation conditions, and counteracted the oxygen-glucose deprivation-mediated apoptotic death of cultured cortical neurons. Leptin-mediated Bcl-xL induction and neuroprotection against oxygen-glucose deprivation were hampered in cortical neurons from c-Rel(-/-) mice. Leptin mRNA was induced and the protein was detectable in microglia/macrophage cells from the ischemic penumbra of wild-type mice subjected to permanent middle cerebral artery occlusion. Ob/ob mice were more susceptible than wild-type mice to the permanent middle cerebral artery occlusion injury. Leptin injection significantly reduced the permanent middle cerebral artery occlusion-mediated cortical damage in wild-type and ob/ob mice, but not in c-Rel(-/-) mice.
Leptin acts as an endogenous mediator of neuroprotection during cerebral ischemia. Exogenous leptin administration protects against ischemic neuronal injury in vitro and in vivo in a c-Rel-dependent manner.
Stroke 12/2008; 40(2):610-7. · 5.73 Impact Factor
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ABSTRACT: Leptin, a hormone produced by adipose tissue, reduces food intake and boosts energy expenditure via activation of the JAK2-STAT3 signalling pathway in adult mammal hypothalamic neurons. It is found in blood early after birth, peaking around postnatal day (P) 10. The hypothalamus of neonatal mice administered intraperitoneal leptin (3 mg/kg of body weight) was investigated for phospho-STAT3-positive cells to gain insights into the timing of maturation of the leptin signal transduction system. Leptin responsiveness was first detected in arcuate nucleus, where it was faint at P1 and evident from P5. It was then identified in medial preoptic area, anterior hypothalamus, retrochiasmatic area, dorsomedial nucleus and premammillary nucleus from P7, and in ventromedial nucleus and lateral hypothalamus from P11. From P13 onwards, hypothalamic P-STAT3 staining was indistinguishable from that of adult mice. Significant hypothalamic STAT3 activation was also detected by Western blotting at P11 and P15. The level of activation seen in adults was comparable to that observed at P15 although, remarkably, leptin-induced feeding reduction is observed only after the fourth postnatal week. Neuronal and glial markers and double-labelling immunohistochemistry showed that leptin-stimulated hypothalamic cells that had already reached their final position in a given area or nucleus were neurons; however, leptin responsiveness preceded positivity for the neuronal markers, suggesting a not fully differentiated status. Interestingly, leptin also increased P-STAT3 and c-Fos immunoreactivity in a distinctive and transient (from P5 to P13) cell population found in the dorsal part of the third ventricle and in subependymal position. These cells did not express mature or immature neuronal or glial markers. Their ultrastructural appearance, though suggestive of differentiating cells, was not conclusive for a specific phenotype.
Brain Research 07/2008; 1215:105-15. · 2.73 Impact Factor
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ABSTRACT: Brown and white adipose tissue have recently gained prominence as key players in obesity and related health problems, such as type-2 diabetes and cardiovascular disease. Brown adipose tissue-dependent nonshivering thermogenesis significantly affects the body's energy balance. Originally considered as a passive store of lipids, white adipose tissue has recently been found to secrete a number of hormones and cytokines and to be thus involved in the control of body metabolism and energy balance at multiple sites. These findings have renewed the interest in adipose organ biology, including its innervation by the autonomic nervous system and sensory nerves. Here, we describe our protocols for detecting different types of adipose tissue nerves by light microscopy using peroxidase immunostaining and by laser scanning confocal microscopy using immunofluorescence. With these techniques, the presence, distribution, and colocalization of autonomic and sensory nerves can be effectively investigated in subcutaneous and visceral adipose depots of normal and obese animals.
Methods in molecular biology (Clifton, N.J.) 02/2008; 456:83-95.
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ABSTRACT: Converging evidence indicates that white adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) based on immunohistochemical labeling of a SNS marker (tyrosine hydroxylase [TH]), tract tracing of WAT sympathetic postganglionic innervation, pseudorabies virus (PRV) transneuronal labeling of WAT SNS outflow neurons, and functional evidence from denervation studies. Recently, WAT para-SNS (PSNS) innervation was suggested because local surgical WAT sympathectomy (sparing hypothesized parasympathetic innervation) followed by PRV injection yielded infected cells in the vagal dorsomotor nucleus (DMV), a traditionally-recognized PSNS brain stem site. In addition, local surgical PSNS WAT denervation triggered WAT catabolic responses. We tested histologically whether WAT was parasympathetically innervated by searching for PSNS markers in rat, and normal (C57BL) and obese (ob/ob) mouse WAT. Vesicular acetylcholine transporter, vasoactive intestinal peptide and neuronal nitric oxide synthase immunoreactivities were absent in WAT pads (retroperitoneal, epididymal, inguinal subcutaneous) from all animals. Nearly all nerves innervating WAT vasculature and parenchyma that were labeled with protein gene product 9.5 (PGP9.5; pan-nerve marker) also contained TH, attesting to pervasive SNS innervation. When Siberian hamster inguinal WAT was sympathetically denervated via local injections of catecholaminergic toxin 6-hydroxydopamine (sparing putative parasympathetic nerves), subsequent PRV injection resulted in no central nervous system (CNS) or sympathetic chain infections suggesting no PSNS innervation. By contrast, vehicle-injected WAT subsequently inoculated with PRV had typical CNS/sympathetic chain viral infection patterns. Collectively, these data indicate no parasympathetic nerve markers in WAT of several species, with sparse DMV innervation and question the claim of PSNS WAT innervation as well as its functional significance.
AJP Regulatory Integrative and Comparative Physiology 12/2006; 291(5):R1243-55. · 3.34 Impact Factor
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Alessandra Valerio,
Valentina Ghisi,
Marta Dossena,
Cristina Tonello, Antonio Giordano,
Andrea Frontini,
Marina Ferrario,
Marina Pizzi,
PierFranco Spano,
Michele O Carruba,
Enzo Nisoli
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ABSTRACT: We examined the effects of the adipose hormone leptin on the development of mouse cortical neurons. Treatment of neonatal and adult mice with intraperitoneal leptin (5 mg/kg) induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in pyriform and entorhinal cortex neurons. Stimulation of cultured embryonic cortical neurons with leptin evoked Janus kinase 2 and ERK1/2 phosphorylation and activated the downstream effector 90-kDa ribosomal protein S6 kinase. Moreover, leptin elicited the phosphorylation of the phosphatidylinositol 3-kinase effector Akt and evoked Ser-9 phosphorylation of glycogen synthase kinase-3beta (GSK3beta), an event inactivating this kinase. Leptin-mediated GSK3beta phosphorylation was prevented by the MEK/ERK inhibitor PD98059, the phosphatidylinositol 3-kinase inhibitor LY294002, or the protein kinase C inhibitor GF109203X. Exposure of cortical neurons to leptin also induced Ser-41 phosphorylation of the neuronal growth-associated protein GAP-43, an effect prevented by LY294002 and GF109203X but not by PD98059. Ser-41-GAP-43 phosphorylation is usually high in expanding axonal growth cones. Neurons exposed to 100 ng/ml leptin for 72 h displayed reduced rate of growth cone collapse, a shift of growth cone size distribution toward higher values, and a 4-fold increase in mean growth cone surface area compared with control cultures. The leptin-induced growth cone spreading was hampered in cortical neurons from Lepr(db/db) mice lacking functional leptin receptors; it was associated with localized Ser-9-GSK3beta phosphorylation and mimicked by the GSK3beta inhibitor SB216763. At concentrations preventing GSK3beta phosphorylation, PD98059, LY294002, or GF109203X reversed the leptin-induced growth cone surface enlargement. We concluded that the leptin-mediated regulation of growth cone morphogenesis in cortical neurons relies on upstream regulators of GSK3beta activity.
Journal of Biological Chemistry 06/2006; 281(18):12950-8. · 4.77 Impact Factor
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ABSTRACT: We studied ob/ob and wild-type (WT) mice to characterize the adipose tissues depots and other visceral organs and to establish an experimental paradigm for in vivo phenotyping.
An in vivo evaluation was conducted using magnetic resonance imaging and 1H-magnetic resonance spectroscopy (1H-MRS). We used T1-weighted images and three-dimensional spin echo T1-weighted images for the morphological analysis and 1H-MRS spectra on all body mass, as well as 1H-MRS spectra focalized on specific lipid depots [triglyceride (TG) depots] for a molecular analysis.
In ob/ob mice, three-dimensional evaluation of the trunk revealed that approximately 64% of the volume consists of white adipose tissue, which is 72% subcutaneous and 28% visceral. In vivo 1H-MRS showed that 20.00 +/- 6.92% in the WT group and 58.67 +/- 6.65% in the ob/ob group of the total proton content is composed of TG protons. In in vivo-localized spectra of ob/ob mice, we found a polyunsaturation degree of 0.5247 in subcutaneous depots. In the liver, we observed that 48.7% of the proton signal is due to water, whereas in the WT group, the water signal amounted to 82.8% of the total proton signal. With the sequences used, the TG amount was not detectable in the brain or kidneys.
The present study shows that several parameters can be obtained by in vivo examination of ob/ob mice by magnetic resonance imaging and 1H-MRS and that the accumulated white adipose tissue displays low polyunsaturation degree and low hydrolipidic ratio. Relevant anatomical alterations observed in urinary and digestive apparatuses should be considered when ob/ob mice are used in experimental paradigms.
Obesity 04/2006; 14(3):405-14. · 4.28 Impact Factor
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ABSTRACT: White adipose tissue (WAT) is innervated by the sympathetic nervous system. A role for WAT sympathetic noradrenergic nerves in lipid mobilization has been suggested. To gain insight into the involvement of nerve activity in the delipidation process, WAT nerves were investigated in rat retroperitoneal and epididymal depots after prolonged fasting. A significant increase in tyrosine hydroxylase (TH) content was found in epididymal and, especially, retroperitoneal WAT by Western blotting. Accordingly, an increased immunoreactivity for TH was detected by immunohistochemistry in epididymal and, especially, retroperitoneal vascular and parenchymal noradrenergic nerves. Neuropeptide Y (NPY)-containing nerves were found around arteries and in the parenchyma. Double-staining experiments and confocal microscopy showed that most perivascular and some parenchymal noradrenergic nerves also contained NPY. Detection of protein gene product (PGP) 9.5, a general marker of peripheral nerves, by Western blotting and PGP 9.5-TH by double-staining experiments showed significantly increased noradrenergic nerve density in fasted retroperitoneal, but not epididymal depots, suggesting that formation of new nerves takes place in retroperitoneal WAT in fasting conditions. On the whole, these data confirm the important role of sympathetic noradrenergic nerves in WAT lipid mobilization during fasting but also raise questions about the physiological role of regional-dependent nerve adjustments and their functional significance in relation to white adipocyte secretory products.
Journal of Histochemistry and Cytochemistry 07/2005; 53(6):679-87. · 2.72 Impact Factor
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ABSTRACT: Functional and histological evidence for the sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) exists for several species; however, its sensory innervation has only been shown in laboratory rats, and its function is unclear. We tested the effects of sensory and SNS innervation of Siberian hamster epididymal and inguinal WAT (EWAT and IWAT) by assessing calcitonin gene-related peptide (CGRP)- and tyrosine hydroxylase-immunoreactivity (ir), respectively. Next, we tested the role of the sensory innervation of WAT on growth and cellularity because WAT surgical denervation increases pad mass via selective increases in fat cell number, an effect ascribed to SNS denervation but that could be due to the accompanying surgical disruption of WAT sensory innervation. Sensory denervation was accomplished via multiple local microinjections of capsaicin into WAT, and its effects were compared with those of surgical denervation. Surgically denervated IWAT and EWAT showed significantly decreased tyrosine hydroxylase-ir and CGRP-ir, whereas capsaicin-treated WAT had only significantly decreased CGRP-ir. Surgically denervated pad masses were significantly increased; this was accompanied by increased total fat cell number in IWAT, with no change in fat cell size. EWAT only showed a significant increase in the number of small- to medium-sized adipocytes (75-125 mum diameter). By contrast, sensory-denervated pad masses were unchanged, but IWAT showed significantly increased average fat cell size. Collectively, these data provide immunohistochemical evidence for sensory and SNS innervation of WAT in Siberian hamsters and differential control of WAT cellularity by these innervations, as well as the ability of locally applied capsaicin to selectively reduce WAT sensory innervation.
AJP Regulatory Integrative and Comparative Physiology 05/2005; 288(4):R1028-37. · 3.34 Impact Factor
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Manrico Morroni, Antonio Giordano,
Maria Cristina Zingaretti,
Romina Boiani,
Rita De Matteis,
Barbara B Kahn,
Enzo Nisoli,
Cristina Tonello,
Catalina Pisoschi,
Michele M Luchetti,
Mariella Marelli,
Saverio Cinti
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ABSTRACT: Mammalian breast adipose tissue is replaced by a milk-secreting gland during pregnancy; the reverse process takes place upon interruption of lactation. Morphological and bromodeoxyuridine studies provide indirect evidence that mouse mammary adipocytes transform into secretory epithelial cells during pregnancy and revert to adipocytes after lactation. By using the Cre-loxP recombination system we show that the mammary gland of whey acidic protein (WAP)-Cre/R26R mice, in which secretory epithelial cells express the lacZ gene during pregnancy, contains labeled adipocytes during involution. Conversely, adipocyte P2-Cre/R26R mice, in which adipocytes are labeled before pregnancy, contain labeled secretory epithelial cells during pregnancy. We conclude that reversible adipocyte-to-epithelium and epithelium-to-adipocyte transdifferentiation occurs in the mammary gland of adult mice during pregnancy and lactation.
Proceedings of the National Academy of Sciences 12/2004; 101(48):16801-6. · 9.68 Impact Factor
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ABSTRACT: Brown adipose tissue (BAT) is richly provided with sympathetic noradrenergic nerves but is believed to lack a parasympathetic nerve supply. Acetylcholine is the predominant transmitter of postganglionic parasympathetic nerves. The vesicular acetylcholine transporter (VAChT) resides in synaptic vesicles of cholinergic nerve terminals and is used as a marker for peripheral cholinergic nerves. We sought cholinergic nerves in rat BAT using VAChT immunohistochemistry (IHC) on cryosections of interscapular, cervical, mediastinal, and perirenal depots. Mediastinal BAT was the sole depot provided with putative parasympathetic perivascular and parenchymal cholinergic nerves. The absence of vasoactive intestinal peptide-positive nerves suggested their nature as pure cholinergic fibers. By confocal microscopy, both cholinergic and noradrenergic nerves were detected in mediastinal BAT. Cold exposure and fasting led to increased density of VAChT-positive fibers and of noradrenergic sympathetic nerves at morphometry. The unexpected double innervation of mediastinal BAT may explain the inhibitory influence on thermogenesis observed after systemic injection of muscarinic antagonists in rats, and raises questions about the physiological role of its cholinergic nerve supply.
Journal of Histochemistry and Cytochemistry 08/2004; 52(7):923-30. · 2.72 Impact Factor
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ABSTRACT: Insulin promotes both metabolism and growth. However, it is unclear whether insulin-dependent growth is merely a result of its metabolic actions. Targeted ablation of insulin receptor (Insr) has not clarified this issue, because of early postnatal lethality. To examine this question, we generated mice with variable cellular mosaicism for null Insr alleles. Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles the human syndrome of leprechaunism. Insr ablation in 98% of cells, while resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia. The growth retardation was associated with a greater than 60-fold increase in the expression of hepatic insulin-like growth factor binding protein-1. These findings indicate that insulin regulates growth independently of metabolism and that the number of insulin receptors is an important determinant of the specificity of insulin action.
Journal of Clinical Investigation 02/2004; 113(2):209-19. · 15.39 Impact Factor
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ABSTRACT: Semaphorins are cell surface and/or soluble signals that exert an inhibitory control on axon guidance. Sema3A, the vertebrate-secreted semaphorin, binds to neuropilin-1, which together with plexins constitutes the functional receptor. To verify whether Sema3A is produced by white adipocytes and, in that case, to detect its targets in white adipose tissue, we studied the cell production and tissue distribution of Sema3A and neuropilin-1 in rat retroperitoneal and epididymal adipose depots. Sema3A and neuropilin-1 were detected in these depots by Western blotting. The immunohistochemical results showed that Sema3A is produced in, and possibly secreted by, smooth muscle cells of arteries and white adipocytes. Accordingly, neuropilin-1 was found on perivascular and parenchymal nerves. Such a pattern of distribution is in line with a role for secreted Sema3A in the growth and plasticity of white adipose tissue nerves. Indeed, after fasting, when white adipocytes are believed to be overstimulated by noradrenaline and rearrangement of the parenchymal nerve supply may occur, adipocytic expression of Sema3A is reduced. Finally, the presence of neuropilin-1 in some white adipocytes raises the interesting possibility that Sema3A also exerts an autocrine-paracrine role on these cells.
Journal of Neurocytology 06/2003; 32(4):345-52. · 1.94 Impact Factor
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ABSTRACT: The intracellular localization and activity of the nitric oxide synthase (NOS) isoforms were investigated in rat brown adipocytes. Immunohistochemistry showed cytoplasmic and nuclear staining for the endothelial NOS (eNOS) and inducible NOS (iNOS) isoforms; accordingly, anti-L-citrulline antibody, a marker of NOS activity, immunostained both the cytoplasm and the nucleus. The presence of metabolically active NOS in the nucleus was further confirmed by immunoblotting analyses of subcellular fractions of homogenates from cultured brown adipocytes and by measurements of NOS activity in the cytosol and nucleus. Sympathetic stimulation in vivo (i.e. cold exposure or beta(3)-adrenergic agonist treatment) and in vitro (i.e. noradrenaline treatment of cultured cells) significantly increased both cytosolic and nuclear eNOS and iNOS expression and activities. By contrast, the number of iNOS-positive, but not eNOS-positive, nuclei was significantly lower in the functionally impaired brown fat of genetically obese Zucker fa/fa rats. These data suggest the existence of a noradrenaline-modulated functional NOS system in the nucleus of brown adipocytes.
FEBS Letters 04/2002; 514(2-3):135-40. · 3.54 Impact Factor
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Chiara Chiellini,
Anna Bertacca,
Silvia E Novelli,
Cem Z Görgün,
Annamaria Ciccarone, Antonio Giordano,
Haiyan Xu,
Alexander Soukas,
Mario Costa,
Daniele Gandini, [......],
Paolo Cecchetti,
Ennia Pardini,
Lucia Perego,
Renzo Navalesi,
Franco Folli,
Luca Benzi,
Saverio Cinti,
Jeffrey M Friedman,
Gökhan S Hotamisligil,
Margherita Maffei
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ABSTRACT: Increase in adipose mass results in obesity and modulation of several factors in white adipose tissue (WAT). Two important examples are tumor necrosis factor alpha (TNFalpha) and leptin, both of which are upregulated in adipose tissue in obesity. In order to isolate genes differentially expressed in the WAT of genetically obese db/db mice compared to their lean littermates, we performed RNA fingerprinting and identified haptoglobin (Hp), which is significantly upregulated in the obese animals. Hp is a glycoprotein induced by a number of cytokines, LPS (Lipopolysaccharide), and more generally by inflammation. A significant upregulation of WAT Hp expression was also evident in several experimental obese models including the yellow agouti (/) A(y), ob/ob and goldthioglucose-treated mice (10-, 8-, and 7-fold, respectively). To identify the potential signals for an increase in Hp expression in obesity, we examined leptin and TNFalpha in vivo. Wild type animals treated with recombinant leptin did not show any alteration in WAT Hp expression compared to controls that were food restricted to the level of intake of the treated animals. On the other hand, Hp expression was induced in mice transgenically expressing TNFalpha in adipose tissue. Finally, a significant downregulation of WAT Hp mRNA was observed in ob/ob mice deficient in TNFalpha function, when compared to the ob/ob controls. These results demonstrate that haptoglobin expression in WAT is increased in obesity in rodents and TNFalpha is an important signal for this regulation.
Journal of Cellular Physiology 03/2002; 190(2):251-8. · 3.87 Impact Factor
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ABSTRACT: Uncoupling protein 1 (UCP1), the mammalian thermogenic mitochondrial protein, is found only in brown adipocytes, but its expression by immunohistochemistry is not homogeneous. Here we present evidence that the non-homogeneous pattern of immunostaining for UCP1 (referred to as the "Harlequin phenomenon") is particularly evident after acute and chronic cold (4C) stimulus and after administration of a specific beta(3)-adrenoceptor agonist (CL316,243). Accordingly, mRNA in situ expression confirmed the UCP1 non-homogeneous pattern of gene activation under conditions of adrenergic stimulus. Furthermore, morphometric analysis of immunogold-stained thin sections showed that UCP1-gold particle density was different among neighboring brown adipocytes with mitochondria of the same size and density. When the adrenergic stimulus was reduced in warm-acclimated animals (28C), UCP1 protein and mRNA expression was reduced and consequently the Harlequin phenomenon was barely visible. These data suggest the existence of an alternative and controlled functional recruitment of brown adipocytes in acute adrenergically stressed animals, possibly to avoid heat and metabolic damage in thermogenically active cells. Of note, the heat shock protein heme oxygenase 1 (HO1) is heterogeneously expressed in adrenergically stimulated brown adipose tissue and, specifically, cells expressing strong immunoreactivity for UCP1 also strongly express HO1.
Journal of Histochemistry and Cytochemistry 02/2002; 50(1):21-31. · 2.72 Impact Factor
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ABSTRACT: Heat production in brown adipose tissue (BAT) and brown adipocyte recruitment depend heavily on BAT vascular and parenchymal sympathetic and sensory innervation. The expression and distribution of Sema3a, a recently discovered chemorepellent neuronal factor active on both sympathetic and sensory peripheral nerves, were studied in interscapular rat BAT. In rats maintained in thermoneutral conditions, brown adipocytes produced both active isoforms of Sema3a and showed a distinct peripheral polarized immunostaining pattern. This suggests a role for Sema3a secreted by brown adipocytes in the guidance of axons toward their correct targets. In cold-acclimated rats, where parenchymal nerve density is higher, both the expression and the immunostaining of the two active isoforms were slightly but significantly reduced and the distinct staining pattern was not observed. These data suggest that the secretion of Sema3a is inhibited in the brown adipocytes of cold-acclimated rats. Thus, Sema3a could play a role in the plastic adjustment of BAT innervation observed in different conditions of functional demand.
Journal of Neurocytology 12/2000; 30(1):5-10. · 1.94 Impact Factor
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ABSTRACT: Severe quantitative and qualitative brown adipocyte defects are common in obesity. To investigate whether aberrant expression
of tumor necrosis factor α (TNF-α) in obesity is involved in functional brown fat atrophy, we have studied genetically obese
(ob/ob) mice with targeted null mutations in the genes encoding the two TNF receptors. The absence of both TNF receptors or p55
receptor alone resulted in a significant reduction in brown adipocyte apoptosis and an increase in β3-adrenoreceptor and uncoupling protein-1 expression in obese mice. Increased numbers of multilocular functionally active brown
adipocytes, and improved thermoregulation was also observed in obese animals lacking TNF-α function. These results indicate
that TNF-α plays an important role in multiple aspects of brown adipose tissue biology and mediates the abnormalities that
occur at this site in obesity.
Proceedings of the National Academy of Sciences 07/2000; 97(14):8033-8038. · 9.68 Impact Factor
