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2.
J Cell Sci ; 134(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34096605

RESUMO

Dysregulated immunity and widespread metabolic dysfunctions are the most relevant hallmarks of the passing of time over the course of adult life, and their combination at midlife is strongly related to increased vulnerability to diseases; however, the causal connection between them remains largely unclear. By combining multi-omics and functional analyses of adipose-derived stromal cells established from young (1 month) and midlife (12 months) mice, we show that an increase in expression of interferon regulatory factor 7 (IRF7) during adult life drives major metabolic changes, which include impaired mitochondrial function, altered amino acid biogenesis and reduced expression of genes involved in branched-chain amino acid (BCAA) degradation. Our results draw a new paradigm of aging as the 'sterile' activation of a cell-autonomous pathway of self-defense and identify a crucial mediator of this pathway, IRF7, as driver of metabolic dysfunction with age.


Assuntos
Aminoácidos de Cadeia Ramificada , Fator Regulador 7 de Interferon , Tecido Adiposo/metabolismo , Envelhecimento/genética , Animais , Fator Regulador 7 de Interferon/metabolismo , Camundongos , Células Estromais/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-33669843

RESUMO

Increased mortality due to malignant mesothelioma has been demonstrated by several epidemiologic studies in the area around Broni (a small town in Lombardy, northern Italy), where a factory producing asbestos cement was active between 1932 and 1993. Until now, the inorganic fiber burden in lungs has not been investigated in this population. The aim of this study is to assess the lung fiber burden in 72 individuals with previous occupational and/or anthropogenic environmental exposure to asbestos during the activity of an important asbestos cement factory. Inorganic fiber lung burden was assessed in autoptic samples taken from individuals deceased from asbestos-related diseases using a scanning electron microscope equipped with an energy-dispersive spectrometer. Significant differences in the detected amount of asbestos were pointed out among the three types of exposure. In most lung samples taken from patients who died of mesothelioma, very little asbestos (or, in some cases, no fibers) was found. Such subjects showed a significantly lower median amount of asbestos as compared to asbestosis. Almost no chrysotile was detected in the examined samples. Overall, crocidolite was the most represented asbestos, followed by amosite, tremolite/actinolite asbestos, and anthophyllite asbestos. There were significant differences in the amount of crocidolite and amosite fibers according to the kind of exposure. Overall, these findings provide novel insights into the link between asbestos exposure and mesothelioma, as well as the different impacts of the various types of asbestos on human health in relation to their different biopersistences in the lung microenvironment.


Assuntos
Asbestos , Neoplasias Pulmonares , Mesotelioma , Exposição Ocupacional , Exposição Ambiental , Humanos , Itália/epidemiologia , Pulmão , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Mesotelioma/induzido quimicamente , Mesotelioma/epidemiologia , Exposição Ocupacional/efeitos adversos , Microambiente Tumoral
4.
FASEB J ; 34(2): 2765-2773, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908033

RESUMO

The brown adipose tissue (BAT) is a thermogenic organ that plays a major role in energy balance, obesity, and diabetes due to the potent glucose and lipid clearance that fuels its thermogenesis, which is largely mediated via sympathetic nervous system activation. However, thus far there has been little experimental validation of the hypothesis that selective neuromodulation of the sympathetic nerves innervating the BAT is sufficient to elicit thermogenesis in mice. We generated mice expressing blue light-activated channelrhodopsin-2 (ChR2) in the sympathetic nerves innervating the BAT using two different strategies: injecting the BAT of C57Bl/6J mice with AAV6-hSyn-ChR2 (H134R)-EYFP; crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2-EYFP mice. The nerves in the BAT expressing ChR2 were selectively stimulated with a blue LED light positioned underneath the fat pad of anesthetized mice, while the BAT and core temperatures were simultaneously recorded. Using immunohistochemistry we confirmed the selective expression of EYFP in TH positive nerves fibers. In addition, local optogenetic stimulation of the sympathetic nerves induced significant increase in the BAT temperature followed by an increase in core temperature in mice expressing ChR2, but not in the respective controls. The BAT activation was also paralleled by increased levels of pre-UCP1 transcript. Our results demonstrate that local optogenetic stimulation of the sympathetic nerves is sufficient to elicit BAT and core thermogenesis, thus suggesting that peripheral neuromodulation has the potential to be exploited as an alternative to pharmacotherapies to elicit organ activation and thus ameliorate type 2 diabetes and/or obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Metabolismo Energético/fisiologia , Optogenética , Termogênese/fisiologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Optogenética/métodos , Sistema Nervoso Simpático/fisiologia
5.
Nat Metab ; 1(8): 830-843, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-32694768

RESUMO

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.


Assuntos
Tecido Adiposo Marrom/fisiologia , Animais , Humanos , Camundongos , Termogênese
7.
Nat Commun ; 9(1): 4974, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478315

RESUMO

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/irrigação sanguínea , Tecido Adiposo Marrom/inervação , Adrenérgicos/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Células 3T3-L1 , Tecido Adiposo Marrom/metabolismo , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Neovascularização Fisiológica , Neurregulinas/genética , Neurregulinas/metabolismo , Proteômica , Transdução de Sinais , Gordura Subcutânea/metabolismo , Termogênese , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Eur J Histochem ; 62(2): 2866, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29943950

RESUMO

The aim of this post-mortem ultrastructural and immunohistochemical study is to explore the characteristics of acute myocardial ischemia in the context of sudden death, using the combination of two different methods, both more insightful than ordinary histology. Transmission electron microscope and immunohistochemistry, in addition to the traditional histology, were applied to study human heart specimens collected during forensic autopsies. The whole series was sub-grouped into cases (n=17) and controls (n=10). The control group consisted of unnatural death with a short agonal period (immediately lethal injuries). Heart samples of the two cohorts of subjects were prepared for electron microscopy. On the other hand, each specimen, formalin fixed and paraffin embedded, was stained with haematoxylin and eosin and immunoreacted with the following primary antibodies: antiFibronectin, antiConnexin-43, anti npCx43 (dephosphorylated form of Connexin43), antiZonula occludens-1. Immunopositivity of each marker in the myocardium was semi-quantitatively graded. Electron microscopy revealed a number of interesting differences between acute myocardial ischemia and controls, regarding the morphology of nucleus, mitochondria and intercellular junctions. By immunohistochemistry, fibronectin was found to be markedly increased in the extracellular matrix of the acute myocardial ischemia cases, with a remarkable difference in respect of controls. Connexin 43 staining disclosed a slightly increase in the cytoplasm of acute myocardial ischemia cases with respect to the controls, whereas no relevant differences were seen between cases and controls at intercellular junctions. Dephosphorylated form of Cx43 showed an evident difference of staining in cases compared to controls and overall this difference more evident in the cytoplasm. Zonula occludens 1, described as an important marker for functional modification of cardiac muscle fibers, resulted negative or very weak in the vast majority of both cases and controls. The present study attempts to simultaneously apply electron microscopy and immunohistochemistry, in order to figure out the morphological changes that might lead to pathological processes underlying the sudden, unexpected death due to acute myocardial ischemia, and consequently to find useful diagnostic markers of very early ischemic injury. Both methods showed significant differences between acute myocardial ischemia and controls, regarding, overall nuclei, mitochondria, and intercellular junctions.Â.


Assuntos
Biomarcadores/análise , Morte Súbita Cardíaca/patologia , Imuno-Histoquímica/métodos , Microscopia Eletrônica de Transmissão/métodos , Isquemia Miocárdica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Morte Súbita Cardíaca/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
9.
Elife ; 62017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28414270

RESUMO

MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.


Assuntos
Tecido Adiposo/fisiopatologia , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Hiperplasia/fisiopatologia , Leptina/biossíntese , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Corpo Humano , Humanos
10.
J Cell Physiol ; 232(11): 2923-2928, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28191637

RESUMO

During pregnancy and lactation, subcutaneous white adipocytes in the mouse mammary gland transdifferentiate reversibly to milk-secreting epithelial cells. In this study, we demonstrate by transmission electron microscopy that in the post-lactating mammary gland interscapular multilocular adipocytes found close to the mammary alveoli contain milk protein granules. Use of the Cre-loxP recombination 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-positive 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.


Assuntos
Adipócitos Marrons/fisiologia , Transdiferenciação Celular , Células Epiteliais/fisiologia , Lactação , Glândulas Mamárias Animais/citologia , Desmame , Adipócitos Marrons/metabolismo , Adipócitos Marrons/ultraestrutura , Animais , Linhagem da Célula , Plasticidade Celular , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Feminino , Genótipo , Integrases/genética , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Proteínas do Leite/genética , Proteínas do Leite/metabolismo , Fenótipo , Gravidez , RNA não Traduzido/genética , Proteína Desacopladora 1/metabolismo , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
11.
Aging (Albany NY) ; 8(6): 1201-22, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27241713

RESUMO

Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance.


Assuntos
Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , RNA Helicases DEAD-box/metabolismo , Metabolismo Energético/fisiologia , Resistência à Insulina/fisiologia , Longevidade/genética , Ribonuclease III/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Envelhecimento/genética , Animais , RNA Helicases DEAD-box/genética , Metabolismo Energético/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metabolômica , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ribonuclease III/genética , Sirolimo/farmacologia
12.
Nat Rev Drug Discov ; 15(6): 405-24, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26965204

RESUMO

New therapeutic and preventative strategies are needed to address the growing obesity epidemic. In animal models, brown adipose tissue activation and the associated heat produced contribute to countering obesity and the accompanying metabolic abnormalities. Adult humans also have functional brown fat. Here, we present and discuss the concepts of murine and human white adipose tissue plasticity and the transdifferentiation of white adipocytes into brown adipocytes. Human visceral adipocytes - which are crucial contributors to the burden of obesity and its complications - are particularly susceptible to such transdifferentiation. Therefore, we propose that this process should be a focus of anti-obesity research. Approved drugs that have browning properties as well as future drugs that target molecular pathways involved in white-to-brown visceral adipocyte transdifferentiation may provide new avenues for obesity therapy.


Assuntos
Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Diferenciação Celular , Obesidade/prevenção & controle , Adulto , Humanos , Termogênese
13.
Mol Metab ; 5(1): 19-33, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26844204

RESUMO

BACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity. METHODS: We used wt and triple ß1,ß2,ß3-Adrenergic Receptors knockout (ß-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays. RESULTS: Departing from our initial observation that ßARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the ßARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in ß-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in ßARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and ß-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT. CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to ßARs agonists for the activation of human BAT.

14.
FASEB J ; 30(2): 909-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26527067

RESUMO

Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired ß3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of ß-adrenergic receptor signaling.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais/fisiologia , Adipócitos Marrons/citologia , Tecido Adiposo Marrom/citologia , Animais , Feminino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Consumo de Oxigênio/fisiologia , Canais de Potássio de Domínios Poros em Tandem/genética , Receptores de Mineralocorticoides/genética , Termogênese/fisiologia
15.
Expert Rev Endocrinol Metab ; 10(2): 143-152, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30293508

RESUMO

Brown adipocytes are located in discrete anatomical locations in both small mammals and in humans. 'Brown-like' adipocytes, also known as brite (brown in white) or beige adipocytes are found interspersed among white adipocytes in several fat depots. From a functional point of view, the activity of brown and brite cells is similar, that is, heat production mediated by uncoupling protein 1. The morphology and expression of 'thermogenic' genes is also very similar in these two cell types. The origin of brite adipocytes is under intense investigation because enhancing their presence and activity has the potential to promote a healthy metabolic profile. Transdifferentiation mechanisms as well as de novo recruitment have been investigated. The characterization of the mechanisms involved in the recruitment and activation of brown/brite adipocytes in adult humans, could open the avenue for promising therapeutic strategies to curb metabolic diseases.

16.
Am J Physiol Endocrinol Metab ; 306(8): E945-64, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24549398

RESUMO

Brown adipocytes dissipate energy, whereas white adipocytes are an energy storage site. We explored the plasticity of different white adipose tissue depots in acquiring a brown phenotype by cold exposure. By comparing cold-induced genes in white fat to those enriched in brown compared with white fat, at thermoneutrality we defined a "brite" transcription signature. We identified the genes, pathways, and promoter regulatory motifs associated with "browning," as these represent novel targets for understanding this process. For example, neuregulin 4 was more highly expressed in brown adipose tissue and upregulated in white fat upon cold exposure, and cell studies showed that it is a neurite outgrowth-promoting adipokine, indicative of a role in increasing adipose tissue innervation in response to cold. A cell culture system that allows us to reproduce the differential properties of the discrete adipose depots was developed to study depot-specific differences at an in vitro level. The key transcriptional events underpinning white adipose tissue to brown transition are important, as they represent an attractive proposition to overcome the detrimental effects associated with metabolic disorders, including obesity and type 2 diabetes.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Resposta ao Choque Frio/genética , Regulação da Expressão Gênica , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Células PC12 , Ratos , Transcriptoma
17.
Mol Endocrinol ; 28(3): 344-56, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24479876

RESUMO

Receptor-interacting protein 140 (RIP140) is a corepressor of nuclear receptors that is highly expressed in adipose tissues. We investigated the role of RIP140 in conditionally immortal preadipocyte cell lines prepared from white or brown fat depots. In white adipocytes, a large set of brown fat-associated genes was up-regulated in the absence of RIP140. In contrast, a relatively minor role can be ascribed to RIP140 in the control of basal gene expression in differentiated brown adipocytes because significant changes were observed only in Ptgds and Fabp3. The minor role of RIP140 in brown adipocytes correlates with the similar histology and uncoupling protein 1 and CIDEA staining in knockout compared with wild-type brown adipose tissue (BAT). In contrast, RIP140 knockout sc white adipose tissue (WAT) shows increased numbers of multilocular adipocytes with elevated staining for uncoupling protein 1 and CIDEA. Furthermore in a white adipocyte cell line, the markers of BRITE adipocytes, Tbx1, CD137, Tmem26, Cited1, and Epsti1 were repressed in the presence of RIP140 as was Prdm16. Microarray analysis of wild-type and RIP140-knockout white fat revealed elevated expression of genes associated with cold-induced expression or high expression in BAT. A set of genes associated with a futile cycle of triacylglycerol breakdown and resynthesis and functional assays revealed that glycerol kinase and glycerol-3-phosphate dehydrogenase activity as well as [(3)H]glycerol incorporation were elevated in the absence of RIP140. Thus, RIP140 blocks the BRITE program in WAT, preventing the expression of brown fat genes and inhibiting a triacylglycerol futile cycle, with important implications for energy homeostasis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/citologia , Proteínas Nucleares/fisiologia , Triglicerídeos/biossíntese , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Inativação Gênica , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 1 de Interação com Receptor Nuclear , Análise de Sequência com Séries de Oligonucleotídeos , Transcriptoma , Triglicerídeos/metabolismo
18.
Eur J Endocrinol ; 170(5): R159-71, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24468979

RESUMO

In mammals, adipocytes are lipid-laden cells making up the parenchyma of the multi-depot adipose organ. White adipocytes store lipids for release as free fatty acids during fasting periods; brown adipocytes burn glucose and lipids to maintain thermal homeostasis. A third type of adipocyte, the pink adipocyte, has recently been characterised in mouse subcutaneous fat depots during pregnancy and lactation. Pink adipocytes are mammary gland alveolar epithelial cells whose role is to produce and secrete milk. Emerging evidence suggests that they derive from the transdifferentiation of subcutaneous white adipocytes. The functional response of the adipose organ to a range of metabolic and environmental challenges highlights its extraordinary plasticity. Cold exposure induces an increase in the 'brown' component of the organ to meet the increased thermal demand; in states of positive energy balance, the 'white' component expands to store excess nutrients; finally, the 'pink' component develops in subcutaneous depots during pregnancy to ensure litter feeding. At the cell level, plasticity is provided not only by stem cell proliferation and differentiation but also, distinctively, by direct transdifferentiation of fully differentiated adipocytes by the stimuli that induce genetic expression reprogramming and through it a change in phenotype and, consequently function. A greater understanding of adipocyte transdifferentiation mechanisms would have the potential to shed light on their biology as well as inspire novel therapeutic strategies against metabolic syndrome (browning) and breast cancer (pinking).


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adipogenia , Transdiferenciação Celular , Metabolismo dos Lipídeos , Glândulas Mamárias Humanas/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Adipócitos Marrons/citologia , Adipócitos Marrons/patologia , Adipócitos Brancos/citologia , Adipócitos Brancos/patologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Lactação , Masculino , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/patologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Obesidade/metabolismo , Obesidade/patologia , Especificidade de Órgãos , Pigmentação , Gravidez , Caracteres Sexuais , Gordura Subcutânea Abdominal/citologia , Gordura Subcutânea Abdominal/patologia
19.
Cell ; 156(1-2): 304-16, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439384

RESUMO

A clear relationship exists between visceral obesity and type 2 diabetes, whereas subcutaneous obesity is comparatively benign. Here, we show that adipocyte-specific deletion of the coregulatory protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or ß3-agonist treatment. These animals developed obesity on a high-fat diet, with severe insulin resistance and hepatic steatosis. They also showed altered fat distribution with markedly increased subcutaneous adiposity. Subcutaneous adipose tissue in mutant mice acquired many key properties of visceral fat, including decreased thermogenic and increased inflammatory gene expression and increased macrophage accumulation. Transplantation of subcutaneous fat into mice with diet-induced obesity showed a loss of metabolic benefit when tissues were derived from PRDM16 mutant animals. These findings indicate that PRDM16 and beige adipocytes are required for the "browning" of white fat and the healthful effects of subcutaneous adipose tissue.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Adipócitos/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica , Resistência à Insulina , Camundongos , Camundongos Knockout , Fatores de Transcrição/genética
20.
Metabolism ; 63(3): 312-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24369918

RESUMO

OBJECTIVE: In rodents, brown (BAT) and white (WAT) adipose tissues are targets and expression sites for fibroblast growth factor-21 (FGF21). In contrast, human WAT expresses negligible levels of FGF21. We examined FGF21 expression in human BAT samples, including the induced BAT found in adult patients with pheochromocytoma, and interscapular and visceral BAT from newborns. METHODS: The expression of FGF21 and uncoupling protein-1 (UCP1, a brown adipocyte marker), was determined by quantitative real-time-PCR and immunoblotting. The transcript levels of marker genes for developmentally-programmed BAT (zinc-finger-protein of the cerebellum-1, ZIC1) and inducible-BAT (cluster of differentiation-137, CD137) were also determined. RESULTS: FGF21 and UCP1 are significantly expressed in visceral adipose tissue from pheochromocytoma patients, but not in visceral fat from healthy individuals. In neonates, FGF21 and UCP1 are both expressed in visceral and interscapular fat, and their expression levels show a significant positive correlation. Marker gene expression profiles suggest that inducible BAT is present in visceral fat from pheochromocytoma patients and neonates, whereas developmentally-programmed BAT is present in neonatal interscapular fat. CONCLUSIONS: Human BAT, but not WAT, expresses FGF21. The expression of FGF21 is especially high in inducible, also called beige/brite, neonatal BAT, but it is also found in the interscapular, developmentally-programmed, BAT of neonates.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Feocromocitoma/genética , Ligante 4-1BB/genética , Ligante 4-1BB/metabolismo , Tecido Adiposo Branco/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Feminino , Humanos , Recém-Nascido , Canais Iônicos/genética , Canais Iônicos/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Feocromocitoma/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genética , Proteína Desacopladora 1
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