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1.
Cell ; 185(8): 1444-1444.e1, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35427500

RESUMO

The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-1α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes. Expressing specific PGC-1α isoforms in mice can confer protection in different disease models. This SnapShot summarizes how regulation of Ppargc1a transcription, splicing, translation, protein stability, and activity underlies its multifaceted functions. To view this SnapShot, open or download the PDF.


Assuntos
Regulação da Expressão Gênica , Mitocôndrias , Animais , Biologia , Metabolismo Energético , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
2.
Cell ; 185(24): 4654-4673.e28, 2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-36334589

RESUMO

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.


Assuntos
Tecido Adiposo Marrom , Proteoma , Humanos , Camundongos , Animais , Tecido Adiposo Marrom/metabolismo , Proteoma/metabolismo , Termogênese/fisiologia , Adiposidade , Obesidade/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas/metabolismo
3.
Cell ; 182(3): 563-577.e20, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32615086

RESUMO

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.


Assuntos
Adipogenia/genética , Tecido Adiposo Bege/metabolismo , Metabolismo Energético/genética , Quinase 1 de Adesão Focal/metabolismo , Transdução de Sinais/genética , Células-Tronco/metabolismo , Tetraspanina 28/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Bege/citologia , Tecido Adiposo Bege/crescimento & desenvolvimento , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Ataxina-1/metabolismo , Feminino , Fibronectinas/farmacologia , Quinase 1 de Adesão Focal/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Resistência à Insulina/genética , Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , RNA-Seq , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Células-Tronco/citologia , Tetraspanina 28/genética
4.
Cell ; 175(7): 1756-1768.e17, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30550785

RESUMO

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/ß5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Remodelação Óssea , Fibronectinas/metabolismo , Integrina alfaV/metabolismo , Osteócitos/metabolismo , Osteólise/metabolismo , Adipócitos/patologia , Animais , Linhagem Celular Tumoral , Feminino , Fibronectinas/genética , Células HEK293 , Humanos , Integrina alfaV/genética , Camundongos , Osteócitos/patologia , Osteólise/genética
5.
Cell ; 171(4): 836-848.e13, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-28988768

RESUMO

Adrenergic stimulation promotes lipid mobilization and oxidation in brown and beige adipocytes, where the harnessed energy is dissipated as heat in a process known as adaptive thermogenesis. The signaling cascades and energy-dissipating pathways that facilitate thermogenesis have been extensively described, yet little is known about the counterbalancing negative regulatory mechanisms. Here, we identify a two-pore-domain potassium channel, KCNK3, as a built-in rheostat negatively regulating thermogenesis. Kcnk3 is transcriptionally wired into the thermogenic program by PRDM16, a master regulator of thermogenesis. KCNK3 antagonizes norepinephrine-induced membrane depolarization by promoting potassium efflux in brown adipocytes. This limits calcium influx through voltage-dependent calcium channels and dampens adrenergic signaling, thereby attenuating lipolysis and thermogenic respiration. Adipose-specific Kcnk3 knockout mice display increased energy expenditure and are resistant to hypothermia and obesity. These findings uncover a critical K+-Ca2+-adrenergic signaling axis that acts to dampen thermogenesis, maintain tissue homeostasis, and reveal an electrophysiological regulatory mechanism of adipocyte function.


Assuntos
Tecido Adiposo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Obesidade/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Receptores Adrenérgicos/metabolismo , Transdução de Sinais , Termogênese , Adipócitos Marrons/metabolismo , Tecido Adiposo/patologia , Animais , Separação Celular , Células Cultivadas , Fenômenos Eletrofisiológicos , Feminino , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Obesidade/patologia , Canais de Potássio de Domínios Poros em Tandem/genética
6.
Cell ; 166(2): 424-435, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27374330

RESUMO

Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders.


Assuntos
Adipócitos/metabolismo , Amidoidrolases/metabolismo , Mitocôndrias/metabolismo , Termogênese , Aminoácidos/sangue , Animais , Respiração Celular , Metabolismo Energético , Ácidos Graxos/sangue , Glucose/metabolismo , Homeostase , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo
7.
Mol Cell ; 83(11): 1903-1920.e12, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37267907

RESUMO

Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys physiological benefits, including improved cognition and resistance to neurodegeneration. Irisin acts via αV integrins; however, a mechanistic understanding of how small polypeptides like irisin can signal through integrins is poorly understood. Using mass spectrometry and cryo-EM, we demonstrate that the extracellular heat shock protein 90α (eHsp90α) is secreted by muscle with exercise and activates integrin αVß5. This allows for high-affinity irisin binding and signaling through an Hsp90α/αV/ß5 complex. By including hydrogen/deuterium exchange data, we generate and experimentally validate a 2.98 Å RMSD irisin/αVß5 complex docking model. Irisin binds very tightly to an alternative interface on αVß5 distinct from that used by known ligands. These data elucidate a non-canonical mechanism by which a small polypeptide hormone like irisin can function through an integrin receptor.


Assuntos
Comunicação Celular , Fibronectinas , Humanos , Fibronectinas/metabolismo , Transdução de Sinais
8.
Cell ; 163(3): 643-55, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26496606

RESUMO

Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a ß3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PAPERCLIP.


Assuntos
Tecido Adiposo Marrom/metabolismo , Creatina/metabolismo , Termogênese , Difosfato de Adenosina/metabolismo , Tecido Adiposo/metabolismo , Animais , Metabolismo Energético , Homeostase , Humanos , Canais Iônicos/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Proteína Desacopladora 1
9.
Cell ; 156(1-2): 20-44, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439368

RESUMO

There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function. The past few years, in particular, have seen significant changes in the way that we classify adipocytes and how we view adipose development and differentiation. We have new perspective on the roles played by adipocytes in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues. Finally, there has been significant progress in understanding how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.


Assuntos
Adipócitos/metabolismo , Metabolismo dos Lipídeos , Obesidade/patologia , Adipogenia , Animais , Humanos , Obesidade/metabolismo
10.
Cell ; 158(1): 69-83, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24995979

RESUMO

Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1(+) cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, ß-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fatores Reguladores de Interferon/metabolismo , Termogênese , Fatores de Transcrição/metabolismo , Ativação Transcricional , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Temperatura Baixa , AMP Cíclico/metabolismo , Metabolismo Energético , Humanos , Canais Iônicos/genética , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Magreza/metabolismo , Ativação Transcricional/efeitos dos fármacos , Proteína Desacopladora 1
11.
Cell ; 157(6): 1279-1291, 2014 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-24906147

RESUMO

Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Glucose/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Fatores de Crescimento Neural/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Termogênese , Fatores de Transcrição/genética
12.
Cell ; 158(1): 41-53, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24995977

RESUMO

A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic ß cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining ß cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca(2+). Finally, we demonstrate that T2DM patients with ß cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to ß cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Tecido Adiposo/metabolismo , Animais , Complemento C3a/metabolismo , Fator D do Complemento/genética , Fator D do Complemento/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Secreção de Insulina , Camundongos
14.
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
15.
Nature ; 616(7958): 755-763, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37046083

RESUMO

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.


Assuntos
Hematopoiese Clonal , Células-Tronco Hematopoéticas , Animais , Humanos , Camundongos , Alelos , Hematopoiese Clonal/genética , Estudo de Associação Genômica Ampla , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Mutação , Regiões Promotoras Genéticas
16.
Cell ; 151(6): 1319-31, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23217713

RESUMO

PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.


Assuntos
Proteínas de Choque Térmico/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Treinamento Resistido , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Adiposidade , Animais , Glucose/metabolismo , Humanos , Hipertrofia , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/metabolismo , Miostatina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Isoformas de Proteínas/metabolismo
17.
Cell ; 150(2): 366-76, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22796012

RESUMO

Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. PAPERCLIP:


Assuntos
Adipócitos/classificação , Adipócitos/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Separação Celular , Perfilação da Expressão Gênica , Humanos , Canais Iônicos/metabolismo , Camundongos , Proteínas Mitocondriais/metabolismo , Proteína Desacopladora 1
18.
Cell ; 151(1): 96-110, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23021218

RESUMO

PGC1α is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor potential vanilloid), a family of ion channels, induced PGC1α expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases.


Assuntos
Metabolismo Energético , Canais de Cátion TRPV/metabolismo , Termogênese , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Feminino , Técnicas de Silenciamento de Genes , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Transativadores/metabolismo , Fatores de Transcrição , Proteína Desacopladora 1
19.
Nature ; 590(7846): 480-485, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33597756

RESUMO

Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle4-to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.


Assuntos
Tecido Adiposo/metabolismo , Creatina Quinase Forma BB/metabolismo , Creatina/metabolismo , Termogênese , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/enzimologia , Animais , Creatina Quinase Forma BB/deficiência , Creatina Quinase Forma BB/genética , AMP Cíclico/metabolismo , Metabolismo Energético/genética , Feminino , Glucose/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Obesidade/enzimologia , Obesidade/genética , Obesidade/metabolismo , Transdução de Sinais
20.
Nature ; 593(7860): 580-585, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33981039

RESUMO

Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1-3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle.


Assuntos
Fosfatase Alcalina/metabolismo , Mitocôndrias/enzimologia , Fosfocreatina/metabolismo , Termogênese , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Animais , Temperatura Baixa , Metabolismo Energético , Hidrólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo
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