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1.
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
2.
Nat Rev Mol Cell Biol ; 23(11): 750-770, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35577989

RESUMO

Transcriptional regulation of catabolic pathways is a central mechanism by which cells respond to physiological cues to generate the energy required for anabolic pathways, transport of molecules and mechanical work. Nuclear receptors are members of a superfamily of transcription factors that transduce hormonal, nutrient, metabolite and redox signals into specific metabolic gene programmes, and thus hold a major status as regulators of cellular energy generation. Nuclear receptors also regulate the expression of genes involved in cellular processes that are implicated in energy production, including mitochondrial biogenesis and autophagy. Recent advances in genome-wide approaches have considerably expanded the repertoire of both nuclear receptors and metabolic genes under their direct transcriptional control. To fine-tune the expression of their target genes, nuclear receptors must act cooperatively with other transcription factors and coregulator proteins, integrate signals from key metabolic sensory systems such as the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complexes and synchronize their activities with the biological clock. Therefore, nuclear receptors must function as more than molecular switches for small lipophilic ligands - as initially ascribed - but rather must be capable of orchestrating a large ensemble of input signals. Therefore, a primary role for several nuclear receptors is to serve as the focal point of transcriptional hubs in energy metabolism: their molecular task is to receive and transduce multiple systemic and intracellular metabolic signals to maintain energy homeostasis from individual cells to the whole organism.


Assuntos
Proteínas Quinases Ativadas por AMP , Serina-Treonina Quinases TOR , Proteínas Quinases Ativadas por AMP/metabolismo , Ligantes , Serina-Treonina Quinases TOR/metabolismo , Metabolismo Energético/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Sirolimo
3.
Cell ; 176(4): 729-742.e18, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30661757

RESUMO

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.


Assuntos
Metabolismo Energético/genética , Melanocortinas/metabolismo , Semaforinas/genética , Adolescente , Adulto , Animais , Peso Corporal , Linhagem Celular , Criança , Pré-Escolar , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Variação Genética/genética , Homeostase , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Obesidade/genética , Obesidade/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Adulto Jovem , Peixe-Zebra
4.
Nat Immunol ; 22(3): 287-300, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33574617

RESUMO

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.


Assuntos
Citocinas/sangue , Dieta Saudável , Metabolismo Energético , Imunidade Inata , Mediadores da Inflamação/sangue , Saúde da População Rural , Saúde da População Urbana , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Citocinas/genética , Metabolismo Energético/genética , Feminino , Humanos , Imunidade Inata/genética , Masculino , Metaboloma , Pessoa de Meia-Idade , Estado Nutricional , Valor Nutritivo , Comportamento de Redução do Risco , Estações do Ano , Tanzânia , Transcriptoma , Fator de Necrose Tumoral alfa/sangue , Urbanização , Adulto Jovem
5.
Nat Rev Mol Cell Biol ; 21(5): 268-283, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32144406

RESUMO

Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.


Assuntos
Hipóxia Celular/genética , Metabolismo Energético/genética , Estresse Oxidativo/genética , Oxigênio/metabolismo , Trifosfato de Adenosina/metabolismo , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
6.
Cell ; 167(3): 722-738.e23, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27768893

RESUMO

A functional crosstalk between epigenetic regulators and metabolic control could provide a mechanism to adapt cellular responses to environmental cues. We report that the well-known nuclear MYST family acetyl transferase MOF and a subset of its non-specific lethal complex partners reside in mitochondria. MOF regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA in aerobically respiring cells. MOF binds mtDNA, and this binding is dependent on KANSL3. The mitochondrial pool of MOF, but not a catalytically deficient mutant, rescues respiratory and mtDNA transcriptional defects triggered by the absence of MOF. Mof conditional knockout has catastrophic consequences for tissues with high-energy consumption, triggering hypertrophic cardiomyopathy and cardiac failure in murine hearts; cardiomyocytes show severe mitochondrial degeneration and deregulation of mitochondrial nutrient metabolism and oxidative phosphorylation pathways. Thus, MOF is a dual-transcriptional regulator of nuclear and mitochondrial genomes connecting epigenetics and metabolism.


Assuntos
Metabolismo Energético/genética , Epigênese Genética , Histona Acetiltransferases/metabolismo , Mitocôndrias Musculares/enzimologia , Fatores de Transcrição/metabolismo , Transcrição Gênica , Animais , Cardiomiopatia Hipertrófica/genética , Respiração Celular/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Células HeLa , Insuficiência Cardíaca/genética , Histona Acetiltransferases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/genética , Mitocôndrias Musculares/genética , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilação Oxidativa , Fatores de Transcrição/genética
7.
Mol Cell ; 83(6): 827-828, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36931253

RESUMO

Osipova et al.1 recently identified an inactivating gene mutation that contributed to the evolution of the hummingbird species by increasing flux of pathways for energy production that are necessary for the unique ability for hovering flight. Lessons from the natural selection for this mutation are applied to physiology and medicine.


Assuntos
Aves , Voo Animal , Animais , Voo Animal/fisiologia , Aves/genética , Aves/metabolismo , Metabolismo Energético/genética , Consumo de Oxigênio , Seleção Genética
8.
Nat Immunol ; 18(5): 519-529, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28346409

RESUMO

Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1α abrogation in Ern1f/f; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1f/f; Lyz2-Cre mice. Furthermore, IRE1α ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1α senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1α pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/patologia , Endorribonucleases/metabolismo , Macrófagos/fisiologia , Obesidade/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Diferenciação Celular/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Endorribonucleases/genética , Metabolismo Energético/genética , Humanos , Ativação de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética
9.
Mol Cell ; 81(11): 2317-2331.e6, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33909988

RESUMO

Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Antígeno CTLA-4/genética , Neoplasias Colorretais/genética , Inibidores de Checkpoint Imunológico , Proteínas Quinases Ativadas por AMP/imunologia , Aloenxertos , Animais , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Antígeno B7-H1/imunologia , Compostos de Bifenilo/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/terapia , Dieta Cetogênica/métodos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia/métodos , Proteínas com Domínio MARVEL/genética , Proteínas com Domínio MARVEL/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Pironas/farmacologia , Transdução de Sinais , Análise de Sobrevida , Tiofenos/farmacologia
10.
Genes Dev ; 35(1-2): 133-146, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33334822

RESUMO

The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.


Assuntos
Tecido Adiposo/fisiologia , Comunicação Autócrina/genética , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/genética , Transdução de Sinais/genética , Adipócitos/metabolismo , Adiponectina/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Sistema Endócrino/metabolismo , Metabolismo Energético/genética , Retroalimentação Fisiológica/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Hepatócitos/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , MAP Quinase Quinase 4/deficiência , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos
11.
Nat Immunol ; 17(9): 1037-1045, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27348412

RESUMO

Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1ß (IL-1ß) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Infecções por Escherichia coli/imunologia , Escherichia coli K12/imunologia , Macrófagos/imunologia , Mitocôndrias/metabolismo , Animais , Células Cultivadas , Metabolismo Energético/genética , Interações Hospedeiro-Parasita , Imunidade Inata/genética , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fagocitose , Espécies Reativas de Oxigênio/metabolismo
12.
Mol Cell ; 78(6): 1034-1044, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32504556

RESUMO

Malignant cells remodel their metabolism to meet the demands of uncontrolled cell proliferation. These demands lead to differential requirements in energy, biosynthetic precursors, and signaling intermediates. Both genetic programs arising from oncogenic events and transcriptional programs and epigenomic events are important in providing the necessary metabolic network activity. Accumulating evidence has established that environmental factors play a major role in shaping cancer cell metabolism. For metabolism, diet and nutrition are the major environmental aspects and have emerged as key components in determining cancer cell metabolism. In this review, we discuss these emerging concepts in cancer metabolism and how diet and nutrition influence cancer cell metabolism.


Assuntos
Dietoterapia/métodos , Neoplasias/dietoterapia , Neoplasias/metabolismo , Carcinogênese/metabolismo , Proliferação de Células/genética , Dieta/tendências , Dietoterapia/tendências , Metabolismo Energético/genética , Humanos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Neoplasias/genética , Terapia Nutricional/métodos , Transdução de Sinais/genética
13.
Genes Dev ; 34(7-8): 495-510, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32139423

RESUMO

Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that ß-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético/genética , Lipólise/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Obesidade/complicações , Células 3T3 , Tecido Adiposo/enzimologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Proteína Forkhead Box O1/metabolismo , Deleção de Genes , Células HEK293 , Humanos , Hipoglicemiantes/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipase/genética , Lipase/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética
14.
Development ; 151(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38063847

RESUMO

Gene expression is a regulated process fueled by ATP consumption. Therefore, regulation must be coupled to constraints imposed by the level of energy metabolism. Here, we explore this relationship both theoretically and experimentally. A stylized mathematical model predicts that activators of gene expression have variable impact depending on metabolic rate. Activators become less essential when metabolic rate is reduced and more essential when metabolic rate is enhanced. We find that, in the Drosophila eye, expression dynamics of the yan gene are less affected by loss of EGFR-mediated activation when metabolism is reduced, and the opposite effect is seen when metabolism is enhanced. The effects are also seen at the level of pattern regularity in the adult eye, where loss of EGFR-mediated activation is mitigated by lower metabolism. We propose that gene activation is tuned by energy metabolism to allow for faithful expression dynamics in the face of variable metabolic conditions.


Assuntos
Proteínas de Drosophila , Proteínas Repressoras , Animais , Proteínas Repressoras/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/genética , Drosophila/metabolismo , Metabolismo Energético/genética , Expressão Gênica , Receptores ErbB/genética , Receptores ErbB/metabolismo
15.
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
16.
Mol Cell ; 74(4): 844-857.e7, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31000437

RESUMO

Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiological and genetic regulation. BAT-specific deletion of Sirt5, a mitochondrial desuccinylase and demalonylase, results in dramatic increases in global protein succinylation and malonylation. Mass spectrometry-based quantification of succinylation reveals that Sirt5 regulates the key thermogenic protein in BAT, UCP1. Mutation of the two succinylated lysines in UCP1 to acyl-mimetic glutamine and glutamic acid significantly decreases its stability and activity. The reduced function of UCP1 and other proteins in Sirt5KO BAT results in impaired mitochondria respiration, defective mitophagy, and metabolic inflexibility. Thus, succinylation of UCP1 and other mitochondrial proteins plays an important role in BAT and in regulation of energy homeostasis.


Assuntos
Metabolismo Energético/genética , Mitocôndrias/metabolismo , Obesidade/genética , Sirtuínas/genética , Proteína Desacopladora 1/genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Regulação da Expressão Gênica , Glucose/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Obesidade/metabolismo , Obesidade/patologia , Proteômica/métodos , Ácido Succínico/metabolismo , Termogênese/genética , Proteína Desacopladora 1/metabolismo
17.
Mol Cell ; 76(6): 909-921.e3, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31676231

RESUMO

Metabolic signaling to chromatin often underlies how adaptive transcriptional responses are controlled. While intermediary metabolites serve as co-factors for histone-modifying enzymes during metabolic flux, how these modifications contribute to transcriptional responses is poorly understood. Here, we utilize the highly synchronized yeast metabolic cycle (YMC) and find that fatty acid ß-oxidation genes are periodically expressed coincident with the ß-oxidation byproduct histone crotonylation. Specifically, we found that H3K9 crotonylation peaks when H3K9 acetylation declines and energy resources become limited. During this metabolic state, pro-growth gene expression is dampened; however, mutation of the Taf14 YEATS domain, a H3K9 crotonylation reader, results in de-repression of these genes. Conversely, exogenous addition of crotonic acid results in increased histone crotonylation, constitutive repression of pro-growth genes, and disrupted YMC oscillations. Together, our findings expose an unexpected link between metabolic flux and transcription and demonstrate that histone crotonylation and Taf14 participate in the repression of energy-demanding gene expression.


Assuntos
Acil Coenzima A/metabolismo , Metabolismo Energético , Regulação Fúngica da Expressão Gênica , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fator de Transcrição TFIID/metabolismo , Metabolismo Energético/genética , Ácidos Graxos/metabolismo , Histonas/genética , Homeostase , Lisina , Oxirredução , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais , Fator de Transcrição TFIID/genética , Transcrição Gênica
18.
Mol Cell ; 74(5): 877-890.e6, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31023583

RESUMO

Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.


Assuntos
Fator 4 Ativador da Transcrição/genética , Metabolismo Energético/genética , Fator de Iniciação 2 em Eucariotos/genética , Mitocôndrias/genética , eIF-2 Quinase/genética , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular/genética , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Glucose/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mutação de Sentido Incorreto/genética , Nutrientes/metabolismo , Fosforilação , Fatores de Processamento de Serina-Arginina/genética , Transdução de Sinais
19.
Mol Cell ; 76(4): 531-545.e5, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31706703

RESUMO

The glucocorticoid receptor (GR) is a potent metabolic regulator and a major drug target. While GR is known to play integral roles in circadian biology, its rhythmic genomic actions have never been characterized. Here we mapped GR's chromatin occupancy in mouse livers throughout the day and night cycle. We show how GR partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting. Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR. This rhythmic pattern is altered by high-fat diet in a ligand-independent manner. We find that the remodeling of oscillatory gene expression and postprandial GR binding results from a concomitant increase of STAT5 co-occupancy in obese mice. Altogether, our findings highlight GR's fundamental role in the rhythmic orchestration of hepatic metabolism.


Assuntos
Cromatina/metabolismo , Relógios Circadianos , Ritmo Circadiano , Dieta Hiperlipídica , Gorduras na Dieta/metabolismo , Metabolismo Energético , Fígado/metabolismo , Obesidade/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Glicemia/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Modelos Animais de Doenças , Metabolismo Energético/genética , Jejum/metabolismo , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Gluconeogênese , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/sangue , Obesidade/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Período Pós-Prandial , Receptores de Glucocorticoides/deficiência , Receptores de Glucocorticoides/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Via Secretória , Transdução de Sinais , Fatores de Tempo , Transcrição Gênica , Triglicerídeos/sangue
20.
Proc Natl Acad Sci U S A ; 121(9): e2308796121, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38386708

RESUMO

Noise control, together with other regulatory functions facilitated by microRNAs (miRNAs), is believed to have played important roles in the evolution of multicellular eukaryotic organisms. miRNAs can dampen protein fluctuations via enhanced degradation of messenger RNA (mRNA), but this requires compensation by increased mRNA transcription to maintain the same expression levels. The overall mechanism is metabolically expensive, leading to questions about how it might have evolved in the first place. We develop a stochastic model of miRNA noise regulation, coupled with a detailed analysis of the associated metabolic costs. Additionally, we calculate binding free energies for a range of miRNA seeds, the short sequences which govern target recognition. We argue that natural selection may have fine-tuned the Michaelis-Menten constant [Formula: see text] describing miRNA-mRNA affinity and show supporting evidence from analysis of experimental data. [Formula: see text] is constrained by seed length, and optimal noise control (minimum protein variance at a given energy cost) is achievable for seeds of 6 to 7 nucleotides in length, the most commonly observed types. Moreover, at optimality, the degree of noise reduction approaches the theoretical bound set by the Wiener-Kolmogorov linear filter. The results illustrate how selective pressure toward energy efficiency has potentially shaped a crucial regulatory pathway in eukaryotes.


Assuntos
Eucariotos , MicroRNAs , MicroRNAs/genética , Proteínas Mutantes , RNA Mensageiro , Metabolismo Energético/genética
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