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1.
Genes Dev ; 33(17-18): 1136-1158, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481537

RESUMO

Circadian rhythms are driven by a transcription-translation feedback loop that separates anabolic and catabolic processes across the Earth's 24-h light-dark cycle. Central pacemaker neurons that perceive light entrain a distributed clock network and are closely juxtaposed with hypothalamic neurons involved in regulation of sleep/wake and fast/feeding states. Gaps remain in identifying how pacemaker and extrapacemaker neurons communicate with energy-sensing neurons and the distinct role of circuit interactions versus transcriptionally driven cell-autonomous clocks in the timing of organismal bioenergetics. In this review, we discuss the reciprocal relationship through which the central clock drives appetitive behavior and metabolic homeostasis and the pathways through which nutrient state and sleep/wake behavior affect central clock function.


Assuntos
Relógios Circadianos/fisiologia , Metabolismo Energético/genética , Hipotálamo/metabolismo , Neurônios/fisiologia , Animais , Ritmo Circadiano/fisiologia , AMP Cíclico/metabolismo , Comportamento Alimentar/fisiologia , Humanos , Transdução de Sinais
2.
Adv Exp Med Biol ; 1158: 247-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452144

RESUMO

The maternally inherited mitochondrial DNA (mtDNA) is located inside every mitochondrion, in variable number of copies, and it contains 37 crucial genes for cellular bioenergetics. This chapter will discuss the unique features of this circular genome including heteroplasmy, haplogroups, among others, along with the corresponding clinical relevance for each. The discussion also covers the nuclear-encoded mitochondrial genes (N > 1000) and the epistatic interactions between mtDNA and the nuclear genome. Examples of mitochondrial diseases related to specific mtDNA mutation sites of relevance for humans are provided. This chapter aims to provide an overview of mitochondrial genetics as an emerging hot topic for the future of medicine.


Assuntos
Metabolismo Energético , Mitocôndrias , DNA Mitocondrial/genética , Metabolismo Energético/genética , Epistasia Genética , Genes Mitocondriais/genética , Genoma/genética , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação
3.
Aquat Toxicol ; 215: 105270, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401473

RESUMO

The study aimed to compare differences in oxidative stress and energy metabolism between the left and right lobe of hepatopancreas in large yellow croaker Larimichthys crocea exposed to 0 (control), 20, and 100 µM Zn for 96 h. Tipical biomarkers were examined including the proportion of white hepatopancreas, lipid content, malondialdehyde (MDA) level, glutathione (GSH) content, activity levels of enzymes (Cu/Zn-superoxide dismutase, Cu/Zn-SOD; catalase, CAT; glutathione peroxidase, GPx; glutathione reductase, GR; mitochondrial ATP synthase, F-ATPase; malate dehydrogenase, MDH; succinate dehydrogenase, SDH; hepatic lipase, HTGL; lipoprotein lipase, LPL), mRNA levels of genes encoding these enzymes (sod1, cat, gpx1a, gr, atp5b, mdh, sdh, htgl, and lpl), and gene expression of signaling molecules the NF-E2-related nuclear factor 2 (nrf2) and Kelch-like ECH-associated protein 1 (keap1). A whitish color in the left lobe of hepatopancreas was observed in the control and Zn-exposed fish. Contrarily, the right lobe of hepatopancreas tended towards red with increasing Zn levels. The phenomenon was further confirmed by that lipid content was reduced in the right lobe and was not significantly affected in the left lobe by Zn. The right lobe showed higher energy consumption than the left lobe as reflected by the up-regulation of activity levels of HTGL, LPL, F-ATPase, MDH, and SDH. Lipid peroxidation declined by 20 µM Zn and was unchanged by 100 µM Zn in both lobes, which could be explained by increased activity levels of Cu/Zn-SOD and GPx. However, the magnitude of increase in Cu/Zn-SOD activity was greater in the right lobe than that in the left one. The difference in enzyme activity between two lobes may be involved in changes in mRNA levels of sod1, gr, atp5b, sdh, htgl, lpl, and nrf2, which was further confirmed by positive relationships between enzyme activity and gene expression. Our data also showed positive correlations between nrf2 expression and mRNA levels of its target genes, suggesting that Nrf2 was required for the protracted induction of these genes. Our results demonstrated the potential molecular mechanism of Zn-induced differences between lobes of hepatopancreas, suggesting that the sampling part of hepatopancreas should be considered with caution when assessing metal contamination.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Hepatopâncreas/metabolismo , Hepatopâncreas/patologia , Estresse Oxidativo/efeitos dos fármacos , Perciformes/metabolismo , Poluentes Químicos da Água/toxicidade , Zinco/toxicidade , Animais , Antioxidantes/metabolismo , Metabolismo Energético/genética , Glutationa/metabolismo , Hepatopâncreas/efeitos dos fármacos , Malondialdeído/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
BMC Bioinformatics ; 20(1): 372, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266442

RESUMO

BACKGROUND: The studies of functions of circular RNAs (circRNAs) are heavily focused on the regulation of gene expression through interactions with multiple miRNAs. However, the number of predicted target genes is typically overwhelming due to the synergistic complexity caused by two factors ─ the binding of multiple miRNAs to a circRNA and the existence of multiple targets for each miRNA. Analysis of common targets (ACT) was designed to facilitate the identification of potential circRNA targets. RESULTS: We demonstrated the feasibility of the proposed feature/measurement to assess which genes are more likely to be regulated by circRNAs with given sequences by calculating the level of co-regulation by multiple miRNAs. The web service is made freely available at http://lab-x-omics.nchu.edu.tw/ACT_Server . CONCLUSIONS: ACT allows users to identify potential circRNA-regulated genes and their associated pathways for further investigation.


Assuntos
RNA/metabolismo , Interface Usuário-Computador , Animais , Metabolismo Energético/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/genética
5.
BMC Vet Res ; 15(1): 241, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296208

RESUMO

BACKGROUND: A major challenge in modern medicine and animal husbandry is the issue of antimicrobial resistance. One approach to solving this potential medical hazard is the selection of farm animals with less susceptibility to infectious diseases. Recent advances in functional genome analysis and quantitative genetics have opened the horizon to apply genetic marker information for efficiently identifying animals with preferential predisposition regarding health traits. The current study characterizes functional traits with a focus on udder health in dairy heifers. The animals were selected for having inherited alternative paternal haplotypes for a genomic region on Bos taurus chromosome (BTA) 18 genetically associated with divergent susceptibility to longevity and animal health, particularly mastitis. RESULTS: In the first weeks of lactation, the q heifers which had inherited the unfavorable (q) paternal haplotype displayed a significantly higher number of udder quarters with very low somatic cell count (< 10,000 cells / ml) compared to their paternal half-sib sisters with the favorable (Q) paternal haplotype. This might result in impaired mammary gland sentinel function towards invading pathogens. Furthermore, across the course of the first lactation, there was indication that q half-sib heifers showed higher somatic cell counts, a surrogate trait for udder health, in whole milkings compared to their paternal half-sib sisters with the favorable (Q) paternal haplotype. Moreover, heifers with the haplotype Q had a higher feed intake and higher milk yield compared to those with the q haplotype. Results of this study indicate that differences in milk production and calculated energy balance per se are not the main drivers of the genetically determined differences between the BTA18 Q and q groups of heifers. CONCLUSIONS: The paternally inherited haplotype from a targeted BTA18 genomic region affect somatic cell count in udder quarters during the early postpartum period and might also contribute to further aspects of animal's health and performance traits due to indirect effects on feed intake and metabolism.


Assuntos
Glândulas Mamárias Animais/fisiologia , Herança Paterna , Animais , Bovinos , Mapeamento Cromossômico , Ingestão de Alimentos/genética , Metabolismo Energético/genética , Feminino , Haplótipos/genética , Lactação/genética , Masculino , Glândulas Mamárias Animais/microbiologia , Mastite Bovina/genética , Período Pós-Parto
6.
J Dairy Sci ; 102(9): 8234-8246, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279561

RESUMO

The objective of the current study was to explore differences in dry matter intake, intake capacity, production efficiency, energy balance, and grazing behavior, of 2 divergent genetic groups (GG) of lactating Holstein-Friesian, selected using the Irish Economic Breeding Index (EBI). The GG were evaluated across 3 spring calving pasture-based feeding treatments (FT) over 3 yr. The 2 divergent GG were (1) high EBI, representative of the top 5% nationally (elite), and (2) EBI representative of the national average (NA). In each year 90 elite and 45 NA cows were randomly allocated to 1 of 3 FT: control, lower grass allowance, and high concentrate. Although FT did affect animal performance, there were few notable incidences of GG × FT interaction. The elite cows expressed lower daily milk yield (-1 kg) compared with NA. Elite cows did, however, express higher daily concentrations of milk fat (+3.7 g/kg) and protein (+2.1 g/kg) compared with NA. Daily yield of milk solids and net energy of lactation (NEL) was similar for both GG. Body weight (BW) was greater for NA (+13 kg) compared with elite, whereas mean body condition score was greater (+0.14) for elite compared with NA. Intake did not differ significantly between GG. Intake capacity, expressed as total dry matter intake/100 kg of BW, was greater with elite compared with NA. Production efficiency expressed as yield of milk solids per 100 kg of BW was greater with elite compared with NA, although milk solids/total dry matter intake did not differ between GG. Expressed as NEL as a proportion of net energy intake minus net energy of maintenance (NEL/NEI - NEM) and NEI/milk solids kg, indicated a slight reduction in the utilization of ingested energy for milk production with elite compared with NA. This is, however, suggested as favorable as it manifested as a more positive energy balance with elite compared with NA and so is likely to enhance robustness, increase longevity, and increase overall lifetime efficiency. Noteworthy was a consistent numerical trend toward more intense grazing activity with elite compared with NA cows, exhibited in the numerically greater grazing time (+19 min) and total number of bites per day (+2,591).


Assuntos
Ração Animal , Cruzamento/economia , Bovinos/genética , Ingestão de Alimentos/genética , Comportamento Alimentar , Animais , Peso Corporal/genética , Cruzamento/métodos , Bovinos/fisiologia , Indústria de Laticínios/economia , Dieta/veterinária , Ingestão de Energia/genética , Metabolismo Energético/genética , Feminino , Lactação/genética , Leite/química , Poaceae , Estações do Ano
7.
Mol Carcinog ; 58(9): 1531-1550, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31168912

RESUMO

Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one-third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta-analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity-induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer-associated genetic instability. In addition, the by-products of the oxidative degradation of lipids (e.g., malondialdehyde, 4-hydroxynonenal, and acrolein), and gut microbiota-mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity-related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity-related cancers.


Assuntos
Instabilidade Genômica/genética , Neoplasias/genética , Neoplasias/metabolismo , Obesidade/genética , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Animais , Dano ao DNA/genética , Reparo do DNA/genética , Metabolismo Energético/genética , Epigênese Genética/genética , Humanos , Estresse Oxidativo/genética
8.
Nat Commun ; 10(1): 2756, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227702

RESUMO

Flight loss in birds is as characteristic of the class Aves as flight itself. Although morphological and physiological differences are recognized in flight-degenerate bird species, their contributions to recurrent flight degeneration events across modern birds and underlying genetic mechanisms remain unclear. Here, in an analysis of 295 million nucleotides from 48 bird genomes, we identify two convergent sites causing amino acid changes in ATGLSer321Gly and ACOT7Ala197Val in flight-degenerate birds, which to our knowledge have not previously been implicated in loss of flight. Functional assays suggest that Ser321Gly reduces lipid hydrolytic ability of ATGL, and Ala197Val enhances acyl-CoA hydrolytic activity of ACOT7. Modeling simulations suggest a switch of main energy sources from lipids to carbohydrates in flight-degenerate birds. Our results thus suggest that physiological convergence plays an important role in flight degeneration, and anatomical convergence often invoked may not.


Assuntos
Evolução Biológica , Aves/fisiologia , Metabolismo Energético/genética , Voo Animal/fisiologia , Genoma/genética , Animais , Metabolismo dos Carboidratos/fisiologia , Genômica/métodos , Lipase/genética , Lipase/metabolismo , Lipólise/fisiologia , Palmitoil-CoA Hidrolase/genética , Palmitoil-CoA Hidrolase/metabolismo , Filogenia
9.
Genes Dev ; 33(13-14): 747-762, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31123067

RESUMO

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.


Assuntos
Adipócitos Bege/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Glucose/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Metabolismo Energético/genética , Deleção de Genes , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , Termogênese/genética
10.
J Dairy Sci ; 102(7): 6603-6613, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103304

RESUMO

Secretory capacity of bovine mammary glands is enabled by a high number of secretory cells and their ability to use a range of metabolites to produce milk components. We isolated RNA from milk fat to measure expression of genes involved in energy-yielding pathways and the unfolded protein response in mammary glands of lactating cows given supplemental energy from protein (PT) and fat (FT) tested in a 2 × 2 factorial arrangement. We hypothesized that PT and FT would affect expression of genes in the branched-chain AA catabolic pathway and tricarboxylic acid (TCA) cycle based on the different energy types (aminogenic versus lipogenic) used to synthesize milk components. We also hypothesized that the response of genes related to endoplasmic reticulum (ER) homeostasis via the unfolded protein response would reflect the increase in milk production stimulated by PT and FT. Fifty-six multiparous Holstein-Friesian dairy cows were fed a basal total mixed ration (34% grass silage, 33% corn silage, 5% grass hay, and 28% concentrate on a dry matter basis) for a 28-d control period. Experimental rations were then fed for 28 d, consisting of (1) low protein, low fat (LP/LF); (2) high protein, low fat (HP/LF); (3) low protein, high fat (LP/HF); or (4) high protein and high fat (HP/HF). To obtain the high-protein (HP) and high-fat (HF) diets, intake of the basal ration was restricted and supplemented isoenergetically (net energy basis) with 2.0 kg/d rumen-protected protein (soybean + rapeseed, 50:50 mixture on dry matter basis) and 0.68 kg/d hydrogenated palm fatty acids on a dry matter basis. RNA from milk fat samples collected on d 27 of each period underwent real-time quantitative PCR. Energy from protein increased expression of BCAT1 (branched-chain amino acid transferase 1) mRNA, but only at the LF level, and tended to decrease expression of mRNA encoding the main subunit of the branched-chain keto-acid dehydrogenase complex. mRNA expression of malic enzyme, a proposed channeling route for AA though the TCA cycle, was decreased by PT, but only at the LF level. Expression of genes associated with de novo fatty acid synthesis was not affected by PT or FT. Energy from fat had no independent effect on genes related to ER homeostasis. At the LF level, PT activated XBP1 (X-box binding protein 1) mRNA. At the HF level, PT increased mRNA expression of the gene encoding GADD34 (growth arrest and DNA damage-inducible 34). These findings support our hypothesis that mammary cells use aminogenic and lipogenic precursors differently for milk component production when dietary intervention alters AA and fatty acid supply. They also suggest that mammary cells respond to increased AA supply through mechanisms of ER homeostasis, dependent on the presence of FT.


Assuntos
Ração Animal , Bovinos/metabolismo , Gorduras na Dieta/metabolismo , Proteínas na Dieta/metabolismo , Metabolismo Energético/genética , Glândulas Mamárias Animais/metabolismo , Resposta a Proteínas não Dobradas/genética , Animais , Dieta/veterinária , Suplementos Nutricionais , Ácidos Graxos/análise , Feminino , Lactação , Glândulas Mamárias Animais/citologia , Leite , Silagem , Zea mays
11.
Biomed Res Int ; 2019: 7052456, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073529

RESUMO

Analysis of the proteome of myostatin (MSTN) knockout (KO) mouse C2C12 cells has proven valuable to studies investigating the molecular mechanisms by which MSTN regulates skeletal muscle development. To identify new protein/pathway alterations and candidate biomarkers for skeletal muscle development, we compared proteomic profiles of MSTN KO C2C12 cells (KO) with corresponding wild-type cells (NC) using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. A total of 2637 proteins were identified and quantified in KO cells. Among these proteins, 77 proteins were significantly differentially expressed, 38 upregulated, and 39 downregulated, in MSTN KO C2C12 cells. These significantly altered proteins are involved in metabolic processes, developmental processes, immune system processes, and the regulation of other biological processes. Enrichment analysis was utilized to link these alterations to biological pathways, which are predominantly related to oxidative phosphorylation, protein digestion and absorption, mitochondrion localisation, antigen processing and presentation, the MAPK signaling pathway, the PPAR signaling pathway, the PI3K-Akt signaling pathway, and the JAK-STAT signaling pathway. Upregulation of several proteins, including epoxide hydrolase, tropomyosin 1, Cyb5a, HTRA1, Cox6a1, CD109, Synap29, and Ugt1a6, likely enhanced skeletal muscle development, the immune system, and energy metabolism. Collectively, our results present a comprehensive proteomics analysis of MSTN KO C2C12 myoblast cells; we hypothesize that MSTN KO could activate p38MAPK signaling pathway by CDC42, and we further deciphered the function of MSTN in the regulation of skeletal muscle development, immune processes, and mitochondrial energy metabolism.


Assuntos
Metabolismo Energético/genética , Miostatina/genética , Proteoma/genética , Proteômica , Animais , Linhagem Celular , Cromatografia Líquida , Humanos , Espectrometria de Massas , Camundongos , Camundongos Knockout/genética , Desenvolvimento Muscular/genética , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
12.
Diabetes Res Clin Pract ; 152: 156-165, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31102684

RESUMO

AIM: To investigate the effect of a single and 15 units of high-intensity circuit training (HICT) programme on glucose metabolism, myokines' response and selected genes' expression in women. METHODS: Thirty-three, non-active women (mean age: 38 ±â€¯12) were split into a HICT (n = 20) or a control group (CON, n = 13). The training protocol included three circuits of nine exercises with own body weight as a workload performed 3 times a week for five weeks. The CON group performed HICT twice. Blood samples were taken before, 1 h and 24 h after the first and last unit to determine IGF-1, myostatin, irisin, decorin, HSP27, interleukin-15 concentrations using the ELISA immunoenzymatic method. To evaluate HSPB1, TNF-α and DCN mRNA, real-time PCR was used. Pre- and post-intervention, the oral glucose test and body composition assessment were completed. RESULTS: The following parameters tended to decrease after the 5-week HICT program: insulin and HOMA-IR Training diminished insulin/IGF-1 ratio (51% CI: -63% to -34%) and induced the drop of myostatin concentration but significantly only among middle-aged women and at baseline insulin resistance. CONCLUSION: Obtained data revealed that HICT improved an insulin sensitivity and diminished myostatin concentration among older, insulin-resistant women with lower baseline physical capacity.


Assuntos
Envelhecimento/fisiologia , Exercícios em Circuitos , Terapia por Exercício/métodos , Tolerância ao Exercício/fisiologia , Resistência à Insulina/fisiologia , Aptidão Física/fisiologia , Adulto , Fatores Etários , Glicemia/metabolismo , Composição Corporal/fisiologia , Exercícios em Circuitos/métodos , Decorina/genética , Decorina/metabolismo , Metabolismo Energético/genética , Exercício/fisiologia , Feminino , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Pessoa de Meia-Idade , Miostatina/genética , Miostatina/metabolismo , Treinamento de Resistência/métodos , Adulto Jovem
13.
Molecules ; 24(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30979097

RESUMO

A Java-based platform, MoleGear, is developed for de novo molecular design based on the chemistry development kit (CDK) and other Java packages. MoleGear uses evolutionary algorithm (EA) to explore chemical space, and a suite of fragment-based operators of growing, crossover, and mutation for assembling novel molecules that can be scored by prediction of binding free energy or a weighted-sum multi-objective fitness function. The EA can be conducted in parallel over multiple nodes to support large-scale molecular optimizations. Some complementary utilities such as fragment library design, chemical space analysis, and graphical user interface are also integrated into MoleGear. The candidate molecules as inhibitors for the human immunodeficiency virus 1 (HIV-1) protease were designed by MoleGear, which validates the potential capability for de novo molecular design.


Assuntos
Metabolismo Energético/genética , Evolução Molecular , Protease de HIV/química , Estrutura Molecular , Algoritmos , Biologia Computacional , Desenho de Drogas , Protease de HIV/efeitos dos fármacos , Humanos , Mutação/genética , Bibliotecas de Moléculas Pequenas/química
14.
Lipids Health Dis ; 18(1): 84, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947712

RESUMO

BACKGROUND: Two important regulators for circulating lipid metabolisms are lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). In relation to this, glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) has been shown to have a vital role in LPL lipolytic processing. However, the relationships between skeletal muscle mass and lipid metabolism, including LPL, GPIHBP1, and HTGL, remain to be elucidated. Demonstration of these relationships may lead to clarification of the metabolic dysfunctions caused by sarcopenia. In this study, these relationships were investigated in young Japanese men who had no age-related factors; participants included wrestling athletes with abundant skeletal muscle. METHODS: A total of 111 young Japanese men who were not taking medications were enrolled; 70 wrestling athletes and 41 control students were included. The participants' body compositions, serum concentrations of lipoprotein, LPL, GPIHBP1 and HTGL and thyroid function test results were determined under conditions of no extreme dietary restrictions and exercises. RESULTS: Compared with the control participants, wrestling athletes had significantly higher skeletal muscle index (SMI) (p < 0.001), higher serum concentrations of LPL (p < 0.001) and GPIHBP1 (p < 0.001), and lower fat mass index (p = 0.024). Kruskal-Wallis tests with Bonferroni multiple comparison tests showed that serum LPL and GPIHBP1 concentrations were significantly higher in the participants with higher SMI. Spearman's correlation analyses showed that SMI was positively correlated with LPL (ρ = 0.341, p < 0.001) and GPIHBP1 (ρ = 0.309, p = 0.001) concentration. The serum concentrations of LPL and GPIHBP1 were also inversely correlated with serum concentrations of triglyceride (LPL, ρ = - 0.198, p = 0.037; GPIHBP1, ρ = - 0.249, p = 0.008). Serum HTGL concentration was positively correlated with serum concentrations of total cholesterol (ρ = 0.308, p = 0.001), low-density lipoprotein-cholesterol (ρ = 0.336, p < 0.001), and free 3,5,3'-triiodothyronine (ρ = 0.260, p = 0.006), but not with SMI. CONCLUSIONS: The results suggest that increased skeletal muscle mass leads to improvements in energy metabolism by promoting triglyceride-rich lipoprotein hydrolysis through the increase in circulating LPL and GPIHBP1.


Assuntos
Lipase/sangue , Lipase Lipoproteica/sangue , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Receptores de Lipoproteínas/sangue , Adolescente , Adulto , Atletas , LDL-Colesterol/sangue , Metabolismo Energético/genética , Exercício/fisiologia , Feminino , Estudos de Associação Genética , Humanos , Lipase/genética , Metabolismo dos Lipídeos/genética , Lipase Lipoproteica/genética , Fígado/metabolismo , Masculino , Músculo Esquelético/fisiologia , Doenças Musculares/sangue , Doenças Musculares/patologia , Receptores de Lipoproteínas/genética , Testes de Função Tireóidea , Triglicerídeos/sangue , Adulto Jovem
15.
Biochem Soc Trans ; 47(2): 733-741, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31000529

RESUMO

The AMP (adenosine 5'-monophosphate)-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis that co-ordinates metabolic processes to ensure energy supply meets demand. At the cellular level, AMPK is activated by metabolic stresses that increase AMP or adenosine 5'-diphosphate (ADP) coupled with falling adenosine 5'-triphosphate (ATP) and acts to restore energy balance by choreographing a shift in metabolism in favour of energy-producing catabolic pathways while inhibiting non-essential anabolic processes. AMPK also regulates systemic energy balance and is activated by hormones and nutritional signals in the hypothalamus to control appetite and body weight. Failure to maintain energy balance plays an important role in chronic diseases such as obesity, type 2 diabetes and inflammatory disorders, which has prompted a major drive to develop pharmacological activators of AMPK. An array of small-molecule allosteric activators has now been developed, several of which can activate AMPK by direct allosteric activation, independently of Thr172 phosphorylation, which was previously regarded as indispensable for AMPK activity. In this review, we summarise the state-of-the-art regarding our understanding of the molecular mechanisms that govern direct allosteric activation of AMPK by adenylate nucleotides and small-molecule drugs.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/genética , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Regulação Alostérica/genética , Regulação Alostérica/fisiologia , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Humanos , Fosforilação
16.
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
17.
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
18.
Neurobiol Aging ; 78: 142-154, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30927700

RESUMO

Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 years), cognitively intact aging (73-95 years) and age-matched AD cases. To identify "anti-aging/AD" transcription patterns associated with physical activity, probesets significantly associated with both physical activity and aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2210 probesets significant in both data sets, nearly 95% showed opposite transcription patterns with physical activity compared with aging/AD. The majority (>70%) of these anti-aging/AD genes showed increased expression with physical activity and decreased expression in aging/AD. Enrichment analysis of the anti-aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling, and spine plasticity. Anti-aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function (notably negative regulation of transcription). These data reveal that physical activity is associated with a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Exercício/fisiologia , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Axônios/fisiologia , Cognição , Metabolismo Energético/genética , Humanos , Análise em Microsséries , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Vesículas Sinápticas/genética , Vesículas Sinápticas/fisiologia , Adulto Jovem
19.
PLoS Biol ; 17(3): e2006146, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30860988

RESUMO

Stress responses are crucial processes that require activation of genetic programs that protect from the stressor. Stress responses are also energy consuming and can thus be deleterious to the organism. The mechanisms coordinating energy consumption during stress response in multicellular organisms are not well understood. Here, we show that loss of the epigenetic regulator G9a in Drosophila causes a shift in the transcriptional and metabolic responses to oxidative stress (OS) that leads to decreased survival time upon feeding the xenobiotic paraquat. During OS exposure, G9a mutants show overactivation of stress response genes, rapid depletion of glycogen, and inability to access lipid energy stores. The OS survival deficiency of G9a mutants can be rescued by a high-sugar diet. Control flies also show improved OS survival when fed a high-sugar diet, suggesting that energy availability is generally a limiting factor for OS tolerance. Directly limiting access to glycogen stores by knocking down glycogen phosphorylase recapitulates the OS-induced survival defects of G9a mutants. We propose that G9a mutants are sensitive to stress because they experience a net reduction in available energy due to (1) rapid glycogen use, (2) an inability to access lipid energy stores, and (3) an overinduced transcriptional response to stress that further exacerbates energy demands. This suggests that G9a acts as a critical regulatory hub between the transcriptional and metabolic responses to OS. Our findings, together with recent studies that established a role for G9a in hypoxia resistance in cancer cell lines, suggest that G9a is of wide importance in controlling the cellular and organismal response to multiple types of stress.


Assuntos
Histona Metiltransferases/metabolismo , Animais , Antioxidantes/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Epigênese Genética/genética , Glicogênio Fosforilase/genética , Glicogênio Fosforilase/metabolismo , Histona Metiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Filogenia , Análise de Sequência de RNA
20.
Metabolism ; 95: 8-20, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30878493

RESUMO

BACKGROUND: The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response and development. Numerous studies relying on tissue-specific invalidation of the Pparg gene have shown distinct facets of its activity, whereas the effects of its systemic inactivation remain unexplored due to embryonic lethality. By maintaining PPARγ expression in the placenta, we recently generated a mouse model carrying Pparg full body deletion (PpargΔ/Δ), which in contrast to a previously published model is totally deprived of any form of adipose tissue. Herein, we propose an in-depth study of the metabolic alterations observed in this new model. METHODS: Young adult mice, both males and females analyzed separately, were first phenotyped for their gross anatomical alterations. Systemic metabolic parameters were analyzed in the blood, in static and in dynamic conditions. A full exploration of energy metabolism was performed in calorimetric cages as well as in metabolic cages. Our study was completed by expression analyses of a set of specific genes. MAIN FINDINGS: PpargΔ/Δ mice show a striking complete absence of any form of adipose tissue, which triggers a complex metabolic phenotype including increased lean mass with organomegaly, hypermetabolism, urinary energy loss, hyperphagia, and increased amino acid metabolism. PpargΔ/Δ mice develop severe type 2 diabetes, characterized by hyperglycemia, hyperinsulinemia, polyuria and polydispsia. They show a remarkable metabolic inflexibility, as indicated by the inability to shift substrate oxidation between glucose and lipids, in both ad libitum fed state and fed/fasted/refed transitions. Moreover, upon fasting PpargΔ/Δ mice enter a severe hypometabolic state. CONCLUSIONS: Our data comprehensively describe the impact of lipoatrophy on metabolic homeostasis. As such, the presented data on PpargΔ/Δ mice gives new clues on what and how to explore severe lipodystrophy and its subsequent metabolic complications in human.


Assuntos
Diabetes Mellitus Tipo 2/genética , Transtornos do Metabolismo dos Lipídeos/genética , Tamanho do Órgão/genética , PPAR gama/genética , Tecido Adiposo/anatomia & histologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/genética , Feminino , Deleção de Genes , Glucose/metabolismo , Transtornos do Metabolismo dos Lipídeos/metabolismo , Lipodistrofia/genética , Lipodistrofia/metabolismo , Camundongos , Gravidez
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