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1.
Nat Commun ; 11(1): 4706, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943618

RESUMO

Yeast physiology is temporally regulated, this becomes apparent under nutrient-limited conditions and results in respiratory oscillations (YROs). YROs share features with circadian rhythms and interact with, but are independent of, the cell division cycle. Here, we show that YROs minimise energy expenditure by restricting protein synthesis until sufficient resources are stored, while maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells sequester and store metabolic resources via increased transport, autophagy and biomolecular condensation. Replete stores trigger increased H+ export which stimulates TORC1 and liberates proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates translational bursting, liquidation of storage carbohydrates, increased ATP turnover, and the export of osmolytes. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints selected for temporal organisation that promotes oscillatory behaviour.


Assuntos
Metabolismo Energético/fisiologia , Células Eucarióticas/fisiologia , Proteostase/fisiologia , Autofagia/fisiologia , Reatores Biológicos , Ritmo Circadiano , Glicogênio/metabolismo , Resposta ao Choque Térmico , Ionomicina , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metabolômica , Chaperonas Moleculares , Concentração Osmolar , Pressão Osmótica , Oxigênio/metabolismo , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Proteoma , Proteômica , Ribossomos , Leveduras/fisiologia
2.
Nat Commun ; 11(1): 4837, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973183

RESUMO

ATP synthesis and thermogenesis are two critical outputs of mitochondrial respiration. How these outputs are regulated to balance the cellular requirement for energy and heat is largely unknown. Here we show that major facilitator superfamily domain containing 7C (MFSD7C) uncouples mitochondrial respiration to switch ATP synthesis to thermogenesis in response to heme. When heme levels are low, MSFD7C promotes ATP synthesis by interacting with components of the electron transport chain (ETC) complexes III, IV, and V, and destabilizing sarcoendoplasmic reticulum Ca2+-ATPase 2b (SERCA2b). Upon heme binding to the N-terminal domain, MFSD7C dissociates from ETC components and SERCA2b, resulting in SERCA2b stabilization and thermogenesis. The heme-regulated switch between ATP synthesis and thermogenesis enables cells to match outputs of mitochondrial respiration to their metabolic state and nutrient supply, and represents a cell intrinsic mechanism to regulate mitochondrial energy metabolism.


Assuntos
Trifosfato de Adenosina/metabolismo , Heme/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/metabolismo , Receptores Virais/metabolismo , Termogênese/fisiologia , Animais , Deficiência de Citocromo-c Oxidase , Complexo III da Cadeia de Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons , Metabolismo Energético/fisiologia , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membranas Mitocondriais/metabolismo , Domínios Proteicos , Receptores Virais/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais , Células THP-1
3.
Nat Commun ; 11(1): 4509, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908151

RESUMO

Glycolysis is one of the primordial pathways of metabolism, playing a pivotal role in energy metabolism and biosynthesis. Glycolytic enzymes are known to form transient multi-enzyme assemblies. Here we examine the wider protein-protein interactions of plant glycolytic enzymes and reveal a moonlighting role for specific glycolytic enzymes in mediating the co-localization of mitochondria and chloroplasts. Knockout mutation of phosphoglycerate mutase or enolase resulted in a significantly reduced association of the two organelles. We provide evidence that phosphoglycerate mutase and enolase form a substrate-channelling metabolon which is part of a larger complex of proteins including pyruvate kinase. These results alongside a range of genetic complementation experiments are discussed in the context of our current understanding of chloroplast-mitochondrial interactions within photosynthetic eukaryotes.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Cloroplastos/enzimologia , Glicólise/fisiologia , Mitocôndrias/enzimologia , Arabidopsis/citologia , Proteínas de Arabidopsis/genética , Metabolismo Energético/fisiologia , Mutação , Fosfoglicerato Mutase/genética , Fosfoglicerato Mutase/metabolismo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Fotossíntese/fisiologia , Plantas Geneticamente Modificadas , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/fisiologia , Piruvato Quinase/genética , Piruvato Quinase/metabolismo
4.
Nat Commun ; 11(1): 4416, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887881

RESUMO

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. Here, we report increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. By contrast, mice with genetic mitochondrial CaMKII inhibition are protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII overexpression (mtCaMKII) have severe dilated cardiomyopathy and decreased ATP that causes elevated cytoplasmic resting (diastolic) Ca2+ concentration and reduced mechanical performance. We map a metabolic pathway that rescues disease phenotypes in mtCaMKII mice, providing insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase or mitochondrial-targeted CaMKII inhibition.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomiopatia Dilatada/metabolismo , Infarto do Miocárdio/fisiopatologia , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/fisiopatologia , Camundongos , Camundongos Transgênicos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Infarto do Miocárdio/cirurgia , Transdução de Sinais
5.
Nat Commun ; 11(1): 4046, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792488

RESUMO

2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)-the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.


Assuntos
Complexo Cetoglutarato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , Mitocôndrias/metabolismo , Mutagênese/fisiologia , Serina Proteases/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Células HeLa , Humanos , Complexo Cetoglutarato Desidrogenase/genética , Modelos Biológicos , Mutagênese/genética , Serina Proteases/genética
6.
Nat Commun ; 11(1): 3794, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732906

RESUMO

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.


Assuntos
Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/fisiologia , Obesidade/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ritmo Circadiano/genética , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Obesidade/genética , Núcleo Hipotalâmico Paraventricular/citologia
7.
PLoS Comput Biol ; 16(8): e1007966, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760072

RESUMO

Protein activity is often regulated by ligand binding or by post-translational modifications such as phosphorylation. Moreover, proteins that are regulated in this way often contain multiple ligand binding sites or modification sites, which can operate to create an ultrasensitive dose response. Here, we consider the contribution of the individual modification/binding sites to the activation process, and how their individual values affect the ultrasensitive behavior of the overall system. We use a generalized Monod-Wyman-Changeux (MWC) model that allows for variable conformational free energy contributions from distinct sites, and associate a so-called activation parameter to each site. Our analysis shows that the ultrasensitivity generally increases as the conformational free energy contribution from one or more sites is strengthened. Furthermore, ultrasensitivity depends on the mean of the activation parameters and not on their variability. In some cases, we find that the best way to maximize ultrasensitivity is to make the contribution from all sites as strong as possible. These results provide insights into the performance objectives of multiple modification/binding sites and thus help gain a greater understanding of signaling and its role in diseases.


Assuntos
Sítios de Ligação/fisiologia , Metabolismo Energético/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas , Transdução de Sinais/fisiologia , Ligantes , Modelos Biológicos , Fosforilação/fisiologia , Conformação Proteica , Subunidades Proteicas , Proteínas/química , Proteínas/metabolismo , Termodinâmica
8.
Proc Biol Sci ; 287(1933): 20200431, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32811308

RESUMO

Ground contact duration and stride frequency each affect muscle metabolism and help scientists link walking and running biomechanics to metabolic energy expenditure. While these parameters are often used independently, the product of ground contact duration and stride frequency (i.e. duty factor) may affect muscle contractile mechanics. Here, we sought to separate the metabolic influence of the duration of active force production, cycle frequency and duty factor. Human participants produced cyclic contractions using their soleus (which has a relatively homogeneous fibre type composition) at prescribed cycle-average ankle moments on a fixed dynamometer. Participants produced these ankle moments over short, medium and long durations while maintaining a constant cycle frequency. Overall, decreased duty factor did not affect cycle-average fascicle force (p ≥ 0.252) but did increase net metabolic power (p ≤ 0.022). Mechanistically, smaller duty factors increased maximum muscle-tendon force (p < 0.001), further stretching in-series tendons and shifting soleus fascicles to shorter lengths and faster velocities, thereby increasing soleus total active muscle volume (p < 0.001). Participant soleus total active muscle volume well-explained net metabolic power (r = 0.845; p < 0.001). Therefore, cyclically producing the same cycle-average muscle-tendon force using a decreased duty factor increases metabolic energy expenditure by eliciting less economical muscle contractile mechanics.


Assuntos
Metabolismo Energético/fisiologia , Músculo Esquelético/fisiologia , Tendões/fisiologia , Adulto , Tornozelo/fisiologia , Feminino , Marcha/fisiologia , Humanos , Masculino , Contração Muscular/fisiologia , Corrida/fisiologia , Caminhada/fisiologia
9.
Life Sci ; 258: 118236, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795537

RESUMO

Cancer cells exhibit distinct energy metabolic pathways due to multiple oncogenic events. In normoxia condition, the anaerobic glycolysis (Warburg effect) is highly observed in head and neck squamous cell carcinoma (HNSCC). HNSCC is associated with smoking, chewing tobacco, consumption of alcohol or Human Papillomavirus (HPV) infection primarily HPV16. In recent years, the correlation of HPV with HNSCC has significantly expanded. Despite the recent advancement in therapeutic approaches, the rate of HPV infected HNSCC has significantly increased in the last few years, specifically, in lower middle-income countries. The oncoproteins of High-risk Human Papillomavirus (HR-HPV), E6 and E7, alter the metabolic phenotype in HNSCC, which is distinct from non-HPV associated HNSCC. These oncoproteins, modulate the cell cycle and metabolic signalling through interacting with tumor suppressor proteins, p53 and pRb. Since, metabolic alteration represents a major hallmark for tumorigenesis, HPV acts as a source of biomarker linked to cancer progression in HNSCC. The dependency of cancer cells to specific nutrients and alteration of various metabolic associated genes may provide a unique opportunity for pharmacological intervention in HPV infected HNSCC. In this review, we have discussed the molecular mechanism (s) and metabolic regulation in HNSCC depending on the HPV status. We have also discussed the possible potential therapeutic approaches for HPV associated HNSCC through targeting metabolic pathways.


Assuntos
Metabolismo Energético/fisiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Glicólise/fisiologia , Humanos
10.
PLoS Med ; 17(8): e1003234, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764760

RESUMO

BACKGROUND: In common with many other low- and middle-income countries (LMICs), rural to urban migrants in India are at increased risk of obesity, but it is unclear whether this is due to increased energy intake, reduced energy expenditure, or both. Knowing this and the relative contribution of specific dietary and physical activity behaviours to greater adiposity among urban migrants could inform policies for control of the obesity epidemic in India and other urbanising LMICs. In the Indian Migration Study, we previously found that urban migrants had greater prevalence of obesity and diabetes compared with their nonmigrant rural-dwelling siblings. In this study, we investigated the relative contribution of energy intake and expenditure and specific diet and activity behaviours to greater adiposity among urban migrants in India. METHODS AND FINDINGS: The Indian Migration Study was conducted between 2005 and 2007. Factory workers and their spouses from four cities in north, central, and south of India, together with their rural-dwelling siblings, were surveyed. Self-reported data on diet and physical activity was collected using validated questionnaires, and adiposity was estimated from thickness of skinfolds. The association of differences in dietary intake, physical activity, and adiposity between siblings was examined using multivariable linear regression. Data on 2,464 participants (median age 43 years) comprised of 1,232 sibling pairs (urban migrant and their rural-dwelling sibling) of the same sex (31% female) were analysed. Compared with the rural siblings, urban migrants had 18% greater adiposity, 12% (360 calories/day) more energy intake, and 18% (11 kilojoules/kg/day) less energy expenditure (P < 0.001 for all). Energy intake and expenditure were independently associated with increased adiposity of urban siblings, accounting for 4% and 6.5% of adiposity difference between siblings, respectively. Difference in dietary fat/oil (10 g/day), time spent engaged in moderate or vigorous activity (69 minutes/day), and watching television (30 minutes/day) were associated with difference in adiposity between siblings, but no clear association was observed for intake of fruits and vegetables, sugary foods and sweets, cereals, animal and dairy products, and sedentary time. The limitations of this study include a cross-sectional design, systematic differences in premigration characteristics of migrants and nonmigrants, low response rate, and measurement error in estimating diet and activity from questionnaires. CONCLUSIONS: We found that increased energy intake and reduced energy expenditure contributed equally to greater adiposity among urban migrants in India. Policies aimed at controlling the rising prevalence of obesity in India and potentially other urbanising LMICs need to be multicomponent, target both energy intake and expenditure, and focus particularly on behaviours such as dietary fat/oil intake, time spent on watching television, and time spent engaged in moderate or vigorous intensity physical activity.


Assuntos
Adiposidade/fisiologia , Dieta/tendências , Ingestão de Energia/fisiologia , Exercício Físico/fisiologia , População Rural/tendências , Migrantes , População Urbana/tendências , Adulto , Índice de Massa Corporal , Estudos Transversais , Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Metabolismo Energético/fisiologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Autorrelato
11.
Nat Commun ; 11(1): 3347, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620768

RESUMO

A sharp increase in mitochondrial Ca2+ marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca2+ extrusion via the mitochondrial Na+/Ca2+ exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO2 measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swelling and cell death. Treatment with mPTP inhibitors rescue mitochondrial function and thermogenesis in NCLX-null BAT, while calcium overload persists. Our findings identify a key pathway through which BA evade apoptosis during adrenergic stimulation of uncoupling. NCLX deletion transforms the adrenergic pathway responsible for thermogenesis activation into a death pathway.


Assuntos
Adipócitos Marrons/patologia , Tecido Adiposo Marrom/metabolismo , Norepinefrina/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Termogênese/fisiologia , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/citologia , Adrenérgicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Temperatura Baixa/efeitos adversos , Ciclosporina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Microscopia Intravital , Masculino , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Cultura Primária de Células , Transdução de Sinais , Trocador de Sódio e Cálcio/genética , Termogênese/efeitos dos fármacos
12.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R148-R155, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32663032

RESUMO

Naked mole-rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to suppress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers). A recent goldfish study demonstrated that remodeling of membrane lipids may mediate these responses, but it is unknown if NMR employs the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals 1) downregulate the activity of key enzymes of glycolysis, tricarboxylic acid (TCA) cycle, and ß-oxidation, 2) inhibit sodium-potassium-ATPase, and 3) alter membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 wk had a lower metabolic rate by 34%. This suppression occurs concurrently with tissue-specific 25-99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium-ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and ß-oxidation fluxes, NMRs decrease the supply of acetyl-CoA to the TCA cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between changes in membrane composition and enzyme activities could not be established. Nevertheless, this is the first demonstration that hypometabolic NMRs alter the lipid composition of their membranes in response to chronic in vivo exposure to hypoxia.


Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Metabolismo Energético/fisiologia , Hipóxia/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Encéfalo/metabolismo , Ratos-Toupeira , Oxigênio/metabolismo
13.
Nature ; 583(7814): 109-114, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32528181

RESUMO

Hibernating mammals actively lower their body temperature to reduce energy expenditure when facing food scarcity1. This ability to induce a hypometabolic state has evoked great interest owing to its potential medical benefits2,3. Here we show that a hypothalamic neuronal circuit in rodents induces a long-lasting hypothermic and hypometabolic state similar to hibernation. In this state, although body temperature and levels of oxygen consumption are kept very low, the ability to regulate metabolism still remains functional, as in hibernation4. There was no obvious damage to tissues and organs or abnormalities in behaviour after recovery from this state. Our findings could enable the development of a method to induce a hibernation-like state, which would have potential applications in non-hibernating mammalian species including humans.


Assuntos
Metabolismo Energético/fisiologia , Hibernação/fisiologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Animais , Metabolismo Basal/fisiologia , Núcleo Hipotalâmico Dorsomedial/citologia , Núcleo Hipotalâmico Dorsomedial/fisiologia , Feminino , Neurônios GABAérgicos/metabolismo , Glutamina/metabolismo , Masculino , Camundongos , Consumo de Oxigênio/fisiologia
14.
PLoS One ; 15(6): e0234426, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525912

RESUMO

BACKGROUND: Activity trackers such as the Fitbit Charge 2 enable users and researchers to monitor physical activity in daily life, which could be beneficial for changing behaviour. However, the accuracy of the Fitbit Charge 2 in a free-living environment is largely unknown. OBJECTIVE: To investigate the agreement between Fitbit Charge 2 and ActiGraph GT3X for the estimation of steps, energy expenditure, time in sedentary behaviour, and light and moderate-to-vigorous physical activity under free-living conditions, and further examine to what extent placing the ActiGraph on the wrist as opposed to the hip would affect the findings. METHODS: 41 adults (n = 10 males, n = 31 females) were asked to wear a Fitbit Charge 2 device and two ActiGraph GT3X devices (one on the hip and one on the wrist) for seven consecutive days and fill out a log of wear times. Agreement was assessed through Bland-Altman plots combined with multilevel analysis. RESULTS: The Fitbit measured 1,492 steps/day more than the hip-worn ActiGraph (limits of agreement [LoA] = -2,250; 5,234), while for sedentary time, it measured 25 min/day less (LoA = -137; 87). Both Bland-Altman plots showed fixed bias. For time in light physical activity, the Fitbit measured 59 min/day more (LoA = -52;169). For time in moderate-to-vigorous physical activity, the Fitbit measured 31 min/day less (LoA = -132; 71) and for activity energy expenditure it measured 408 kcal/day more than the hip-worn ActiGraph (LoA = -385; 1,200). For the two latter outputs, the plots indicated proportional bias. Similar or more pronounced discrepancies, mostly in opposite direction, appeared when comparing to the wrist-worn ActiGraph. CONCLUSION: Moderate to substantial differences between devices were found for most outputs, which could be due to differences in algorithms. Caution should be taken if replacing one device with another and when comparing results.


Assuntos
Acelerometria/instrumentação , Exercício Físico/fisiologia , Monitores de Aptidão Física , Monitorização Ambulatorial/instrumentação , Adulto , Metabolismo Energético/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Comportamento Sedentário
15.
PLoS One ; 15(6): e0234443, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32598395

RESUMO

Ramadan fasting is associated with changes in eating, physical activity, sleeping patterns, and medication. Unfortunately, only limited studies examine glucose variability in subjects with type 2 diabetes who fast in Ramadan. Our study aims to evaluate glucose variability in subjects with type 2 diabetes on oral antidiabetic agents using continuous glucose monitoring system (CGMS) during and after Ramadan fasting. This observational study was done in The Indonesian Medical Education and Research Institute, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia, which recruited 10 subjects with type 2 diabetes who underwent Ramadan fasting in 2019. These subjects were free from cardiovascular disease, kidney disease, severe liver disease, chronic gastrointestinal disease and autoimmune disease. Insertion of CGMS for measuring interstitial glucose was performed after at least 2 weeks of Ramadan fasting and 4 weeks after the end of the Ramadan fasting, with a minimum of 3 days observation. The mean amplitude of glycemic excursion (MAGE) during and after Ramadan were similar (p = 0.94). In line with this, the average interstitial glucose (p = 0.48), the maximum interstitial glucose (p = 0.35), the minimum interstitial glucose (p = 0.24), and the duration of hypoglycemia (p = 0.25) were also similar in both periods. Overall, nutritional intake and energy expenditure during both periods were comparable. Ramadan fasting is not associated with increased glucose variability in subjects with type 2 diabetes. Thus, Ramadan fasting is safe in subjects with type 2 diabetes with no complications.


Assuntos
Glicemia/fisiologia , Diabetes Mellitus Tipo 2/sangue , Jejum/fisiologia , Hipoglicemiantes/administração & dosagem , Islamismo , Administração Oral , Glicemia/análise , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético/fisiologia , Feminino , Humanos , Indonésia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial , Estudos Prospectivos
16.
Proc Natl Acad Sci U S A ; 117(25): 14473-14481, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513737

RESUMO

Hypothalamic tanycytes are chemosensitive glial cells that contact the cerebrospinal fluid in the third ventricle and send processes into the hypothalamic parenchyma. To test whether they can activate neurons of the arcuate nucleus, we targeted expression of a Ca2+-permeable channelrhodopsin (CatCh) specifically to tanycytes. Activation of tanycytes ex vivo depolarized orexigenic (neuropeptide Y/agouti-related protein; NPY/AgRP) and anorexigenic (proopiomelanocortin; POMC) neurons via an ATP-dependent mechanism. In vivo, activation of tanycytes triggered acute hyperphagia only in the fed state during the inactive phase of the light-dark cycle.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiopatologia , Células Ependimogliais/fisiologia , Hiperfagia/fisiopatologia , Neurônios/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Apetite/fisiologia , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/diagnóstico por imagem , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Genes Reporter , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Rede Nervosa/fisiologia , Neuropeptídeo Y/metabolismo , Imagem Óptica , Optogenética , Técnicas de Patch-Clamp , Pró-Opiomelanocortina/metabolismo , Técnicas Estereotáxicas
17.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R171-R183, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32551825

RESUMO

Exercise is often used as a strategy for weight loss maintenance. In preclinical models, we have shown that exercise may be beneficial because it counters the biological drive to regain weight. However, our studies have demonstrated sex differences in the response to exercise in this context. In the present study, we sought to better understand why females and males exhibit different compensatory food eating behaviors in response to regular exercise. Using a forced treadmill exercise paradigm, we measured weight gain, energy expenditure, food intake in real time, and the anorectic effects of leptin. The 4-wk exercise training resulted in reduced weight gain in males and sustained weight gain in females. In male rats, exercise decreased intake, whereas it increased food intake in females. Our results suggest that the anorectic effects of leptin were not responsible for these sex differences in appetite in response to exercise. If these results translate to the human condition, they may reveal important information for the use and application of regular exercise programs.


Assuntos
Apetite/fisiologia , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Ingestão de Energia/fisiologia , Feminino , Masculino , Ratos
18.
Nature ; 583(7814): 115-121, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32528180

RESUMO

The advent of endothermy, which is achieved through the continuous homeostatic regulation of body temperature and metabolism1,2, is a defining feature of mammalian and avian evolution. However, when challenged by food deprivation or harsh environmental conditions, many mammalian species initiate adaptive energy-conserving survival strategies-including torpor and hibernation-during which their body temperature decreases far below its homeostatic set-point3-5. How homeothermic mammals initiate and regulate these hypothermic states remains largely unknown. Here we show that entry into mouse torpor, a fasting-induced state with a greatly decreased metabolic rate and a body temperature as low as 20 °C6, is regulated by neurons in the medial and lateral preoptic area of the hypothalamus. We show that restimulation of neurons that were activated during a previous bout of torpor is sufficient to initiate the key features of torpor, even in mice that are not calorically restricted. Among these neurons we identify a population of glutamatergic Adcyap1-positive cells, the activity of which accurately determines when mice naturally initiate and exit torpor, and the inhibition of which disrupts the natural process of torpor entry, maintenance and arousal. Taken together, our results reveal a specific neuronal population in the mouse hypothalamus that serves as a core regulator of torpor. This work forms a basis for the future exploration of mechanisms and circuitry that regulate extreme hypothermic and hypometabolic states, and enables genetic access to monitor, initiate, manipulate and study these ancient adaptations of homeotherm biology.


Assuntos
Metabolismo Energético/fisiologia , Hipotálamo/citologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Torpor/fisiologia , Animais , Jejum , Feminino , Privação de Alimentos , Glutamina/metabolismo , Hipotálamo/fisiologia , Masculino , Camundongos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo
19.
Toxicol Appl Pharmacol ; 401: 115076, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479918

RESUMO

Statin induced myopathy (SIM) is a main deleterious effect leading to the poor treatment compliance, while the preventive or therapeutic treatments are absent. Mounting evidences demonstrated that vitamin D plays a vital role in muscle as a direct modulator. The deficiency of vitamin D was considered as a cause of muscle dysfunction, whereas the supplementation resulted in a remission. However, there is no causal proof that vitamin D supplementation rescues SIM. Here, using the mice model of simvastatin-induced myopathy, we investigated the role of vitamin D supplementation and the mechanisms associated with mitochondria. Results indicated that simvastatin administration (80 mg/kg) impaired skeletal muscle with the increased serum creatine kinase (CK) level and the declined grip strength, which were alleviated by vitamin D supplementation. Moreover, vitamin D supplementation rescued the energy metabolism dysfunction in simvastatin-treated mice gastrocnemius by reducing the abnormal aggregation of muscular glycogen and lactic acid. Mitochondrial homeostasis plays a key role in the process of energy metabolism. Thus, the mitochondrial dysfunction is a mortal damage for the highly energy-requiring tissue. In our study, the mitochondrial cristae observed under transmission electron microscope (TEM) were lytic in simvastatin-treated gastrocnemius. Interestingly, vitamin D supplementation improved the mitochondrial cristae shape by regulating the expression of mitofusin-1/2 (MFN1/2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (Drp1). As expected, the mitochondrial dysfunction and oxidative stress was mitigated by vitamin D supplementation. In conclusion, these findings suggested that moderate vitamin D supplementation rescued simvastatin induced myopathy via improving the mitochondrial cristae shape and function.


Assuntos
Suplementos Nutricionais , Mitocôndrias/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Sinvastatina/toxicidade , Vitamina D/administração & dosagem , Animais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Doenças Musculares/metabolismo , Distribuição Aleatória
20.
PLoS One ; 15(6): e0235144, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579613

RESUMO

BACKGROUND: Commercial physical activity monitors have wide utility in the assessment of physical activity in research and clinical settings, however, the removal of devices results in missing data and has the potential to bias study conclusions. This study aimed to evaluate methods to address missingness in data collected from commercial activity monitors. METHODS: This study utilised 1526 days of near complete data from 109 adults participating in a European weight loss maintenance study (NoHoW). We conducted simulation experiments to test a novel scaling methodology (NoHoW method) and alternative imputation strategies (overall/individual mean imputation, overall/individual multiple imputation, Kalman imputation and random forest imputation). Methods were compared for hourly, daily and 14-day physical activity estimates for steps, total daily energy expenditure (TDEE) and time in physical activity categories. In a second simulation study, individual multiple imputation, Kalman imputation and the NoHoW method were tested at different positions and quantities of missingness. Equivalence testing and root mean squared error (RMSE) were used to evaluate the ability of each of the strategies relative to the true data. RESULTS: The NoHoW method, Kalman imputation and multiple imputation methods remained statistically equivalent (p<0.05) for all physical activity metrics at the 14-day level. In the second simulation study, RMSE tended to increase with increased missingness. Multiple imputation showed the smallest RMSE for Steps and TDEE at lower levels of missingness (<19%) and the Kalman and NoHoW methods were generally superior for imputing time in physical activity categories. CONCLUSION: Individual centred imputation approaches (NoHoW method, Kalman imputation and individual Multiple imputation) offer an effective means to reduce the biases associated with missing data from activity monitors and maximise data retention.


Assuntos
Exercício Físico/fisiologia , Monitores de Aptidão Física/estatística & dados numéricos , Monitorização Fisiológica/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Adulto , Idoso , Algoritmos , Viés , Peso Corporal/fisiologia , Simulação por Computador , Metabolismo Energético/fisiologia , Feminino , Monitores de Aptidão Física/normas , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Projetos de Pesquisa/normas , Perda de Peso/fisiologia , Adulto Jovem
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