RESUMEN
Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.
Asunto(s)
Tejido Adiposo Pardo , Proteoma , Humanos , Ratones , Animales , Tejido Adiposo Pardo/metabolismo , Proteoma/metabolismo , Termogénesis/fisiología , Adiposidad , Obesidad/metabolismo , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology, and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we 1) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; 2) discuss the interaction between circadian molecular metabolism and TRE; 3) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; 4) summarize other time-related dietary interventions that have been studied in people; and 4) identify current gaps in knowledge and provide a framework for future research directions.
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Ritmo Circadiano , Ayuno , Peso Corporal , Ritmo Circadiano/fisiología , Ingestión de Alimentos , Ayuno/fisiología , HumanosRESUMEN
Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Metabolismo Energético , Homeostasis , Proteínas Mitocondriales/metabolismo , Proteínas Transportadoras de Solutos/metabolismo , Termogénesis , Tejido Adiposo Pardo/citología , Animales , Frío , Intolerancia a la Glucosa/metabolismo , Humanos , Masculino , Ratones , Mitocondrias/metabolismo , Obesidad/metabolismoRESUMEN
OBJECTIVE: Chronic kidney disease (CKD) is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. METHODS: Using targeted metabolic profiling, we studied the plasma metabolome response in 41 moderate-to-severe nondiabetic CKD patients and 20 healthy controls at fasting and 2 hours after an oral glucose load. We used linear mixed modeling with random intercepts, adjusting for age, gender, race/ethnicity, body weight, and batch to assess heterogeneity in response to OGTT by CKD status. RESULTS: Mean estimated glomerular filtration rate among CKD participants was 38.9 ± 12.7 mL/min per 1.73 m2 compared to 87.2 ± 17.7 mL/min per 1.73 m2 among controls. Glucose ingestion induced an anabolic response resulting in increased glycolysis products and a reduction in a wide range of metabolites including amino acids, tricarboxylic acid cycle intermediates, and purine nucleotides compared to fasting. Participants with CKD demonstrated a blunted anabolic response to OGTT evidenced by significant changes in 13 metabolites compared to controls. The attenuated metabolome response predominant involved mitochondrial energy metabolism, vitamin B family, and purine nucleotides. Compared to controls, CKD participants had elevated lactate:pyruvate (L:P) ratio and decreased guanosine diphosphate:guanosine triphosphate ratio during OGTT. CONCLUSION: Metabolic profiling of OGTT response suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into the impact of insulin sensitizers and mitochondrial targeted therapeutics on energy metabolism in patients with nondiabetic CKD.
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Resistencia a la Insulina , Insuficiencia Renal Crónica , Humanos , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina/fisiología , Insulina , Glucosa , Metaboloma , Glucemia/metabolismoRESUMEN
Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of ß-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.
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Adaptación Fisiológica , Tejido Adiposo Pardo/metabolismo , Metabolismo Energético , Homeostasis , NAD/biosíntesis , Termogénesis , Tejido Adiposo Pardo/enzimología , Animales , Caveolina 1/antagonistas & inhibidores , Frío , Citocinas/genética , Ayuno , Humanos , Ratones , Ratones Noqueados , Mononucleótido de Nicotinamida/administración & dosificación , Nicotinamida Fosforribosiltransferasa/genéticaRESUMEN
PURPOSE OF REVIEW: Brown adipose tissue (BAT) and the thermogenic adipocytes in white adipose tissue (WAT) are considered emerging targets against obesity-related metabolic perturbations given their high capacity for thermogenesis and glucose and lipid disposal. This manuscript summarizes and critically evaluates the recent advances on the role of BAT and thermogenic adipocytes in glucose homeostasis in humans. RECENT FINDINGS: Recent studies support that BAT has high capacity for glucose disposal not only during cold but during rewarming and thermoneutrality as well. Moreover, BAT is now considered a metabolic sink for the disposal of branched-chain amino acids improving whole-body glucose metabolism in rodents and, potentially, in humans. ß3 adrenergic agonism and glucagon-like peptide 1 increase BAT metabolic activity for glucose and/or induce the browning of WAT. Finally, recent findings support the association of glucose disposal in BAT with subclinical atherosclerosis and the reproducibility of two advanced medical imaging methods for the assessment of BAT using a glucose radiotracer. SUMMARY: Recent studies provide new insights on the role of human BAT and thermogenic adipocytes in glucose metabolism. However, further research is needed to unequivocally establish the clinical significance of BAT and the thermogenic adipocytes in glucose homeostasis in humans.
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Adipocitos/metabolismo , Tejido Adiposo Pardo/citología , Metabolismo de los Hidratos de Carbono/fisiología , Glucosa/metabolismo , Termogénesis/fisiología , Homeostasis , HumanosRESUMEN
PURPOSE OF REVIEW: Intermittent fasting has been proposed as a potential nutrition approach against obesity and metabolic disease. Although data from studies in rodents convincingly support the antiobesity and cardiometabolic benefits of intermittent fasting, its effects in human health are still debatable. RECENT FINDINGS: Recent studies have examined the effect of two intermittent fasting approaches, that is, alternate day fasting (ADF) and time-restricted eating (TRE), on weight loss and cardiometabolic risk factors. ADF seems to be an equally effective weight loss approach to caloric restriction, but adherence to ADF is more challenging. ADF improves cardiometabolic risk factors, whereas it may have superior metabolic benefits compared to caloric restriction in people with insulin resistance. TRE with ad libitum food intake is well tolerated and induces 2-4% weight loss in approximatively 3 months. Additionally, TRE may have metabolic benefits particularly in people with metabolically abnormal obesity even without weight loss. SUMMARY: Intermittent fasting is a promising nutritional approach against obesity and its related metabolic diseases. Further research is needed to: i) establish the long-term effectiveness of TRE in weight loss and metabolic health, ii) improve the long-term adherence to ADF and investigate its weight loss independent effects in metabolic health, and iii) determine the mechanisms underlying the potential cardiometabolic benefits of intermittent fasting in humans.
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Restricción Calórica/métodos , Ayuno/metabolismo , Enfermedades Metabólicas/dietoterapia , Obesidad/dietoterapia , Humanos , Enfermedades Metabólicas/fisiopatología , Obesidad/fisiopatología , Pérdida de PesoRESUMEN
Intramyocellular triglyceride (imTG) in skeletal muscle plays a significant role in metabolic health, and an infusion of [13C16]palmitate can be used to quantitate the in vivo fractional synthesis rate (FSR) and absolute synthesis rate (ASR) of imTGs. However, the extramyocellular TG (emTG) pool, unless precisely excised, contaminates the imTG pool, diluting the imTG-bound tracer enrichment and leading to underestimation of FSR. Because of the difficulty of excising the emTGs precisely, it would be advantageous to be able to calculate the imTG synthesis rate without dissecting the emTGs from each sample. Here, we tested the hypothesis that the ASR of total TGs (tTGs), a combination of imTGs and emTGs, calculated as "FSR × tTG pool," reasonably represents the imTG synthesis. Muscle lipid parameters were measured in nine healthy women at 90 and 170 min after the start of [13C16]palmitate infusion. While the measurements of tTG content, enrichment, and FSR did not correlate (P > 0.05), those of the tTG ASR were significantly correlated (r = 0.947, P < 0.05). These results demonstrate that when imTGs and emTGs are pooled, the resulting underestimation of imTG FSR is balanced by the overestimation of the imTG content. We conclude that imTG metabolism is reflected by the measurement of the tTG ASR.
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Músculo Esquelético/metabolismo , Triglicéridos/biosíntesis , Triglicéridos/sangre , Artefactos , Femenino , Voluntarios Sanos , Humanos , Cinética , Persona de Mediana EdadRESUMEN
Brown adipose tissue (BAT) is a recently rediscovered tissue in people that has shown promise as a potential therapeutic target against obesity and its metabolic abnormalities. Reliable non-invasive assessment of BAT volume and activity is critical to allow its importance in metabolic control to be evaluated. Positron emission tomography/computed tomography (PET/CT) in combination with 2-deoxy-2-[18 F]fluoroglucose administration is currently the most frequently used and most established method for the detection and quantification of activated BAT in humans. However, it involves radiation exposure and can detect activated (e.g. after cold exposure), but not quiescent, BAT. Several alternative methods that overcome some of these limitations have been developed including different PET approaches, single-photon emission imaging, CT, magnetic resonance based approaches, contrast-enhanced ultrasound, near infrared spectroscopy, and temperature assessment of fat depots containing brown adipocytes. The purpose of this review is to summarize and critically evaluate the currently available methods that non-invasively probe various aspects of BAT biology in order to assess BAT volume and/or metabolism. Although several of these methods show promise for the non-invasive assessment of BAT volume and function, further research is needed to optimize them to enable an accurate, reproducible and practical means for the assessment of human BAT content and its metabolic function.
Asunto(s)
Tejido Adiposo Pardo/diagnóstico por imagen , Diagnóstico por Imagen/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Enfermedades Metabólicas/diagnóstico por imagen , Obesidad/diagnóstico por imagen , Animales , HumanosRESUMEN
PURPOSE: Lifestyle (diet and physical activity) may increase asthma risk, but evidence in this area is lacking. The aims of the present study were to calculate an obesity-preventive lifestyle score comprising of eating and physical activity behaviors and investigate the overall effect of lifestyle on asthma in children. METHODS: A cross-sectional case-control study was carried out in 514 children (217 asthma cases and 297 healthy controls). Data were collected on medical history, anthropometry, dietary intake, and physical activity. We constructed an overweight/obesity-preventive score (OPLS) using study-specific quartile rankings for nine target lifestyle behaviors that were either favorable or unfavorable in preventing obesity (i.e., screen time was an unfavorable lifestyle behavior). The score was developed using the recommendations of the Expert Committee of American Academy of Pediatrics. Score values ranged from 0-18 points; the higher the score, the more protective against high body weight. RESULTS: The OPLS was negatively associated with obesity indices (BMI, waist circumference, and hip circumference), (p < 0.05). Control children had a higher score when compared to asthma cases (9.3 ± 2.7 vs. 8.6 ± 2.9, p = 0.007). A high OPLS was protective against physician-diagnosed asthma (OR 0.92; 95% CI 0.86-0.98, p = 0.014), adjusted for several confounders. The OPLS was no longer protective after adjustment for BMI. CONCLUSION: Higher adherence to an obesity-preventive lifestyle score-consistent with several behaviors for the prevention of childhood overweight/obesity-is negatively associated with obesity indices and lowers the odds for asthma in children. Lifestyle behaviors that contribute to a higher body weight may contribute to the obesity-asthma link. These findings are hypothesis-generating and warrant further investigation in prospective intervention studies.
Asunto(s)
Asma/prevención & control , Estilo de Vida , Obesidad Infantil/prevención & control , Asma/epidemiología , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Dieta , Femenino , Grecia , Humanos , Masculino , Obesidad , Sobrepeso , Obesidad Infantil/epidemiología , Estudios ProspectivosRESUMEN
Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients (n = 14) with burns covering >30% of their total body surface area were studied. Controls (n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria. In skeletal muscle of burn patients, concurrent activation of mTORC1 signaling and elevation in the fractional synthetic rate paralleled increased levels of proteasomes and elevated fractional breakdown rate. Burn patients had greater levels of oxidative stress markers as well as higher expression of mtUPR-related genes and proteins, suggesting that burns increased mitochondrial stress and protein damage. Indeed, upregulation of cytoprotective genes suggests hypermetabolism-induced oxidative stress postburn. In parallel to mtUPR activation postburn, mitochondrial-specific proteases (LONP1 and CLPP) and mitochondrial translocases (TIM23, TIM17B, and TOM40) were upregulated, suggesting increased mitochondrial protein degradation and transport of preprotein, respectively. Our data demonstrate that proteolysis occurs in both the cytosolic and mitochondrial compartments of skeletal muscle in severely burned patients. Increased mitochondrial protein turnover may be associated with increased protein damage due to hypermetabolism-induced oxidative stress and activation of mtUPR. Our results suggest a novel role for the mitochondria in burn-induced cachexia.
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Quemaduras/metabolismo , Caquexia/metabolismo , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Estrés Oxidativo , Consumo de Oxígeno , ARN Mensajero/metabolismo , Proteasas ATP-Dependientes/genética , Proteasas ATP-Dependientes/metabolismo , Adolescente , Adulto , Western Blotting , Superficie Corporal , Quemaduras/complicaciones , Quemaduras/genética , Caquexia/etiología , Caquexia/genética , Estudios de Casos y Controles , Endopeptidasa Clp/genética , Endopeptidasa Clp/metabolismo , Femenino , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolismo , Persona de Mediana Edad , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteínas Musculares/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba , Adulto JovenRESUMEN
INTRODUCTION: Evidence supports a significant yet weak association between high-body weight and asthma in children. However, most studies investigating the obesity-asthma link use Body Mass Index (BMI) to evaluate body fatness. The relationship between body fat distribution and asthma remains largely unknown, especially in children. This pediatric case-control investigation examined associations between central obesity/high-body weight and asthma diagnosis. METHODS: Five-hundred and fourteen children (217 physician diagnosed asthma cases and 297 healthy controls) of 5-11 years were recruited. Height, weight and waist circumference were measured. Asthma symptoms, past medical history, personal lifestyle, socioeconomic status, diet and physical activity history were also collected. RESULTS: A higher proportion of children with asthma were centrally obese [(≥90th waist percentile) 15.2 vs. 9.4%, p<0.0001; (≥90th waist-to-height ratio percentile) 39.6 vs. 24.2%, p<0.0001)]. Regression analyses revealed that centrally obese children were more likely to have asthma (high-waist circumference (OR = 1.99, 95% CI: 1.07-3.68) and high-waist circumference to height ratio (OR = 2.24, 95% CI: 1.47-3.40), following adjustment for various confounders. Overweight/obese participants (BMI defined) were more likely to be asthmatic [odds ratio (OR) = 1.52, 95% confidence interval (CI): 1.03-2.70)] when compared to controls. CONCLUSIONS: Presence of central obesity and high-body weight (at least overweight) as assessed by waist circumference, waist-to-height ratio, and BMI are associated with asthma diagnosis. More studies are needed, especially in children and adolescents, to confirm these findings and better understand how body fat distribution impacts the obesity-asthma relationship.
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Asma/epidemiología , Obesidad Abdominal/epidemiología , Obesidad Infantil/epidemiología , Factores de Edad , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Preescolar , Dieta , Ejercicio Físico , Femenino , Conductas Relacionadas con la Salud , Humanos , Estilo de Vida , Masculino , Sobrepeso/epidemiología , Factores de Riesgo , Factores Sexuales , Factores Socioeconómicos , Circunferencia de la CinturaRESUMEN
Elevated metabolic rate is a hallmark of the stress response to severe burn injury. This response is mediated in part by adrenergic stress and is responsive to changes in ambient temperature. We hypothesize that uncoupling of oxidative phosphorylation in skeletal muscle mitochondria contributes to increased metabolic rate in burn survivors. Here, we determined skeletal muscle mitochondrial function in healthy and severely burned adults. Indirect calorimetry was used to estimate metabolic rate in burn patients. Quadriceps muscle biopsies were collected on two separate occasions (11 ± 5 and 21 ± 8 days postinjury) from six severely burned adults (68 ± 19% of total body surface area burned) and 12 healthy adults. Leak, coupled, and uncoupled mitochondrial respiration was determined in permeabilized myofiber bundles. Metabolic rate was significantly greater than predicted values for burn patients at both time points (P < 0.05). Skeletal muscle oxidative capacity, citrate synthase activity, a marker of mitochondrial abundance, and mitochondrial sensitivity to oligomycin were all lower in burn patients vs. controls at both time points (P < 0.05). A greater proportion of maximal mitochondrial respiration was linked to thermogenesis in burn patients compared with controls (P < 0.05). Increased metabolic rate in severely burned adults is accompanied by derangements in skeletal muscle mitochondrial function. Skeletal muscle mitochondria from burn victims are more uncoupled, indicating greater heat production within skeletal muscle. Our findings suggest that skeletal muscle mitochondrial dysfunction contributes to increased metabolic rate in burn victims.
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Quemaduras/complicaciones , Quemaduras/metabolismo , Mitocondrias Musculares/fisiología , Enfermedades Mitocondriales/etiología , Músculo Esquelético/metabolismo , Adulto , Metabolismo Basal , Biopsia , Quemaduras/patología , Estudios de Casos y Controles , Respiración de la Célula , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Descanso , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).
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Ácidos Grasos no Esterificados , Sobrepeso , Humanos , Femenino , Tejido Adiposo Pardo/diagnóstico por imagen , Obesidad , Triglicéridos , Lipoproteínas VLDLRESUMEN
Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPß was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPß in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPß-dependent and HDAC3-independent cold-adaptive epigenomic memory.
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Tejido Adiposo Pardo , Frío , Histona Desacetilasas , Ratones Noqueados , Animales , Tejido Adiposo Pardo/metabolismo , Histona Desacetilasas/metabolismo , Ratones , Humanos , Termogénesis/genética , Ratones Endogámicos C57BL , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Masculino , Epigenómica , Epigénesis GenéticaRESUMEN
Brown adipose tissue (BAT) in rodents appears to be an important tissue for the clearance of plasma branched-chain amino acids (BCAAs) contributing to improved metabolic health. However, the role of human BAT in plasma BCAA clearance is poorly understood. Here, we evaluate patients with prostate cancer who underwent positron emission tomography-computed tomography imaging after an injection of 18F-fluciclovine (L-leucine analog). Supraclavicular adipose tissue (AT; primary location of human BAT) has a higher net uptake rate for 18F-fluciclovine compared to subcutaneous abdominal and upper chest AT. Supraclavicular AT 18F-fluciclovine net uptake rate is lower in patients with obesity and type 2 diabetes. Finally, the expression of genes involved in BCAA catabolism is higher in the supraclavicular AT of healthy people with high BAT volume compared to those with low BAT volume. These findings support the notion that BAT can potentially function as a metabolic sink for plasma BCAA clearance in people.
RESUMEN
Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of ß-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and ß3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
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Creatina , Termogénesis , Creatina/metabolismo , Termogénesis/genética , Adipocitos/metabolismo , Metabolismo Energético/genética , Creatina Quinasa/metabolismoRESUMEN
Brown adipose tissue (BAT) is an emerging target against obesity and its related metabolic diseases. Wibmer et al.1 recently reported that human BAT is associated with a healthier fat distribution and improved cardiometabolic health independent of adiposity and fat distribution.
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Enfermedades Cardiovasculares , Enfermedades Metabólicas , Tejido Adiposo Pardo/metabolismo , Adiposidad , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Metabólicas/metabolismo , Obesidad/metabolismoRESUMEN
Obesity and associated metabolic syndrome are a global public health issue. Understanding the pathophysiology of this systemic disease is of critical importance for the development of future therapeutic interventions to improve clinical outcomes. The multiorgan nature of the pathophysiology of obesity presents a unique challenge. Total-body PET imaging, either static or dynamic, provides a vital set of tools to study organ crosstalk. The visualization and quantification of tissue metabolic kinetics with total-body PET in health and disease provides essential information to better understand disease physiology and potentially develop diagnostic and therapeutic modalities.
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Enfermedades Metabólicas/diagnóstico por imagen , Obesidad/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Imagen de Cuerpo Entero/métodos , HumanosRESUMEN
Hyperglycemia during pregnancy and gestational diabetes mellitus (GDM) constitute an important public health problem due to their prevalence and long-term health consequences both for the mother and offspring. Results from studies in rodents and some clinical investigations suggest that meal time manipulation may be a potential lifestyle approach against conditions involving perturbations in glucose homeostasis (e.g., hyperglycemia, insulin resistance, diabetes, etc.). The purpose of this review is to summarize and critically evaluate the current literature on the role of meal timing and daily nutrient distribution on glycemic control during pregnancy. Only a small number of mostly observational studies have assessed the role of meal timing in glucose homeostasis during pregnancy. Food consumption earlier in the day and short-term fasting with adequate nutrient intake may improve glycemic control during the second and third trimester of gestation. Considering that the field of chrononutrition is still in its infancy and many questions remain unanswered, future prospective and carefully designed studies are needed to better understand the role of meal timing in metabolic homeostasis and maternal and fetal health outcomes during pregnancy.