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1.
Arch Dis Child ; 108(7): 545-549, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36863849

RESUMO

OBJECTIVE: Reference centile charts are widely used for the assessment of growth and have progressed from describing height and weight to include body composition variables such as fat and lean mass. Here, we present centile charts for an index of resting energy expenditure (REE) or metabolic rate, adjusted for lean mass versus age, including both children and adults across the life course. DESIGN, PARTICIPANTS AND INTERVENTION: Measurements of REE by indirect calorimetry and body composition using dual-energy X-ray absorptiometry were made in 411 healthy children and adults (age range 6-64 years) and serially in a patient with resistance to thyroid hormone α (RTHα) between age 15 and 21 years during thyroxine therapy. SETTING: NIHR Cambridge Clinical Research Facility, UK. RESULTS: The centile chart indicates substantial variability, with the REE index ranging between 0.41 and 0.59 units at age 6 years, and 0.28 and 0.40 units at age 25 years (2nd and 98th centile, respectively). The 50th centile of the index ranged from 0.49 units (age 6 years) to 0.34 units (age 25 years). Over 6 years, the REE index of the patient with RTHα varied from 0.35 units (25th centile) to 0.28 units (<2nd centile), depending on changes in lean mass and adherence to treatment. CONCLUSION: We have developed a reference centile chart for an index of resting metabolic rate in childhood and adults, and shown its clinical utility in assessing response to therapy of an endocrine disorder during a patient's transition from childhood to adult.


Assuntos
Metabolismo Basal , Acontecimentos que Mudam a Vida , Criança , Adulto , Humanos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Metabolismo Energético , Peso Corporal , Composição Corporal , Absorciometria de Fóton , Índice de Massa Corporal
2.
Obesity (Silver Spring) ; 28(9): 1613-1625, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32841524

RESUMO

Whole-room indirect calorimeters have been used to study human metabolism for more than a century. These studies have contributed substantial knowledge to the assessment of nutritional needs and the regulation of energy expenditure and substrate oxidation in humans. However, comparing results from studies conducted at different sites is challenging because of a lack of consistency in reporting technical performance, study design, and results. In May 2019, an expert panel was convened to consider minimal requirements for conducting and reporting the results of human whole-room indirect calorimeter studies. We propose Room Indirect Calorimetry Operating and Reporting Standards, version 1.0 (RICORS 1.0) to provide guidance to ensure consistency and facilitate meaningful comparisons of human energy metabolism studies across publications, laboratories, and clinical sites.


Assuntos
Calorimetria Indireta/métodos , Metabolismo Energético/fisiologia , Padrões de Referência , Humanos
3.
Am J Clin Nutr ; 110(5): 1186-1191, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31410443

RESUMO

BACKGROUND: Energy expenditure prediction equations are used to estimate energy intake based on general population measures. However, when using equations to compare with a disease cohort with known metabolic abnormalities, it is important to derive one's own equations based on measurement conditions matching the disease cohort. OBJECTIVE: We aimed to use newly developed prediction equations based on a healthy pediatric population to describe and predict resting energy expenditure (REE) in a cohort of pediatric patients with thyroid disorders. METHODS: Body composition was measured by DXA and REE was assessed by indirect calorimetry in 201 healthy participants. A prediction equation for REE was derived in 100 healthy participants using multiple linear regression and z scores were calculated. The equation was validated in 101 healthy participants. This method was applied to participants with resistance to thyroid hormone (RTH) disorders, due to mutations in either thyroid hormone receptor ß or α (ß: female n = 17, male n = 9; α: female n = 1, male n = 1), with deviation of REE in patients compared with the healthy population presented by the difference in z scores. RESULTS: The prediction equation for REE = 0.061 * Lean soft tissue (kg) - 0.138 * Sex (0 male, 1 female) + 2.41 (R2 = 0.816). The mean ± SD of the residuals is -0.02 ± 0.44 kJ/min. Mean ± SD REE z scores for RTHß patients are -0.02 ± 1.26. z Scores of -1.69 and -2.05 were recorded in male (n = 1) and female ( n = 1) RTHα patients. CONCLUSIONS: We have described methodology whereby differences in REE between patients with a metabolic disorder and healthy participants can be expressed as a z score. This approach also enables change in REE after a clinical intervention (e.g., thyroxine treatment of RTHα) to be monitored.


Assuntos
Metabolismo Energético , Doenças Metabólicas/terapia , Estado Pré-Diabético/terapia , Adolescente , Metabolismo Basal , Composição Corporal , Criança , Feminino , Humanos , Masculino , Doenças Metabólicas/metabolismo , Estado Pré-Diabético/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/terapia
4.
Mol Metab ; 13: 24-29, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29789270

RESUMO

OBJECTIVE: Surplus dietary fat cannot be converted into other macronutrient forms or excreted, so has to be stored or oxidized. Healthy mammals store excess energy in the form of triacylgycerol (TAG) in lipid droplets within adipocytes rather than oxidizing it, and thus ultimately gain weight. The 'overflow hypothesis' posits that the capacity to increase the size and number of adipocytes is finite and that when this limit is exceeded, fat accumulates in ectopic sites and leads to metabolic disease. METHODS: Here we studied the energetic and biochemical consequences of short-term (2-day) excess fat ingestion in a lipodystrophic (A-ZIP/F-1) mouse model in which adipose capacity is severely restricted. RESULTS: In wildtype littermates, this acute exposure to high fat diets resulted in excess energy intake and weight gain without any significant changes in macronutrient oxidation rates, glucose, TAG, or insulin levels. In contrast, hyperphagic lipodystrophic mice failed to gain weight; rather, they significantly increased hepatic steatosis and fat oxidation. This response was associated with a significant increase in hyperglycemia, hyperinsulinemia, glucosuria, hypertriglyceridemia, and worsening insulin tolerance. CONCLUSIONS: These data suggest that when adipose storage reserves are saturated, excess fat intake necessarily increases fat oxidation and induces oxidative substrate competition which exacerbates insulin resistance resolving any residual energy surplus through excretion of glucose.


Assuntos
Gorduras na Dieta/metabolismo , Lipídeos/fisiologia , Lipodistrofia/metabolismo , Adipócitos , Tecido Adiposo , Adiposidade , Animais , Dieta Hiperlipídica , Ingestão de Energia , Metabolismo Energético , Fígado Gorduroso , Glucose , Hiperinsulinismo , Resistência à Insulina/fisiologia , Lipodistrofia/fisiopatologia , Fígado , Camundongos , Obesidade , Oxirredução , Aumento de Peso
6.
Am J Clin Nutr ; 106(5): 1197-1205, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29070564

RESUMO

Background: Induction of nonshivering thermogenesis can be used to influence energy balance to prevent or even treat obesity. The pungent component of mustard, allyl-isothiocyanate (AITC), activates the extreme cold receptor transient receptor potential channel, subfamily A, member 1 and may thus induce energy expenditure and metabolic changes.Objective: The objective of our study was to evaluate the potential of mustard AITC to induce thermogenesis (primary outcome) and alter body temperature, cold and hunger sensations, plasma metabolic parameters, and energy intake (secondary outcomes).Design: Energy expenditure in mice was measured after subcutaneous injection with vehicle, 1 mg norepinephrine/kg, or 5 mg AITC/kg. In our human crossover study, 11 healthy subjects were studied under temperature-controlled conditions after an overnight fast. After ingestion of 10 g of capsulated mustard or uncapsulated mustard or a capsulated placebo mixture, measurements of energy expenditure, substrate oxidation, core temperature, cold and hunger scores, and plasma parameters were repeated every 30 min during a 150-min period. Subjects were randomly selected for the placebo and capsulated mustard intervention; 9 of 11 subjects received the uncapsulated mustard as the final intervention because this could not be blinded. After the experiments, energy intake was measured with the universal eating monitor in a test meal.Results: In mice, AITC administration induced a 32% increase in energy expenditure compared with vehicle (17.5 ± 4.9 J · min-1 · mouse-1 compared with 12.5 ± 1.2 J · min-1 · mouse-1, P = 0.03). Of the 11 randomly selected participants, 1 was excluded because of intercurrent illness after the first visit and 1 withdrew after the second visit. Energy expenditure did not increase after ingestion of capsulated or uncapsulated mustard compared with placebo. No differences in substrate oxidation, core temperature, cold and hunger scores, or plasma parameters were found, nor was the energy intake at the end of the experiment different between the 3 conditions.Conclusion: The highest tolerable dose of mustard we were able to use did not elicit a relevant thermogenic response in humans. This trial was registered at www.controlled-trials.com as ISRCTN19147515.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Fome/efeitos dos fármacos , Isotiocianatos/farmacologia , Mostardeira/química , Termogênese/efeitos dos fármacos , Adolescente , Adulto , Idoso , Animais , Glicemia/metabolismo , Estudos Cross-Over , Ingestão de Energia , Metabolismo Energético , Feminino , Humanos , Isotiocianatos/análise , Masculino , Camundongos , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Consumo de Oxigênio , Adulto Jovem
7.
J Clin Densitom ; 20(4): 498-506, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28756995

RESUMO

We describe a study to assess the precision of the GE Lunar iDXA and the agreement between the iDXA and GE Lunar Prodigy densitometers for the measurement of regional- and total-body bone and body composition in normal to obese healthy adults. We compare the whole-body fat mass by dual-energy X-ray absorptiometry (DXA) to measurements by a 4-component (4-C) model. Sixty-nine participants, aged 37 ± 12 yr, with a body mass index of 26.2 ± 5.1 kg/cm2, were measured once on the Prodigy and twice on the iDXA. The 4-C model estimated fat mass from body mass, total body water by deuterium dilution, body volume by air displacement plethysmography, and bone mass by DXA. Agreements between measurements made on the 2 instruments and by the 4-C model were analyzed by Bland-Altman and linear regression analyses. Where appropriate, translational cross-calibration equations were derived. Differences between DXA software versions were investigated. iDXA precision was less than 2% of the measured value for all regional- and whole-body bone and body composition measurements with the exception of arm fat mass (2.28%). We found significant differences between iDXA and Prodigy (p < 0.05) whole-body and regional bone, fat mass (FM), and lean mass, with the exception of hip bone mass, area and density, and spine area. Compared to iDXA, Prodigy overestimated FM and underestimated lean mass. However, compared to 4-C, iDXA showed a smaller bias and narrower limits of agreement than Prodigy. No significant differences between software versions in FM estimations existed. Our results demonstrate excellent iDXA precision. However, significant differences exist between the 2 GE Lunar instruments, Prodigy and iDXA measurement values. A divergence from the reference 4-C observations remains in FM estimations made by DXA even following the recent advances in technology. Further studies are particularly warranted in individuals with large FM contents.


Assuntos
Absorciometria de Fóton/instrumentação , Adiposidade , Densidade Óssea , Adulto , Idoso , Índice de Massa Corporal , Água Corporal , Quadril , Humanos , Peso Corporal Ideal/fisiologia , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Pletismografia , Análise de Regressão , Reprodutibilidade dos Testes , Coluna Vertebral , Tronco , Adulto Jovem
8.
Clin Endocrinol (Oxf) ; 87(3): 272-278, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28434207

RESUMO

OBJECTIVE: Associations between maternal glucose levels and increased foetal growth are well established, and independent relationships with maternal weight, weight gain and insulin resistance are also observed. The relative roles of lipolysis and glucose production in the determination of these observations remain unclear. DESIGN: We examined, through detailed physiological studies, the relationship between maternal late gestational energy substrate production (glucose and glycerol), maternal weight and weight gain, and estimated foetal size in the third trimester. PATIENTS: Twenty-one nulliparous pregnant women, without gestational diabetes (GDM) assessed at 28 weeks with oral glucose tolerance test, were recruited. MEASUREMENTS: Rates of hepatic glucose production (GPR) and rates of glycerol production (reflecting lipolysis) using [13 C6 ]-glucose and [2 H5 ]-glycerol were measured at 34-36 weeks of gestation. Respiratory quotient was assessed by indirect calorimetry and body composition by measurements of total body water (TBW; H218 O) and body density (BODPOD). Foetal weight was estimated from ultrasound measures of biparietal diameter, femoral length and abdominal circumference. RESULTS: At 34-36 weeks, bivariate analyses showed that GPR and lipolysis correlated with estimated foetal weight (r=.71 and .72, respectively) as well as with maternal weight, fat mass and fat-free mass, but not maternal weight gain. In multivariate analyses, rates of both glucose production (r=.42) and lipolysis (r=.47) were independently associated with foetal size explaining 63% of the variance. CONCLUSIONS: Both maternal rates of lipolysis and hepatic glucose production in late gestation are strongly related to estimated foetal weight.


Assuntos
Peso Fetal , Glucose/biossíntese , Lipólise , Adulto , Feminino , Humanos , Cinética , Fígado/metabolismo , Gravidez , Terceiro Trimestre da Gravidez , Adulto Jovem
9.
Arch Biochem Biophys ; 606: 73-80, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27444119

RESUMO

Acylcarnitines, fatty acid oxidation (FAO) intermediates, have been implicated in diet-induced insulin resistance and type 2 diabetes mellitus, as increased levels are found in obese insulin resistant humans. Moreover plasma acylcarnitines have been associated with clinical parameters related to glucose metabolism, such as fasting glucose levels and HbA1c. We hypothesized that plasma acylcarnitines would correlate with energy expenditure, insulin sensitivity and other clinical parameters before and during a weight loss intervention. We measured plasma acylcarnitines in 60 obese subjects before and after a 12 week weight loss intervention. These samples originated from three different interventions (diet alone (n = 20); diet and exercise (n = 21); diet and drug treatment (n = 19)). Acylcarnitine profiles were analysed in relation to clinical parameters of glucose metabolism, insulin sensitivity and energy expenditure. Conclusions were drawn from all 60 subjects together. Despite amelioration of HOMA-IR, plasma acylcarnitines levels increased during weight loss. HOMA-IR, energy expenditure and respiratory exchange ratio were not related to plasma acylcarnitines. However non-esterified fatty acids correlated strongly with several acylcarnitines at baseline and during the weight loss intervention (p < 0.001). Acylcarnitines did not correlate with clinical parameters of glucose metabolism during weight loss, questioning their role in insulin resistance and type 2 diabetes mellitus.


Assuntos
Carnitina/análogos & derivados , Diabetes Mellitus Tipo 2/sangue , Obesidade/sangue , Redução de Peso , Adulto , Antropometria , Composição Corporal , Carnitina/sangue , Ácidos Graxos/química , Ácidos Graxos não Esterificados/sangue , Feminino , Glucose/química , Humanos , Resistência à Insulina , Lipólise , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Oxigênio/química , Respiração , Adulto Jovem
10.
Ann Neurol ; 78(4): 630-48, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26224419

RESUMO

OBJECTIVE: Huntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage. METHODS: We performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age- and sex-matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x-ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain. RESULTS: Compared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4-7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations. INTERPRETATION: The results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology.


Assuntos
Doenças Assintomáticas , Doença de Huntington/diagnóstico , Doença de Huntington/metabolismo , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/metabolismo , Adulto , Feminino , Humanos , Doença de Huntington/complicações , Masculino , Pessoa de Meia-Idade , Transtornos do Sono-Vigília/etiologia
11.
J Clin Transl Endocrinol ; 1(1): e3-e8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29235586

RESUMO

Inhibitors of sodium-dependent glucose co-transporter 2 (SGLT2) increase glucose excretion in the urine and improve blood glucose in Type 2 diabetes mellitus. Glycosuria provides an energy and osmotic drain that could alter body composition. We therefore conducted a pilot study comparing the effects on body composition of two SGLT2 inhibitors, remogliflozin etabonate (RE) 250 mg TID (n = 9) and sergliflozin etabonate (SE) (1000 mg TID) (n = 9), with placebo (n = 12) in obese non-diabetic subjects. Both drugs were well tolerated during 8 weeks of dosing, and the most common adverse event was headache. No urinary tract infections were observed, but there was one case of vaginal candidiasis in the RE group. As expected, RE and SE increased urine glucose excretion, with no change in the placebo group. All the subjects lost weight over 8 weeks, irrespective of treatment assignment. There was a reduction in TBW measured by D2O dilution in the RE group that was significantly greater than placebo (1.4 kg, p = 0.029). This was corroborated by calculation of fat-free mass using a quantitative magnetic resonance technique. All but one subject had a measurable decrease in fat mass. There was significant between-subject variability of weight and fat loss, and no statistically significant differences were observed between groups. Despite a lack of a difference in weight and fat mass loss, the leptin/adiponectin ratio, a measure of insulin resistance, was significantly decreased in the RE group when compared to placebo and SE, suggesting that this SGTL-2 inhibitor may improve metabolic health independent of a change in fat mass.

12.
Br J Nutr ; 110(6): 1061-7, 2013 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23388346

RESUMO

Few studies have investigated the effects of infant nutrition on later bone health in term infants, although low sn-2 palmitate in infant formulas has been shown to result in the formation of stool fatty acid soaps, reduced Ca absorption and lower bone mass in the short term. To investigate the effect of (1) breast-feeding (BF) and (2) the type of infant formula (standard fat blend v. high-sn-2 fat blend) on bone mass at age 10 years, anthropometry and bone mass (from dual-energy X-ray absorptiometry (GE Lunar Prodigy); lumbar spine (LS) and total body less head; adjusted for size (bone mineral apparent density standard deviation score (SDS) and regression)) were measured in 10-year-old subjects born at term and either breast-fed (n 34) or randomised to a standard control formula (n 27) or a high-sn-2 palmitate formula (n 30) for the first 12 weeks of life. At follow-up, previously BF children were older but lighter (by 0·5 SDS, P= 0·03) than formula-fed children with a lower LS bone mineral density SDS (by 0·44, P= 0·03), but size-adjusted bone mass did not differ. There were no significant differences in bone mass between the formula-fed groups. These findings suggest that there is no significant effect of BF or high-sn-2 infant formula on size-adjusted bone mass in mid-childhood, and that the effects of infant nutrition on bone mass previously reported may be confined to the short term. A larger study would be required to exclude smaller effects.


Assuntos
Envelhecimento , Densidade Óssea/fisiologia , Aleitamento Materno , Desenvolvimento Infantil , Criança , Feminino , Humanos , Lactente , Fórmulas Infantis , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Masculino
13.
J Clin Endocrinol Metab ; 97(3): E438-42, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22238385

RESUMO

OBJECTIVE: Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle. RESEARCH DESIGN AND METHODS: Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls. RESULTS: The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P<0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates. CONCLUSIONS: Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.


Assuntos
Lipodistrofia Generalizada Congênita/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Quadríceps/metabolismo , Adulto , Glicemia/metabolismo , Feminino , Humanos , Resistência à Insulina/fisiologia , Lipodistrofia Generalizada Congênita/fisiopatologia , Masculino , Fosforilação Oxidativa , Fosfocreatina/metabolismo , Músculo Quadríceps/fisiopatologia
14.
J Clin Invest ; 121(6): 2457-61, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21555852

RESUMO

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.


Assuntos
Metabolismo Basal/fisiologia , Hiperinsulinismo/congênito , Resistência à Insulina/genética , Mitocôndrias Musculares/fisiologia , Receptor de Insulina/deficiência , Adiponectina/sangue , Tecido Adiposo/patologia , Adulto , Antígenos CD/genética , Antígenos CD/fisiologia , Estudos de Casos e Controles , Teste de Esforço , Jejum/sangue , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Insulina/fisiologia , Masculino , Mutação de Sentido Incorreto , Consumo de Oxigênio , Fosfocreatina/metabolismo , Mutação Puntual , Estrutura Terciária de Proteína , Receptor de Insulina/genética , Receptor de Insulina/fisiologia , Comportamento Sedentário , Sono/fisiologia
15.
J Obes ; 20112011.
Artigo em Inglês | MEDLINE | ID: mdl-20847897

RESUMO

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID (n = 8) or placebo (n = 6) were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds.

16.
J Clin Invest ; 120(4): 1345-54, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20237409

RESUMO

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor beta (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor alpha sensitivity to elevated thyroid hormone levels.


Assuntos
Metabolismo Energético , Hiperfagia/etiologia , Mitocôndrias Musculares/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Trifosfato de Adenosina/biossíntese , Adulto , Criança , Ciclo do Ácido Cítrico , Ingestão de Alimentos , Humanos , Hiperfagia/metabolismo , Resistência à Insulina , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Receptores beta dos Hormônios Tireóideos/genética
17.
Obesity (Silver Spring) ; 18(2): 391-6, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19696753

RESUMO

We have recently reported a validation study of a prototype low-field strength quantitative magnetic resonance (QMR) instrument for measurement of human body composition (EchoMRI-AH). QMR was very precise, but underreported fat mass (FM) by 2-4 kg when compared to a 4-compartment (4C) model in this cross-sectional study. Here, we report the performance of an updated instrument in two longitudinal studies where FM was decreasing. Healthy obese volunteers were given a modest energy deficit diet for 8 weeks (study A) and obese patients with heart failure and/or at high cardiovascular risk were prescribed a low energy liquid diet for 6 weeks (study B). FM was measured at the start and end of these periods by QMR, dual-energy X-ray absorptiometry (DXA) and 4C. A higher proportion of the weight lost came from fat in study A compared with study B, where loss of total body water (TBW) played a greater part. The intraclass correlation between QMR and 4C estimates of FM loss (DeltaFat) was 0.95, but 20 of 22 estimates of DeltaFat by QMR were lower than the corresponding estimate by the 4C model. Bland-Altman analysis demonstrated that estimates of FM loss by QMR were ~1.0 and 0.7 kg lower than those obtained with 4C (P = 0.0008) and DXA (P = 0.049), respectively. Measurement precision remained high. QMR measurement should prove valuable for quantifying modest changes of FM in small trials.


Assuntos
Composição Corporal , Dieta Redutora , Ingestão de Energia , Insuficiência Cardíaca/dietoterapia , Imageamento por Ressonância Magnética , Obesidade/dietoterapia , Redução de Peso , Absorciometria de Fóton , Adulto , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
18.
Bone ; 45(1): 142-9, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19306955

RESUMO

BACKGROUND: Preterm infants are at risk of metabolic bone disease due to inadequate mineral intake with unknown consequences for later bone health. OBJECTIVE: To test the hypotheses that (1) early diet programs peak bone mass and bone turnover; (2) human milk has a beneficial effect on these outcomes; (3) preterm subjects have reduced peak bone mass compared to population reference data. DESIGN: 20 year follow-up of 202 subjects (43% male; 24% of survivors) who were born preterm and randomized to: (i) preterm formula versus banked breast milk or (ii) preterm versus term formula; as sole diet or supplement to maternal milk. Outcome measures were (i) anthropometry; (ii) hip, lumbar spine (LS) and whole body (WB) bone mineral content (BMC) and bone area (BA) measured using DXA; (iii) bone turnover markers. RESULTS: Infant dietary randomization group did not influence peak bone mass or turnover. The proportion of human milk in the diet was significantly positively associated with WBBA and BMC. Subjects receiving >90% human milk had significantly higher WBBA (by 3.5%, p=0.01) and BMC (by 4.8%, p=0.03) than those receiving <10%. Compared to population data, subjects had significantly lower height SDS (-0.41 (SD 1.05)), higher BMI SDS (0.31 (1.33)) and lower LSBMD SDS (-0.29 (1.16)); height and bone mass deficits were greatest in those born SGA with birthweight <1250 g (height SDS -0.81 (0.95), LSBMD SDS -0.61 (1.3)). CONCLUSION: Infant dietary randomization group did not affect peak bone mass or turnover suggesting the observed reduced final height and LS bone mass, most marked in growth restricted subjects with the lowest birthweight, may not be related to sub-optimal early nutrition. The higher WB bone mass associated with human milk intake, despite its low nutrient content, may reflect non-nutritive factors in breast milk. These findings may have implications for later osteoporosis risk and require further investigation.


Assuntos
Osso e Ossos/anatomia & histologia , Dieta , Recém-Nascido Prematuro/crescimento & desenvolvimento , Nascimento Prematuro/fisiopatologia , Adulto , Antropometria , Biomarcadores/metabolismo , Peso ao Nascer , Estatura , Índice de Massa Corporal , Densidade Óssea , Remodelação Óssea , Cálcio/metabolismo , Feminino , Seguimentos , Fraturas Ósseas/fisiopatologia , Saúde , Humanos , Recém-Nascido , Masculino , Leite Humano , Tamanho do Órgão
19.
J Clin Invest ; 119(2): 315-22, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19164855

RESUMO

Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.


Assuntos
Dislipidemias/etiologia , Fígado Gorduroso/etiologia , Resistência à Insulina , Receptor de Insulina/fisiologia , Adolescente , Adulto , Ácidos Graxos não Esterificados/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Receptor de Insulina/genética , Transdução de Sinais
20.
EMBO Mol Med ; 1(5): 280-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20049731

RESUMO

Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.


Assuntos
Códon sem Sentido , Diabetes Mellitus/genética , Resistência à Insulina , Lipodistrofia/genética , Proteínas/genética , Células 3T3 , Animais , Proteínas Reguladoras de Apoptose , Sequência de Bases , Diabetes Mellitus/metabolismo , Feminino , Humanos , Lipodistrofia/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Transporte Proteico , Proteínas/metabolismo , Adulto Jovem
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