Validity of Resting Energy Expenditure Predictive Equations before and after an Energy-Restricted Diet Intervention in Obese Women

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Autophagy in hypothalamic cells: role of Neuropeptide Y

Dissertação de mest.Ciências Biomédicas. Departamento de Ciências Biomédicas e Medicina, Univ. do Algarve, 2011

Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology

Objective: Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with bodyfat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between fecal A. muciniphila abundance, fecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR). Design: The intervention consisted of a 6-week CR period followed by a 6-week weight stabilization (WS) diet in overweight and obese adults (N=49, including 41 women). Fecal A. muciniphila abundance, fecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and WS. Results: At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio, and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. A. muciniphila was associated with microbial species known to be related to health. Conclusion: A. muciniphila is associated with a healthier metabolic status and better clinicaloutcomes after CR in overweight/obese adults, however the interaction between gut microbiota ecology and A. muciniphila has to be taken into account.

Le vieillissement chronologique de Schizosaccharomyces pombe : Implication des voies de détection du glucose

La première augmentation de la longévité en laboratoire fût observée à la suite d’une intervention nutritionnelle consistant en une réduction de l’apport alimentaire chez le rat. Plus tard, ce phénomène a été reproduit dans de très nombreuses espèces et référé en tant que restriction calorique. Le développement des techniques de biologie moléculaire moderne a permis de montrer dans des organismes modèles simples que cette flexibilité du processus de vieillissement était régulée par des facteurs génétiques. De fait, plusieurs mécanismes cellulaires ont alors pu être identifiés comme responsables de ce contrôle du vieillissement. Ces voies de régulation ont révélées être conservées entre les espèces, depuis les levures jusqu’aux organismes multicellulaires tels que le nématode, la mouche ou la souris, suggérant l’existence d’un programme universel de vieillissement dans le vivant. La levure s’est avéré à plusieurs reprises être un modèle puissant et fiable pour la découverte de gènes impliqués dans ce phénomène. Mon étude a consisté au développement d’un nouveau modèle unicellulaire d’étude du vieillissement à travers l’espèce Schizosaccharomyces pombe appelée aussi levure à fission. La première étape de mon travail a montré que les voies de détection des nutriments gouvernées par la sérine/thréonine protéine kinase A (Pka1) et la sérine/thréonine kinase Sck2 contrôlent le vieillissement chronologique de ces cellules comme il était connu dans la levure Saccharomyces cerevisiae. Ceci permit de valider l’utilisation de la levure à fission pour l’étude du vieillissement. Ensuite, nous avons analysé plus en détail l’effet pro-vieillissement du glucose en étudiant le rôle de sa détection par le récepteur membranaire Git3 couplé à la protéine G (Gpa2) en amont de la kinase Pka1. La perte du signal du glucose par la délétion de Git3 imite partiellement l’effet d’augmentation de longévité obtenu par baisse de la concentration en glucose dans le milieu. De plus, l’effet néfaste du signal du glucose est maintenu en absence de tout métabolisme du glucose suite à la mutation des hexokinases, premières enzymes de la glycolyse. L’ensemble de ces résultats suggèrent que la signalisation du glucose est prédominante sur son métabolisme pour son effet pro-vieillissement. D’autre part, à la fois la suppression de cette signalisation et la baisse de niveau de glucose disponible allongent la durée de vie en corrélation avec une augmentation de la résistance au stress, une hausse d’activité mitochondriale et une baisse de production de radicaux libres. Finalement, le criblage d’une banque de surexpression d’ADNc a permis d’identifier plusieurs gènes candidats responsables de ces effets en aval de la voie de signalisation Git3/PKA. La recherche sur les mécanismes moléculaires du vieillissement propose une nouvelle approche, un nouvel angle de vue, pour la compréhension des fonctions cellulaires et promet d’apporter de précieuses clefs pour mieux comprendre certaines maladies. En effet, le vieillissement est la première cause d’apparition de nombreuses affections comme les cancers, les maladies cardiovasculaires et métaboliques ou les maladies neurodégénératives tels que les syndromes d’Alzheimer et de Parkinson.

Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle

Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle. The propensity to undertake voluntary exercise or indulge in spontaneous physical exercise, which might be termed "exercise salience", is drawing increased scientific attention. Despite its genetic aspects, this complex behaviour is clearly modulated by the environment and influenced by physiological states. Inflammation is often overlooked as one of these conditions even though it is known to induce a state of reduced mobility. Chronic subclinical inflammation is associated with the metabolic syndrome; a largely lifestyle-induced disease which can lead to decreased exercise salience. The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity. One general consequence of hormesis is upregulation of mitochondrial function and resistance to oxidative stress. Examples of hormetic factors include calorie restriction, extreme environmental temperatures, physical activity and polyphenols. The hormetic modulation of inflammation, and thus, exercise salience, may help to explain the highly heterogeneous expression of voluntary exercise behaviour and therefore body composition phenotypes of humans living in similar obesogenic environments.

The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle.

Obesity, diabetes and longevity in the Gulf: is there a Gulf Metabolic Syndrome?

The Gulf is experiencing a pandemic of lifestyle-induced obesity and type 2 diabetes mellitus (T2DM), with rates exceeding 50 and 30%, respectively. It is likely that T2DM represents the tip of a very large metabolic syndrome iceberg, which precedes T2DM by many years and is associated with abnormal/ectopic fat distribution, pathological systemic oxidative stress and inflammation. However, the definitions are still evolving with the role of different fat depots being critical. Hormetic stimuli, which include exercise, calorie restriction, temperature extremes, dehydration and even some dietary components (such as plant polyphenols), may well modulate fat deposition. All induce physiological levels of oxidative stress, which results in mitochondrial biogenesis and increased anti-oxidant capacity, improving metabolic flexibility and the ability to deal with lipids. We propose that the Gulf Metabolic Syndrome results from an unusually rapid loss of hormetic stimuli within an epigenetically important time frame of 2-3 generations. Epigenetics indicates that thriftiness can be programmed by the environment and passed down through several generations. Thus this loss of hormesis can result in continuation of metabolic inflexibility, with mothers exposing the foetus to a milieu that perpetuates a stressed epigenotype. As the metabolic syndrome increases oxidative stress and reduces life expectancy, a better descriptor may therefore be the Lifestyle-Induced Metabolic Inflexibility and accelerated AGEing syndrome – LIMIT-AGE. As life expectancy in the Gulf begins to fall, with perhaps a third of this life being unhealthy – including premature loss of sexual function, it is vital to detect evidence of this condition as early in life as possible. One effective way to do this is by detecting evidence of metabolic inflexibility by studying body fat content and distribution by magnetic resonance (MR). The Gulf Metabolic Syndrome thus represents an accelerated form of the metabolic syndrome induced by the unprecedented rapidity of lifestyle change in the region, the stress of which is being passed from generation to generation and may be accumulative. The fundamental cause is probably due to a rapid increase in countrywide wealth. This has benefited most socioeconomic groups, resulting in the development of an obesogenic environment as the result of the rapid adoption of Western labour saving and stress relieving devices (e.g. cars and air conditioning), as well as the associated high calorie diet.

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Caloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.

Metabolismo mitocondrial, radicais livres e envelhecimento

O envelhecimento pode estar associado ao maior acúmulo de lesões celulares decorrentes das espécies reativas do oxigênio e do nitrogênio derivadas do metabolismo mitocondrial. Com a progressão da idade, há acúmulo de proteínas, lipídeos, carboidratos e DNA oxidados em relação a organismos jovens, de acordo com a teoria dos radicais livres. Entretanto, nem sempre os idosos ou animais envelhecidos apresentam maior estresse oxidativo que os jovens. Este artigo discute o paradoxo da teoria dos radicais livres de acordo com a teoria da biogênese da manutenção adequada do metabolismo mitocondrial. Diversos fatores podem contribuir para a redução do estresse oxidativo, como a hormese induzida pela prática regular de exercícios físicos, a restrição calórica, a ingestão de antioxidantes nutricionais e o aumento da produção de antioxidantes celulares que. em conjunto, estes promovem a expressão das sirtuínas e das proteínas do choque térmico, protegendo a integridade e funcionalidade mitocondriais, reduzindo o estresse oxidativo e nitrosativo, o que está associado à redução do envelhecimento e aumento da longevidade.

Study of the evolution of the placenta and fetal pancreas in the pathophysiology of growth retardation intrauterine due to restricted maternal diet

CONTEXTO: O retardo do crescimento intra-uterino (RCIU) continua sendo importante problema em perinatologia neste final de século. A natureza do agente etiológico, o período da gestação em que ocorreu o insulto e a sua duração influenciam o tipo de RCIU. OBJETIVO: Estudar a fisiopatologia do retardo de crescimento intrauterino (RCIU) em ratas, decorrente da restrição protéico-calórica materna, em relação à evolução do pâncreas fetal e placenta entre o 18o e 21o dias de prenhez. TIPO DE ESTUDO: Ensaio clínico randomizado em animal de laboratório. PARTICIPANTES: 41 ratas prenhes, normoglicêmicas, da raça Wistar. INTERVENÇÃO: Constituíram-se seis grupos experimentais: controle, com dieta ad libitum e cesárea, respectivamente, no 18º e 21º dias; grupos dieta restritiva a 25% introduzida no 1o dia da prenhez e cesárea no 18o e 21o dias; grupos com a mesma restrição, porém iniciada no 3o dia, com cesárea no 18o e 21o dias. VARIÁVEIS ESTUDADAS: Os recém-nascidos foram classificados, em relação à média mais ou menos um desvio padrão do grupo controle, em peso pequeno (PIP), adequado (AIP) e grande (GIP) para a idade de prenhez; as placentas foram pesadas e processadas para estudo histopatológico, incluindo morfologia e histoquímica, e os pâncreas fetais, para estudo morfológico. RESULTADOS: A desnutrição protéico-calórica materna causou RCIU após o 18o dia da prenhez. Antes desse período não ocorreu RCIU, porque a desnutrição materna diminuiu o número da prole e a placenta tornou-se vicariante. A restrição alimentar não interferiu com a morfologia do pâncreas fetal, e o estudo imunohistoquímico da placenta mostrou que, quando a restrição é introduzida no 1o dia de prenhez, os estoques de glicogênio também não sofrem alterações, diminuindo entre o 18o e 21o dias, como na prenhez normal. A restrição no 3o dia cursou com baixas concentrações de glicogênio placentário no 18o dia e desaparecimento no 21o dia. CONCLUSÃO: A fisiopatologia do RCIU, decorrente da restrição protéico-calórica materna em ratas, está relacionada com menor peso placentário e baixos estoques de glicogênio placentário.

Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae

Increased replicative longevity in Saccharomyces cerevisiae because of calorie restriction has been linked to enhanced mitochondrial respiratory activity. Here we have further investigated how mitochondrial respiration affects yeast life span. We found that calorie restriction by growth in low glucose increased respiration but decreased mitochondrial reactive oxygen species production relative to oxygen consumption. Calorie restriction also enhanced chronological life span. The beneficial effects of calorie restriction on mitochondrial respiration, reactive oxygen species release, and replicative and chronological life span could be mimicked by uncoupling agents such as dinitrophenol. Conversely, chronological life span decreased in cells treated with antimycin (which strongly increases mitochondrial reactive oxygen species generation) or in yeast mutants null for mitochondrial superoxide dismutase (which removes superoxide radicals) and for RTG2 (which participates in retrograde feedback signaling between mitochondria and the nucleus). These results suggest that yeast aging is linked to changes in mitochondrial metabolism and oxidative stress and that mild mitochondrial uncoupling can increase both chronological and replicative life span.

Inter-relação da leptina e dos hormônios tireoidianos na perda de peso de ratos obesos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Influência de diferentes doses suprafisiológicas de triidotironina sobre adipocinas na obesidade e após a perda de peso

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Femoral Biomechanic and microtomography from male rats submitted to dietary restricition supplemented with sucrose

Food restriction reduces body weight and influence bone mass and also is correlated with bone mineral density (BMD). Mechanisms have been proposed for the loss of BMD after body weight reduction, including reduced energy intake. Growing 8 wk-old Wistar male rats were randomly divided into Control and Calorie restriction associated with sucrose 30% (CRS). These animals were subjected to intermittent food restriction during 8 weeks and had free access to tap water and sucrose30% in distilled water. The rats were euthanized at the end of week 8, blood collected from abdominal aorta artery, femurs cleaned of adherent soft tissues, scanned using dual energy X-ray absorptiometry, structural and material properties determined by three-point bending testing in the mid-diaphyseal region, bone surface tested in a microhardness tester and microstructure was assessed in a microcomputer tomography. In CRS animals body weight decreased significantly relative to the Control animals. There was a clear option for high-sucrose beverage in CRS animals. No difference was observed in biochemical, densitometric and biomechanical analyzes. Results from micro CT showed only significant difference in connectivity of trabecular bone. It has been suggested that rats submitted to food restriction consumed sugar not because of its inherent palatability, but in order to alter their macronutrient balance and animals need to meet energy demands in high-sucrose.

Age-dependent changes in rat lacrimal gland anti-oxidant and vesicular related protein expression profiles

Purpose: Anti-oxidation and exocytosis are important for maintaining exocrine tissue homeostasis. During aging, functional and structural alterations occur in the lacrimal gland (LG), including oxidative damage to proteins, lipids, and DNA. The aims of the present study were to determine in the aging LG: a) the effects of aging on LG structure and secretory activity and b) changes in the expression of oxidative stress markers. Methods: To address these goals, tear secretion composition and corneal impression cytology were compared between male Wistar rats of 2 (control) and 24 (aged) months. LG morphology and the expression levels of vitamin E and malonaldehyde (MDA) were evaluated to determine the anti-oxidant activity and lipid peroxidation, respectively. RT-PCR and western blot analysis were used for the analysis of Ras related in brain GTPase protein (Rab) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins of the secretory machinery (i.e.; Rab 3d, Rab 27, vesicle-associated membrane protein-2 (Vamp-2), and syntaxin). Results: Histological analysis of aged rats revealed a higher frequency of corneal epithelia metaplasia. In the acinar cells, organelles underwent degeneration, and lipofucsin-like material accumulated in the cytoplasm along with declines in the anti-oxidant marker vitamin E. Rab3d and Rab27b mRNA levels fell along with Rab3d protein expression, whereas syntaxin levels increased. Conclusions: These findings indicate that exocytotic and anti-oxidant mechanisms become impaired with age in the rat LG. In parallel with these structural alterations, functional declines may contribute to the pathophysiology caused by tear film modification in dry eye disease.