Estratègies de modulació de l'oxidació d'àcids grassos com a tractament per combatre l'obesitat

L'estil de vida actual, amb dietes d'alt contingut calòric i falta d'exercici físic, fa que la incidència d'obesitat s'incrementi notablement. Augmentar la degradació de greixos o bé reduir la ingesta calòrica poden ser potencials estratègies terapèutiques. L'enzim carnitina palmitoïltransferasa I (CPT1) és el pas limitant de l'oxidació dels àcids grassos. En aquest article, es mostra com la modulació de la seva activitat en diferents teixits, com el fetge, el teixit adipós o l'hipotàlem, pot ser clau a l'hora d'augmentar la despesa energètica i controlar la ingesta d'aliments.Current lifestyles, with high-energy diets and little exercise, are triggering an alarming growth in obesity. Strategies that enhance fat degradation or reduce caloric food intake could be considered therapeutic interventions to reduce not only obesity, but also its associated disorders. The enzyme carnitine palmitoyltransferase I (CPT1) is the critical rate-determining regulator of fatty acid oxidation. In this paper, we show that this enzyme might play a key role in different tissues, such as liver, adipose tissue and hypothalamus, increasing energy expenditure and controlling food intake

Estratègies de modulació de l'oxidació d'àcids grassos com a tractament per combatre l'obesitat

L'estil de vida actual, amb dietes d'alt contingut calòric i falta d'exercici físic, fa que la incidència d'obesitat s'incrementi notablement. Augmentar la degradació de greixos o bé reduir la ingesta calòrica poden ser potencials estratègies terapèutiques. L'enzim carnitina palmitoïltransferasa I (CPT1) és el pas limitant de l'oxidació dels àcids grassos. En aquest article, es mostra com la modulació de la seva activitat en diferents teixits, com el fetge, el teixit adipós o l'hipotàlem, pot ser clau a l'hora d'augmentar la despesa energètica i controlar la ingesta d'aliments

Fatty acid metabolism and the basis of brown adipose tissue function

Obesity has reached epidemic proportions, leading to severe associated pathologies such as insulin resistance, cardiovascular disease, cancer and type 2 diabetes. Adipose tissue has become crucial due to its involvement in the pathogenesis of obesity-induced insulin resistance, and traditionally white adipose tissue has captured the most attention. However in the last decade the presence and activity of heat-generating brown adipose tissue (BAT) in adult humans has been rediscovered. BAT decreases with age and in obese and diabetic patients. It has thus attracted strong scientific interest, and any strategy to increase its mass or activity might lead to new therapeutic approaches to obesity and associated metabolic diseases. In this review we highlight the mechanisms of fatty acid uptake, trafficking and oxidation in brown fat thermogenesis. We focus on BAT's morphological and functional characteristics and fatty acid synthesis, storage, oxidation and use as a source of energy

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CARΔ1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes

Ghrelin causes a decline in GABA release by reducing fatty acid oxidation in cortex

Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and α-ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system. Keywords: Ghrelin, GABA, Fatty acid oxidation, CPT1A, Cortical neuron

Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans

Reversión del fenotipo obeso en ratones tratados con AAV9 que expresan la carnitina palmitoiltransferasa 1A humana en hígado

[spa] La obesidad es una enfermedad crónica de origen multifactorial y se caracteriza por una acumulación excesiva de grasa en todo el organismo. La obesidad y los transtornos metabólicos asociados, como son la resistencia a la insulina, la diabetes mellitus tipo 2, la enfermedad cardiovascular, el cáncer y otras patologías, se han convertido en un grave problema de salud pública del siglo XXI. En los últimos años se está realizando un gran esfuerzo para entender los mecanismos fisiopatológicos de la obesidad y también en la búsqueda de nuevas estrategias terapéuticas efectivas. El hígado juega un papel clave en la homeostasis energética del organismo regulando el metabolismo lipídico y de la glucosa. En condiciones de exceso crónico de energía se produce una considerable acumulación de lípidos, alterando el metabolismo lipídico hepático que conlleva al desarrollo de la enfermedad del hígado graso, al aumento de la gluconeogénesis hepática, a la resistencia a la insulina y posteriormente a alteraciones más graves como la esteatohepatitis, la cirrosis y el carcinoma hepatocelular. Dado que un hígado graso es consecuencia de un desequilibrio entre la entrada y la salida de lípidos, nuestra hipótesis es que una intervención que estimule la oxidación hepática de los ácidos grasos (AG) dará lugar a una disminución de la esteatosis hepática y una mejora del fenotipo obeso. Estudios previos realizados por nuestro grupo y Monsenego et al. han mostrado que un aumento de la expresión de la carnitina palmitoiltransferasa 1A, enzima limitante de la entrada de los AG en la mitocondria para ser oxidados, en hígado previene la obesidad inducida por dieta grasa en ratones. Ante esos resultados prometedores y con el fin de ir dirigidos hacia una posible terapia génica de la obesidad, en este estudio hemos expresado en hígado de ratones obesos una forma humana mutada de CPT1A permanentemente activa (hCPT1AM) mediante la utilización de virus adenoasociados (AAV) del serotipo 9. Estos vectores víricos permiten un alto grado y durante largo plazo (1 año) la expresión del gen de interés. La expresión de la hCPT1AM en hígado de ratones obesos ha dado lugar a un aumento del flujo de los AG hacia la mitocondria y una mayor oxidación de dichos AG que ha conducido a: una activación de la lipólisis y la autofagia hepáticas, una mejora del metabolismo del colesterol, una disminución de la esteatosis hepática, una mejora de la sensibilidad hepática a la insulina y una disminución de la hiperglicemia, la hiperinsulinemia y el peso. Por tanto, la sobreexpresión de la hCPT1AM es capaz de revertir la obesidad y muchos de sus problemas asociados y puede ser una buena estrategia para el futuro tratamiento de la enfermedad.[eng] Obesity is a multifactorial chronic disease, characterized by excessive accumulation of fat throughout the body. Obesity is associated with severe metabolic disorders such as insulin resistance, type 2 diabetes mellitus, cardiovascular disease, and cancer among others and has become a serious public health problem of the XXI century. Recently, a great effort has been made to understand the pathophysiological mechanisms of obesity and to find potential new effective therapeutic strategies. The liver plays a key role in regulating body energy homeostasis and lipid and glucose metabolism. In conditions of chronic energy excess, there is a considerable lipid accumulation, altering the hepatic lipid metabolism that entails the development of fatty liver disease, increased hepatic gluconeogenesis, insulin resistance and subsequently to more serious changes as steatohepatitis, cirrhosis, and hepatocellular carcinoma. Since fatty liver is caused by an imbalance between input and output of lipids, we hypothesize that an intervention that stimulates hepatic fatty acid oxidation will lead to decreased hepatic steatosis and an improved obese phenotype. Previous studies by our group and Monsenego et al. have shown that increased expression of Carnitine Palmitoyltransferase 1A (CPT1A), the key enzyme regulating the entry of fatty acids into the mitochondria to be oxidized, in the liver prevents high-fat diet-induced obesity in mice. Given these promising results and in order to target a potential gene therapy for obesity, in this study we have expressed in liver of obese mice a permanently active mutated human form of CPT1A (hCPT1AM) using adeno-associated virus (AAV) serotype 9. These viral vectors allow a long term (1 year) and a high degree of expression of the gene of interest. hCPT1AM expression in liver of obese mice resulted in increased flux of fatty acids into the mitochondria and increased fatty acid oxidation. These led to an activation of lipolysis and hepatic autophagy, an improvement in cholesterol metabolism, decreased hepatic steatosis, improved hepatic insulin sensitivity and decreased hyperglycemia, hyperinsulinemia and weight. Therefore, hCPT1AM overexpression is able to reverse obesity and many its associated derangements, being a potential effective strategy for the treatment of the disease

O FENÓTIPO COMPORTAMENTAL DO IDOSO COM DOENÇA DE ALZHEIMER

A Doença de Alzheimer (DA) é de origem genética, caracterizada por pequenos lapsos de memória que com oagravamento da doença evolui e se transforma em uma grave degeneração no Sistema Nervoso Central (SNC). Oobjetivo deste trabalho constitui-se em descrever, através de uma pesquisa bibliográfica, o comportamento de idososcom Doença de Alzheimer. A metodologia utilizada foi de uma pesquisa bibliográfica em fontes virtuais, qualitativa de cunho descritivo. Os resultados mostraram que os idosos com DA apresentam um comportamento típico dessa doença, repleto de lapsos de memórias e com o agravamento desta enfermidade tem-se uma perda da capacidade cognitiva. Assim, há uma influência da DA no fenótipo comportamental do idoso, já que essa enfermidade provoca uma série de retrações na capacidade funcional do Sistema Nervoso Central do idoso com Doença de Alzheimer

Fatty acid oxidation regulation strategies to treat obesity

L’estil de vida actual, amb dietes d’alt contingut calòric i falta d’exercici físic, fa que la incidència d’obesitat s’incrementi notablement. Augmentar la degradació de greixos o bé reduir la ingesta calòrica poden ser potencials estratègies terapèutiques. L’enzim carnitina palmitoïltransferasa I (CPT1) és el pas limitant de l’oxidació dels àcids grassos. En aquest article, es mostra com la modulació de la seva activitat en diferents teixits, com el fetge, el teixit adipós o l’hipotàlem, pot ser clau a l’hora d’augmentar la despesa energètica i controlar la ingesta d’aliments.Paraules clau: Obesitat, ingesta, oxidació d’àcids grassos, CPT1.Current lifestyles, with high-energy diets and little exercise, are triggering an alarming growth in obesity. Strategies that enhance fat degradation or reduce caloric food intake could be considered therapeutic interventions to reduce not only obesity, but also its associated disorders. The enzyme carnitine palmitoyltransferase I (CPT1) is the critical rate-determiningregulator of fatty acid oxidation. In this paper, we show that this enzyme might play a key role in different tissues, such as liver, adipose tissue and hypothalamus, increasing energy expenditure and controlling food intake.Keywords: Obesity, food intake, fatty acid oxidation, CPT1

Estratègies de modulació de l'oxidació d'àcids grassos com a tractament per combatre l'obesitat

L'estil de vida actual, amb dietes d'alt contingut calòric i falta d'exercici físic, fa que la incidència d'obesitat s'incrementi notablement. Augmentar la degradació de greixos o bé reduir la ingesta calòrica poden ser potencials estratègies terapèutiques. L'enzim carnitina palmitoïltransferasa I (CPT1) és el pas limitant de l'oxidació dels àcids grassos. En aquest article, es mostra com la modulació de la seva activitat en diferents teixits, com el fetge, el teixit adipós o l'hipotàlem, pot ser clau a l'hora d'augmentar la despesa energètica i controlar la ingesta d'aliments