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

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

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

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

Carnitine palmitoyltransferase 1 increases lipolysis, UCP1 protein expression and mitochondrial activity in brown adipocytes

The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders

Carnitine palmitoyltransferase 1 increases lipolysis, UCP1 protein expression and mitochondrial activity in brown adipocytes

The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders

Carnitine palmitoyltransferase 1 increases lipolysis, UCP1 protein expression and mitochondrial activity in brown adipocytes

The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders

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