at the CNIC

Tag: obesity (Page 1 of 10)

Brain JNK and metabolic disease

Rubén Nogueiras & Guadalupe Sabio.

Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain.

Opposing roles of JNK1 and JNK3 in the hypothalamus.

Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic–pituitary–thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology.

Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance.

JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Elisa Manieri, Cintia Folgueira, María Elena Rodríguez, Luis Leiva-Vega, Laura Esteban-Lafuente, Chaobo Chen, Francisco Javier Cubero, Tamera Barrett, Julie Cavanagh-Kyros, Davide Seruggia, Alejandro Rosell, Fátima Sanchez-Cabo, Manuel Jose Gómez, Maria J. Monte, Jose J. G. Marin, Roger J. Davis, Alfonso Mora & Guadalupe Sabio.

Obesity is associated with hepatic steatosis and activation of the cJun NH2-terminal kinase (JNK) stress-signaling pathway. Studies in mice demonstrate that JNK deficiency in the liver prevents the development of hepatic steatosis. This observation suggests that inhibition of JNK signaling may represent a possible treatment for hepatic steatosis. However, the long-term consequences of JNK inhibition are poorly understood.

Liver cholangiocarcinoma (Photo: Chaobo Chen).

Here we demonstrate that loss of JNK causes changes in cholesterol and bile acid metabolism that promote cholestasis, bile duct proliferation, and intrahepatic cholangiocarcinoma. We identify PPARα activation as the molecular mechanism that accounts for this phenotype .

Our analysis has important implications for the long-term use of JNK inhibitors for the treatment of obesity.

¿De qué mueren los extremeños?

«Aunque la supervivencia del cáncer ha aumentado hasta superar el 50% de forma global, la incidencia y la mortalidad siguen al alza por el envejecimiento de la población», explica Guadalupe Sabio, científica del Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), que incide también en que «los tratamientos de las afecciones circulatorias cada vez son mejores y se está consiguiendo aumentar la supervivencia de los pacientes tras, por ejemplo, un ataque de miocardio».

[Read more in El Periódico Extremadura]

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