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3. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Gonzalez-Franquesa, Alba, primary, Gama-Perez, Pau, additional, Kulis, Marta, additional, Szczepanowska, Karolina, additional, Dahdah, Norma, additional, Moreno-Gomez, Sonia, additional, Latorre-Pellicer, Ana, additional, Fernández-Ruiz, Rebeca, additional, Aguilar-Mogas, Antoni, additional, Hoffman, Anne, additional, Monelli, Erika, additional, Samino, Sara, additional, Miró-Blanch, Joan, additional, Oemer, Gregor, additional, Duran, Xavier, additional, Sanchez-Rebordelo, Estrella, additional, Schneeberger, Marc, additional, Obach, Merce, additional, Montane, Joel, additional, Castellano, Giancarlo, additional, Chapaprieta, Vicente, additional, Sun, Wenfei, additional, Navarro, Lourdes, additional, Prieto, Ignacio, additional, Castaño, Carlos, additional, Novials, Anna, additional, Gomis, Ramon, additional, Monsalve, Maria, additional, Claret, Marc, additional, Graupera, Mariona, additional, Soria, Guadalupe, additional, Wolfrum, Christian, additional, Vendrell, Joan, additional, Fernández-Veledo, Sonia, additional, Enríquez, Jose Antonio, additional, Carracedo, Angel, additional, Perales, José Carlos, additional, Nogueiras, Rubén, additional, Herrero, Laura, additional, Trifunovic, Aleksandra, additional, Keller, Markus A., additional, Yanes, Oscar, additional, Sales-Pardo, Marta, additional, Guimerà, Roger, additional, Blüher, Matthias, additional, Martín-Subero, José Ignacio, additional, and Garcia-Roves, Pablo M., additional

Published
2022
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4. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernandez-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miro-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castano, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernandez-Veledo, Sonia, Antonio Enriquez, Jose, Carracedo, Angel, Carlos Perales, Jose, Nogueiras, Ruben, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimera, Roger, Blueher, Matthias, Ignacio Martin-Subero, Jose, Garcia-Roves, Pablo M., Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernandez-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miro-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castano, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernandez-Veledo, Sonia, Antonio Enriquez, Jose, Carracedo, Angel, Carlos Perales, Jose, Nogueiras, Ruben, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimera, Roger, Blueher, Matthias, Ignacio Martin-Subero, Jose, and Garcia-Roves, Pablo M.

Abstract

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Published
2022

5. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, European Foundation for the Study of Diabetes, Novo Nordisk Foundation, European Commission, Centro Esther Koplowitz, González-Franquesa, Alba, Gama-Pérez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Durán, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramón, Monsalve, María, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, José Antonio, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Óscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, Garcia-Roves, Pablo M., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, European Foundation for the Study of Diabetes, Novo Nordisk Foundation, European Commission, Centro Esther Koplowitz, González-Franquesa, Alba, Gama-Pérez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Durán, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramón, Monsalve, María, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, José Antonio, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Óscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, and Garcia-Roves, Pablo M.

Abstract

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Published
2022

6. Brain-derived neurotrophic factor is expressed in rat and human placenta and its serum levels are similarly regulated throughout pregnancy in both species

Author

Garcés, María F., Sanchez, Elizabeth, Torres-Sierra, Alejandra L., Ruíz-Parra, Ariel I., Angel-Müller, Edith, Alzate, Juan P., Sánchez, Ángel Y., Gomez, Martín A., Romero, Ximena C., Castañeda, Zoila E., Sanchez-Rebordelo, Estrella, Diéguez, Carlos, Nogueiras, Rubén, and Caminos, Jorge E.

Published
2014
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7. Obesity causes irreversible mitochondria failure in visceral adipose tissue despite successful anti-obesogenic lifestyle-based interventions

Author

Gonzalez-Franquesa, Alba, primary, Gama-Perez, Pau, additional, Kulis, Marta, additional, Dahdah, Norma, additional, Moreno-Gomez, Sonia, additional, Latorre-Pellicer, Ana, additional, Fernández-Ruiz, Rebeca, additional, Aguilar-Mogas, Antoni, additional, Monelli, Erika, additional, Samino, Sara, additional, Miró, Joan, additional, Oemer, Gregor, additional, Duran, Xavier, additional, Sanchez-Rebordelo, Estrella, additional, Schneeberger, Marc, additional, Obach, Merce, additional, Montane, Joel, additional, Castellano, Giancarlo, additional, Chapaprieta, Vicente, additional, Navarro, Lourdes, additional, Prieto, Ignacio, additional, Castaño, Carlos, additional, Novials, Anna, additional, Gomis, Ramon, additional, Monsalve, Maria, additional, Claret, Marc, additional, Graupera, Mariona, additional, Soria, Guadalupe, additional, Vendrell, Joan, additional, Fernandez-Veledo, Sonia, additional, Enríquez, Jose Antonio, additional, Carracedo, Angel, additional, Perales, José Carlos, additional, Nogueiras, Rubén, additional, Herrero, Laura, additional, Keller, Markus A., additional, Yanes, Oscar, additional, Sales-Pardo, Marta, additional, Guimerà, Roger, additional, Martín-Subero, José Ignacio, additional, and Garcia-Roves, Pablo M., additional

Published
2020
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8. p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1

Author

Quinones, Mar, Al-Massadi, Omar, Folgueira, Cintia, Bremser, Stephan, Gallego, Rosalia, Torres-Leal, Leonardo, Haddad-Tovolli, Roberta, Garcia-Caceres, Cristina, Hernandez-Bautista, Rene, Lam, Brian Y. H., Beiroa, Daniel, Sanchez-Rebordelo, Estrella, Senra, Ana, Malagon, Jose A., Valerio, Patricia, Fondevila, Marcos F., Ferno, Johan, Malagon, Maria M., Contreras, Raian, Pfluger, Paul, Bruening, Jens C., Yeo, Giles, Tschoep, Matthias, Dieguez, Carlos, Lopez, Miguel, Claret, Marc, Kloppenburg, Peter, Sabio, Guadalupe, Nogueiras, Ruben, Quinones, Mar, Al-Massadi, Omar, Folgueira, Cintia, Bremser, Stephan, Gallego, Rosalia, Torres-Leal, Leonardo, Haddad-Tovolli, Roberta, Garcia-Caceres, Cristina, Hernandez-Bautista, Rene, Lam, Brian Y. H., Beiroa, Daniel, Sanchez-Rebordelo, Estrella, Senra, Ana, Malagon, Jose A., Valerio, Patricia, Fondevila, Marcos F., Ferno, Johan, Malagon, Maria M., Contreras, Raian, Pfluger, Paul, Bruening, Jens C., Yeo, Giles, Tschoep, Matthias, Dieguez, Carlos, Lopez, Miguel, Claret, Marc, Kloppenburg, Peter, Sabio, Guadalupe, and Nogueiras, Ruben

Abstract

p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.

Published
2018

9. Melanin-Concentrating Hormone acts through hypothalamic kappa opioid system and p70S6K to stimulate acute food intake

Author

Communicatie, TN groep Adan, Brain, Circulatory Health, Romero-Picó, Amparo, Sanchez-Rebordelo, Estrella, Imbernon, Monica, González-Touceda, David, Folgueira, Cintia, Senra, Ana, Fernø, Johan, Blouet, Clémence, Cabrera, Roberto, van Gestel, Margriet, Adan, Roger A, López-Jamar, Jose Miguel Esteban, Maldonado, Rafael, Nogueiras, Ruben, Diéguez, Carlos, Communicatie, TN groep Adan, Brain, Circulatory Health, Romero-Picó, Amparo, Sanchez-Rebordelo, Estrella, Imbernon, Monica, González-Touceda, David, Folgueira, Cintia, Senra, Ana, Fernø, Johan, Blouet, Clémence, Cabrera, Roberto, van Gestel, Margriet, Adan, Roger A, López-Jamar, Jose Miguel Esteban, Maldonado, Rafael, Nogueiras, Ruben, and Diéguez, Carlos

Published
2018

11. p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1

Author

Quiñones, Mar, primary, Al-Massadi, Omar, additional, Folgueira, Cintia, additional, Bremser, Stephan, additional, Gallego, Rosalía, additional, Torres-Leal, Leonardo, additional, Haddad-Tóvolli, Roberta, additional, García-Caceres, Cristina, additional, Hernandez-Bautista, Rene, additional, Lam, Brian Y. H., additional, Beiroa, Daniel, additional, Sanchez-Rebordelo, Estrella, additional, Senra, Ana, additional, Malagon, Jose A., additional, Valerio, Patricia, additional, Fondevila, Marcos F., additional, Fernø, Johan, additional, Malagon, Maria M., additional, Contreras, Raian, additional, Pfluger, Paul, additional, Brüning, Jens C., additional, Yeo, Giles, additional, Tschöp, Matthias, additional, Diéguez, Carlos, additional, López, Miguel, additional, Claret, Marc, additional, Kloppenburg, Peter, additional, Sabio, Guadalupe, additional, and Nogueiras, Ruben, additional

Published
2018
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12. Hypothalamic kappa opioid receptor mediates both diet- and MCH-induced liver damage through inflammation and ER stress

Author

Imbernon, Monica, Sanchez-Rebordelo, Estrella, Romero-Picó, Amparo, Kalló, Imre, Chee, Melissa J, Porteiro, Begoña, Al-Massadi, Omar, Contreras, Cristina, Fernø, Johan, Senra, Ana, Gallego, Rosalia, Folgueira, Cintia, Seoane, Luisa M, van Gestel, Margriet, Adan, Roger A, Liposits, Zsolt, Dieguez, Carlos, Lopez, Miguel, and Nogueiras, Ruben

Subjects
Journal Article
Abstract

The opioid system is widely known to modulate the brain reward system and thus affect human and animal behaviour, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors over-expressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. ER stress was inhibited by pharmacological (tauroursodeoxycholic acid - TUDCA) and genetic (over-expression of the chaperone glucose-regulated protein 78 kDa - GRP78) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and Western blot. We show that in the LHA, κOR directly controls hepatic lipid metabolism via the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor (MCH-R1) in the LHA and genetic disruption of κOR reduced MCH-induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline-deficient diet- and choline deficient-high fat diet-induced ER stress, inflammation, steatohepatitis and fibrosis, whereas over-expression of κOR in this area promoted liver steatosis. Over-expression of the GRP78 in the liver abolished hypothalamic κOR-induced steatosis by reducing hepatic ER stress. CONCLUSIONS: Overall, this study reveals a novel hypothalamic-parasympathetic circuit modulating hepatic function via inflammation and ER stress independent of changes in food intake or body weight. These findings might have implications for the clinical use of opioid receptor antagonists. This article is protected by copyright. All rights reserved.

Published
2016

13. Hypothalamic kappa opioid receptor mediates both diet- and MCH-induced liver damage through inflammation and ER stress

Author

Communicatie, TN groep Adan, Brain, Circulatory Health, Imbernon, Monica, Sanchez-Rebordelo, Estrella, Romero-Picó, Amparo, Kalló, Imre, Chee, Melissa J, Porteiro, Begoña, Al-Massadi, Omar, Contreras, Cristina, Fernø, Johan, Senra, Ana, Gallego, Rosalia, Folgueira, Cintia, Seoane, Luisa M, van Gestel, Margriet, Adan, Roger A, Liposits, Zsolt, Dieguez, Carlos, Lopez, Miguel, Nogueiras, Ruben, Communicatie, TN groep Adan, Brain, Circulatory Health, Imbernon, Monica, Sanchez-Rebordelo, Estrella, Romero-Picó, Amparo, Kalló, Imre, Chee, Melissa J, Porteiro, Begoña, Al-Massadi, Omar, Contreras, Cristina, Fernø, Johan, Senra, Ana, Gallego, Rosalia, Folgueira, Cintia, Seoane, Luisa M, van Gestel, Margriet, Adan, Roger A, Liposits, Zsolt, Dieguez, Carlos, Lopez, Miguel, and Nogueiras, Ruben

Published
2016

14. Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress

Author

Imbernon, Monica, primary, Sanchez‐Rebordelo, Estrella, additional, Romero‐Picó, Amparo, additional, Kalló, Imre, additional, Chee, Melissa J., additional, Porteiro, Begoña, additional, Al‐Massadi, Omar, additional, Contreras, Cristina, additional, Fernø, Johan, additional, Senra, Ana, additional, Gallego, Rosalia, additional, Folgueira, Cintia, additional, Seoane, Luisa M., additional, van Gestel, Margriet, additional, Adan, Roger A., additional, Liposits, Zsolt, additional, Dieguez, Carlos, additional, López, Miguel, additional, and Nogueiras, Ruben, additional

Published
2016
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