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1. A GnRH neuronal population in the olfactory bulb translates socially relevant odors into reproductive behavior in male mice

Author

Decoster, Laurine, Trova, Sara, Zucca, Stefano, Bulk, Janice, Gouveia, Ayden, Ternier, Gaetan, Lhomme, Tori, Legrand, Amandine, Gallet, Sarah, Boehm, Ulrich, Wyatt, Amanda, Wahl, Vanessa, Wartenberg, Philipp, Hrabovszky, Erik, Rácz, Gergely, Luzzati, Federico, Nato, Giulia, Fogli, Marco, Peretto, Paolo, Schriever, Sonja C., Bernecker, Miriam, Pfluger, Paul T., Steculorum, Sophie M., Bovetti, Serena, Rasika, Sowmyalakshmi, Prevot, Vincent, Silva, Mauro S. B., and Giacobini, Paolo

Published
2024
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2. Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion

Author

Correa-da-Silva, Felipe, Carter, Jenny, Wang, Xin-Yuan, Sun, Rui, Pathak, Ekta, Kuhn, José Manuel Monroy, Schriever, Sonja C., Maya-Monteiro, Clarissa M., Jiao, Han, Kalsbeek, Martin J., Moraes-Vieira, Pedro M. M., Gille, Johan J. P., Sinnema, Margje, Stumpel, Constance T. R. M., Curfs, Leopold M. G., Stenvers, Dirk Jan, Pfluger, Paul T., Lutter, Dominik, Pereira, Alberto M., Kalsbeek, Andries, Fliers, Eric, Swaab, Dick F., Wilkinson, Lawrence, Gao, Yuanqing, and Yi, Chun-Xia

Published
2024
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5. Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Author

Kulaj, Konxhe, Harger, Alexandra, Bauer, Michaela, Caliskan, Özüm S., Gupta, Tilak Kumar, Chiang, Dapi Menglin, Milbank, Edward, Reber, Josefine, Karlas, Angelos, Kotzbeck, Petra, Sailer, David N., Volta, Francesco, Lutter, Dominik, Prakash, Sneha, Merl-Pham, Juliane, Ntziachristos, Vasilis, Hauner, Hans, Pfaffl, Michael W., Tschöp, Matthias H., Müller, Timo D., Hauck, Stefanie M., Engel, Benjamin D., Gerdes, Jantje M., Pfluger, Paul T., Krahmer, Natalie, and Stemmer, Kerstin

Published
2023
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6. Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice

Author

Akindehin, Seun, Liskiewicz, Arkadiusz, Liskiewicz, Daniela, Bernecker, Miriam, Garcia-Caceres, Cristina, Drucker, Daniel J., Finan, Brian, Grandl, Gerald, Gutgesell, Robert, Hofmann, Susanna M., Khalil, Ahmed, Liu, Xue, Cota, Perla, Bakhti, Mostafa, Czarnecki, Oliver, Bastidas-Ponce, Aimée, Lickert, Heiko, Kang, Lingru, Maity, Gandhari, Novikoff, Aaron, Parlee, Sebastian, Pathak, Ekta, Schriever, Sonja C., Sterr, Michael, Ussar, Siegfried, Zhang, Qian, DiMarchi, Richard, Tschöp, Matthias H., Pfluger, Paul T., Douros, Jonathan D., and Müller, Timo D.

Published
2024
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7. High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling

Author

Gruber, Tim, Lechner, Franziska, Murat, Cahuê, Contreras, Raian E., Sanchez-Quant, Eva, Miok, Viktorian, Makris, Konstantinos, Le Thuc, Ophélia, González-García, Ismael, García-Clave, Elena, Althammer, Ferdinand, Krabichler, Quirin, DeCamp, Lisa M., Jones, Russell G., Lutter, Dominik, Williams, Rhiannan H., Pfluger, Paul T., Müller, Timo D., Woods, Stephen C., Pospisilik, John Andrew, Martinez-Jimenez, Celia P., Tschöp, Matthias H., Grinevich, Valery, and García-Cáceres, Cristina

Published
2023
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8. Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1

Author

González-García, Ismael, García-Clavé, Elena, Cebrian-Serrano, Alberto, Le Thuc, Ophélia, Contreras, Raian E., Xu, Yanjun, Gruber, Tim, Schriever, Sonja C., Legutko, Beata, Lintelmann, Jutta, Adamski, Jerzy, Wurst, Wolfgang, Müller, Timo D., Woods, Stephen C., Pfluger, Paul T., Tschöp, Matthias H., Fisette, Alexandre, and García-Cáceres, Cristina

Published
2023
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9. Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Author

Maity-Kumar, Gandhari, Ständer, Lisa, DeAngelis, Meri, Lee, Sooyeon, Molenaar, Anna, Becker, Lore, Garrett, Lillian, Amerie, Oana V., Hoelter, Sabine M., Wurst, Wolfgang, Fuchs, Helmut, Feuchtinger, Annette, Gailus-Durner, Valerie, Garcia-Caceres, Cristina, Othman, Ahmed E., Brockmann, Caroline, Schöffling, Vanessa I., Beiser, Katja, Krude, Heiko, Mroz, Piotr A., Hofmann, Susanna, Tuckermann, Jan, DiMarchi, Richard D., Hrabe de Angelis, Martin, Tschöp, Matthias H., Pfluger, Paul T., and Müller, Timo D.

Published
2022
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16. Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

Author

Krause, Christin, primary, Britsemmer, Jan H., additional, Bernecker, Miriam, additional, Molenaar, Anna, additional, Taege, Natalie, additional, Geißler, Cathleen, additional, Kaehler, Meike, additional, Iben, Katharina, additional, Judycka, Anna, additional, Wagner, Jonas, additional, Wolter, Stefan, additional, Mann, Oliver, additional, Pfluger, Paul T., additional, Cascorbi, Ingolf, additional, Lehnert, Hendrik, additional, Stemmer, Kerstin, additional, Schriever, Sonja C., additional, and Kirchner, Henriette, additional

Published
2023
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17. A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

Author

Chan, Calvin C., Harley, Isaac T. W., Pfluger, Paul T., Trompette, Aurelien, Stankiewicz, Traci E., Allen, Jessica L., Moreno-Fernandez, Maria E., Damen, Michelle S. M. A., Oates, Jarren R., Alarcon, Pablo C., Doll, Jessica R., Flick, Matthew J., Flick, Leah M., Sanchez-Gurmaches, Joan, Mukherjee, Rajib, Karns, Rebekah, Helmrath, Michael, Inge, Thomas H., Weisberg, Stuart P., Pamp, Sünje J., Relman, David A., Seeley, Randy J., Tschöp, Matthias H., Karp, Christopher L., and Divanovic, Senad

Published
2021
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18. Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

Author

Pfluger, Paul T., Schriever, Sonja C., Kabra, Dhiraj G., Pfuhlmann, Katrin, Baumann, Peter, Baumgart, Emily V., Nagler, Joachim, Seebacher, Fabian, Harrison, Luke, Irmler, Martin, Kullmann, Stephanie, Corrêa-da-Silva, Felipe, Giesert, Florian, Jain, Ruchi, Schug, Hanna, Castel, Julien, Martinez, Sarah, Wu, Moya, Haring, Hans-Ulrich, de Angelis, Martin Hrabe, Beckers, Johannes, Muller, Timo D., Stemmer, Kerstin, Wurst, Wolfgang, Rozman, Jan, Nogueiras, Ruben, De Angelis, Meri, Molkentin, Jeffery D., Krahmer, Natalie, Yi, Chun-Xia, Schmidt, Mathias V., Luquet, Serge, Heni, Martin, and Tschop, Matthias H.

Subjects
Genetic research, Mitogen-activated protein kinases -- Genetic aspects -- Health aspects, Type 2 diabetes -- Genetic aspects -- Risk factors, Insulin resistance -- Genetic aspects, Cellular signal transduction -- Research, Hypothalamus -- Genetic aspects -- Health aspects, Health care industry
Abstract

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic- pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D., Introduction Obesity-induced insulin resistance is associated with an increase in circulating levels of cytokines and free fatty acids (1) that activate proinflammatory signaling pathways. Mitogen-activated protein kinase (MAPK) signaling plays [...]

Published
2020
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19. Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ

Author

Hönes, Georg Sebastian, primary, Geist, Daniela, additional, Wenzek, Christina, additional, Pfluger, Paul T, additional, Müller, Timo D, additional, Amarie, Oana V, additional, Becker, Lore, additional, Dragano, Nathalia, additional, Garrett, Lillian, additional, Hölter, Sabine M, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Spielmann, Nadine, additional, Treise, Irina, additional, Wolf, Eckhard, additional, Wurst, Wolfgang, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, de Angelis, Martin H, additional, Führer, Dagmar, additional, and Moeller, Lars C, additional

Published
2023
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20. CNS-targeting pharmacological interventions for the metabolic syndrome

Author

Stemmer, Kerstin, Muller, Timo D., DiMarchi, Richard D., Pfluger, Paul T., Tschop, Matthias H., and Scherer, Philipp E.

Subjects
Obesity -- Development and progression, Hypertension -- Development and progression, Phendimetrazine, Zonisamide, Bariatric surgery, Type 2 diabetes -- Development and progression, Body weight, Sibutramine, Lorcaserin, Weight loss -- Development and progression, Etiology (Medicine), Surgery, Adipose tissue, Heart attack, Disabilities, Pharmacology, Hyperglycemia, Alzheimer's disease, Comorbidity, Health care industry
Abstract

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae., Introduction The metabolic syndrome (MetS) encompasses a cluster of pernicious metabolic diseases that include visceral obesity, dyslipidemia, hyperglycemia, and hypertension (1). It is considered to be a silent killer owing [...]

Published
2019
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23. Dusp8 affects hippocampal size and behavior in mice and humans

Author

Baumann, Peter, Schriever, Sonja C., Kullmann, Stephanie, Zimprich, Annemarie, Feuchtinger, Annette, Amarie, Oana, Peter, Andreas, Walch, Axel, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabě de Angelis, Martin, Wurst, Wolfgang, Tschöp, Matthias H., Heni, Martin, Hölter, Sabine M., and Pfluger, Paul T.

Published
2019
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24. Regulation of the endosomal SNX27-retromer by OTULIN

Author

Stangl, Aurelia, Elliott, Paul R., Pinto-Fernandez, Adan, Bonham, Sarah, Harrison, Luke, Schaub, Annalisa, Kutzner, Kerstin, Keusekotten, Kirstin, Pfluger, Paul T., El Oualid, Farid, Kessler, Benedikt M., Komander, David, and Krappmann, Daniel

Published
2019
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26. Calcineurin Links Mitochondrial Elongation with Energy Metabolism

Author

Pfluger, Paul T., Kabra, Dhiraj G., Aichler, Michaela, Schriever, Sonja C., Pfuhlmann, Katrin, García, Verónica Casquero, Lehti, Maarit, Weber, Jon, Kutschke, Maria, Rozman, Jan, Elrod, John W., Hevener, Andrea L., Feuchtinger, Annette, Hrabě de Angelis, Martin, Walch, Axel, Rollmann, Stephanie M., Aronow, Bruce J., Müller, Timo D., Perez-Tilve, Diego, Jastroch, Martin, De Luca, Maria, Molkentin, Jeffery D., and Tschöp, Matthias H.

Published
2015
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27. Differential colonization with segmented filamentous bacteria and Lactobacillus murinus do not drive divergent development of diet-induced obesity in C57BL/6 mice

Author

Harley, Isaac T.W., Giles, Daniel A., Pfluger, Paul T., Burgess, Stacey L., Walters, Stephanie, Hembree, Jazzminn, Raver, Christine, Rewerts, Cheryl L., Downey, Jordan, Flick, Leah M., Stankiewicz, Traci E., McAlees, Jaclyn W., Wills-Karp, Marsha, Balfour Sartor, R., Divanovic, Senad, Tschöp, Matthias H., and Karp, Christopher L.

Published
2013
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28. RNA sequencing and data integration in the context of nutrition and weight loss intervention

Author

Pfluger, Paul T. (Prof. Dr.), Pfluger, Paul T. (Prof. Dr.);Krumsiek, Jan (Dr.), Klaus, Valentina Sabinia, Pfluger, Paul T. (Prof. Dr.), Pfluger, Paul T. (Prof. Dr.);Krumsiek, Jan (Dr.), and Klaus, Valentina Sabinia

Abstract

Overall this thesis presents three studies that highlight the complexity of molecular systems in response to nutritional dysregulation. They accentuate that the sophisticated integration of data from multiple sources such as transcriptome profiles together with quantified DNA adduct levels or metabolome profiles, as performed with our new data integration approach CoNI, is key to predict the cellular influences of potentially harmful substances or to identify new genes that could be used as druggable targets., Insgesamt präsentiert diese Arbeit drei Studien, die zeigen wie komplex die Reaktion der molekularen Systeme auf eine Ernährungsdysregulation ist. Die Studien legen außerdem dar, dass die hochentwickelte Integration von Daten aus verschiedenen Quellen, zum Beispiel Transkriptionsprofile mit DNS-Adduktkonzentrationen oder Metabolitenprofilen, wie sie mit unserer neuentwickelten Methode zur Datenintegration CoNI durchgeführt wurde, entscheidend für die Vorhersage des Einflusses von möglicherweise schädlichen Substanzen auf die Zelle oder für die Entdeckung von neuen krankheitsrelevanten Zielmolekülen sind.

Published
2020

30. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Author

Finan, Brian, Yang, Bin, Ottaway, Nickki, Smiley, David L., Ma, Tao, Clemmensen, Christoffer, Chabenne, Joe, Zhang, Lianshan, Habegger, Kirk M., Fischer, Katrin, Campbell, Jonathan E., Sandoval, Darleen, Seeley, Randy J., Bleicher, Konrad, Uhles, Sabine, Riboulet, William, Funk, Jurgen, Hertel, Cornelia, Belli, Sara, Sebokova, Elena, Conde-Knape, Karin, Konkar, Anish, Drucker, Daniel J., Gelfanov, Vasily, Pfluger, Paul T., Muller, Timo D., Perez-Tilve, Diego, DiMarchi, Richard D., and Tschop, Matthias H.

Subjects
Obesity -- Complications and side effects -- Care and treatment -- Research, Diabetes -- Risk factors -- Prevention -- Research, Peptides -- Physiological aspects -- Research, Biological sciences, Health
Abstract

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders., Obesity and its comorbidities, including type 2 diabetes, represent a global health threat and a rapidly increasing burden to economic prosperity (1). Therapeutic intervention is urgently required because lifestyle modification [...]

Published
2015
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34. Additional file 1 of Pharmacologically induced weight loss is associated with distinct gut microbiome changes in obese rats

Author

Raineri, Silvia, Sherriff, Julia A., Thompson, Kevin S. J., Jones, Huw, Pfluger, Paul T., Ilott, Nicholas E., and Mellor, Jane

Abstract

Additional file 1: Additional Figure 1. Long-term treatment of adult rats maintained on a high fat diet with different dosages of FK506 induces weight loss and promotes maintenance of a healthier weight. Additional Figure 2. Tukey’s post-hoc test following ANOVA statistical test on timepoint reveals early but temporary anorexigenic effects of sibutramine, and significant changes due to fasting on Day 36. Additional Figure 3. Pancreatic Insulin levels at Day 42. Additional Figure 4. Combination treatment of bupropion and naltrexone impacts on the host gut microbiome. Additional Figure 5. Differentially abundant genes and species upon bupropion and naltrexone combination treatment. Additional Table 2. Current pharmacotherapies for obesity. Additional Table 2. Tukey’s post-hoc test significant comparisons following ANOVA on pancreatic insulin levels at Day 42. Additional Table 3. Percentage of unassigned reads per sample for representative genes fliC, flgE and motA.

Published
2022
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39. Genetic variation of the ghrelin activator gene ghrelin O-acyltransferase ( GOAT) is associated with anorexia nervosa

Author

Müller, Timo D., Tschöp, Matthias H., Jarick, Ivonne, Ehrlich, Stefan, Scherag, Susann, Herpertz-Dahlmann, Beate, Zipfel, Stefan, Herzog, Wolfgang, de Zwaan, Martina, Burghardt, Roland, Fleischhaker, Christian, Klampfl, Karin, Wewetzer, Christoph, Herpertz, Stephan, Zeeck, Almut, Tagay, Sefik, Burgmer, Markus, Pfluger, Paul T., Scherag, André, Hebebrand, Johannes, and Hinney, Anke

Published
2011
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43. KSR2 Is an Essential Regulator of AMP Kinase, Energy Expenditure, and Insulin Sensitivity

Author

Costanzo-Garvey, Diane L., Pfluger, Paul T., Dougherty, Michele K., Stock, Jeffery L., Boehm, Matthew, Chaika, Oleg, Fernandez, Mario R., Fisher, Kurt, Kortum, Robert L., Hong, Eun-Gyoung, Jun, John Y., Ko, Hwi Jin, Schreiner, Aimee, Volle, Deanna J., Treece, Tina, Swift, Amy L., Winer, Mike, Chen, Denise, Wu, Min, Leon, Lisa R., Shaw, Andrey S., McNeish, John, Kim, Jason K., Morrison, Deborah K., Tschöp, Matthias H., and Lewis, Robert E.

Published
2009
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44. p62 Links β-adrenergic input to mitochondrial function and thermogenesis

Author

Muller, Timo D., Lee, Sang Jun, Jastroch, Martin, Kabra, Dhiraj, Stemmer, Kerstin, Aichler, Michaela, Abplanalp, Bill, Ananthakrishnan, Gayathri, Bhardwaj, Nakul, Collins, Sheila, Divanovic, Senad, Endele, Max, Finan, Brian, Gao, Yuanqing, Habegger, Kirk M., Hembree, Jazzmin, Heppner, Kristy M., Hofmann, Susanna, Holland, Jenna, Kuchler, Daniela, Kutschke, Maria, Krishna, Radha, Lehti, Maarit, Oelkrug, Rebecca, Ottaway, Nickki, Perez-Tilve, Diego, Raver, Christine, Walch, Axel K., Schriever, Sonja C., Speakman, John, Tseng, Yu-Hua, Diaz-Meco, Maria, Pfluger, Paul T., Moscat, Jorge, and Tschop, Matthias H.

Subjects
Obesity -- Genetic aspects -- Physiological aspects, Proteins -- Properties -- Physiological aspects, Mitochondrial DNA -- Research, Health care industry
Abstract

The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not [...]

Published
2013
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46. A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

Author

Chan, Calvin C, Harley, Isaac T W, Pfluger, Paul T, Trompette, Aurelien, Stankiewicz, Traci E, Allen, Jessica L, Moreno-Fernandez, Maria E, Damen, Michelle S M A, Oates, Jarren R, Alarcon, Pablo C, Doll, Jessica R, Flick, Matthew J, Flick, Leah M, Sanchez-Gurmaches, Joan, Mukherjee, Rajib, Karns, Rebekah, Helmrath, Michael, Inge, Thomas H, Weisberg, Stuart P, Pamp, Sünje J, Relman, David A, Seeley, Randy J, Tschöp, Matthias H, Karp, Christopher L, Divanovic, Senad, Chan, Calvin C, Harley, Isaac T W, Pfluger, Paul T, Trompette, Aurelien, Stankiewicz, Traci E, Allen, Jessica L, Moreno-Fernandez, Maria E, Damen, Michelle S M A, Oates, Jarren R, Alarcon, Pablo C, Doll, Jessica R, Flick, Matthew J, Flick, Leah M, Sanchez-Gurmaches, Joan, Mukherjee, Rajib, Karns, Rebekah, Helmrath, Michael, Inge, Thomas H, Weisberg, Stuart P, Pamp, Sünje J, Relman, David A, Seeley, Randy J, Tschöp, Matthias H, Karp, Christopher L, and Divanovic, Senad

Abstract

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

Published
2021

49. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet

Author

Clemmensen, Christoffer, Chabenne, Joseph, Finan, Brian, Sullivan, Lorraine, Fischer, Katrin, Kuchler, Daniela, Sehrer, Laura, Ograjsek, Teja, Hofmann, Susanna M., Schriever, Sonja C., Pfluger, Paul T., Pinkstaff, Jason, Tschop, Matthias H., DiMarchi, Richard, and Muller, Timo D.

Subjects
Leptin -- Research -- Analysis, Glucagon -- Research -- Analysis -- Physiological aspects, Health
Abstract

We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ~15% body weight loss, upon which they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ~18% greater weight loss as compared with PEG-GLP-1/glucagon alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes. Diabetes 2014;63:1422-1427 | DOI: 10.2337/db13-1609, Pharmacological approaches to combat obesity are hampered by limited efficacy or considerable adverse effects. Therefore the development of safe and efficient pharmacotherapies is an increasing global priority. The adipocyte hormone [...]

Published
2014
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50. GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats

Author

Habegger, Kirk M., Heppner, Kristy M., Amburgy, Sarah E., Ottaway, Nickki, Holland, Jenna, Raver, Christine, Bartley, Erin, Muller, Timo D., Pfluger, Paul T., Berger, Jose, Toure, Mouhamadoul, Benoit, Stephen C., DiMarchi, Richard D., Perez- Tilve, Diego, D'Alessio, David A., Seeley, Randy J., and Tschop, Matthias H.

Subjects
Diabetes -- Care and treatment, Gastric bypass -- Patient outcomes, Gastrointestinal hormones -- Identification and classification, Health
Abstract

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1-based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet-induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP1-induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome. Diabetes 2014;63:505-513 | DOI: 10.2337/db13-0511, Both developed and developing countries have seen increased rates of obesity over the last 30 years that has been paralleled by an unprecedented increase in the incidence of metabolic disturbances [...]

Published
2014
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