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1. Parabrachial Interleukin-6 reduces body weight and food intake and increases thermogenesis to regulate energy metabolism

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Mishra, Devesh, Richard, Jennifer E., Maric, Ivana, Porteiro Couto, Begoña, Häring, Martin, Kooijman, Sander, Musovic, Saliha, Eerola, Kim, López Ferreras, Lorena, Peris, Eduard, Grycel, Katarzyna, Shevchouk, Olesya T., Micallef, Peter, Olofsson, Charlotta S., Wernstedt Asterholm, Ingrid, Grill, Harvey J., Nogueiras Pozo, Rubén, Skibicka, Karolina P., Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Mishra, Devesh, Richard, Jennifer E., Maric, Ivana, Porteiro Couto, Begoña, Häring, Martin, Kooijman, Sander, Musovic, Saliha, Eerola, Kim, López Ferreras, Lorena, Peris, Eduard, Grycel, Katarzyna, Shevchouk, Olesya T., Micallef, Peter, Olofsson, Charlotta S., Wernstedt Asterholm, Ingrid, Grill, Harvey J., Nogueiras Pozo, Rubén, and Skibicka, Karolina P.

Abstract

Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6

Published
2019

2. Glucagon-like peptide-1 and its analogues act in the dorsal raphe and modulate central serotonin to reduce appetite and body weight

Author

Anderberg, Rozita H, Richard, Jennifer E, Eerola, Kim, Ferreras, Lorena Lopez, Nordbeck, Elin Banke, Hansson, Caroline, Nissbrandt, Hans, Berqquist, Filip, Gribble, Fiona M, Reimann, Frank, Wernstedt-Asterholm, Ingrid, Lamy, Christophe M., Skibicka, Karolina P, Anderberg, Rozita H, Richard, Jennifer E, Eerola, Kim, Ferreras, Lorena Lopez, Nordbeck, Elin Banke, Hansson, Caroline, Nissbrandt, Hans, Berqquist, Filip, Gribble, Fiona M, Reimann, Frank, Wernstedt-Asterholm, Ingrid, Lamy, Christophe M., and Skibicka, Karolina P

Abstract

Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase electrical activity of the DR serotonin neurons. Finally our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.

Published
2017

3. Predicting missing biomarker data in a longitudinal study of Alzheimer disease

Author

Lo, Raymond Y., Jagust, William J., Aisen, Paul, Jack, Clifford R., Toga, Arthur W., Beckett, Laurel, Gamst, Anthony, Soares, Holly, C. Green, Robert, Montine, Tom, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Chen, Kewei, Morris, John, Lee, Virginia M.-Y., Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Buckholtz, Neil, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Mintun, Mark A., Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, Toledo-Morrell, Leylade, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn S., Pedroso, Julia, Toroney, Jaimie, Rusinek, Henry, de Leon, Mony J, De Santi, Susan M, Doraiswamy, P. Murali, Petrella, Jeffrey R., Aiello, Marilyn, Clark, Christopher M., Pham, Cassie, Nunez, Jessica, Smith, Charles D., Given, Curtis A., Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Ismail, M. Saleem, Brand, Connie, Richard, Jennifer, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Laubinger, Mary M., Bartzokis, George, Silverman, Daniel H.S., Lu, Po H., Graff-Radford MBBCH, Neill R, Parfitt, Francine, Johnson, Heather, Farlow, Martin, Herring, Scott, Hake, Ann M., van Dyck, Christopher H., MacAvoy, Martha G., Benincasa, Amanda L., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Graham, Simon, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Scott, Johnson, Kathleen B., Behan, Kelly E., Sperling, Reisa A., Rentz, Dorene M., Johnson, Keith A., Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Connor, Donald, Jacobson, Sandra, Killiany, Ronald, Norbash, Alexander, Nair, Anil, Obisesan, Thomas O., Jayam-Trouth, Annapurni, Wang, Paul, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Kittur, Smita, Mirje, Seema, Borrie, Michael, Lee, T-Y, Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A., Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Gandy, Sam, Marenberg, Marjorie E., Rovner, Barry W., Pearlson, Godfrey, Anderson, Karen, Santulli, Robert B., Englert, Jessica, Williamson, Jeff D., Sink, Kaycee M., Watkins, Franklin, Ott, Brian R., Cohen, Ronald, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Lo, Raymond Y., Jagust, William J., Aisen, Paul, Jack, Clifford R., Toga, Arthur W., Beckett, Laurel, Gamst, Anthony, Soares, Holly, C. Green, Robert, Montine, Tom, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Chen, Kewei, Morris, John, Lee, Virginia M.-Y., Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Buckholtz, Neil, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Mintun, Mark A., Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, Toledo-Morrell, Leylade, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn S., Pedroso, Julia, Toroney, Jaimie, Rusinek, Henry, de Leon, Mony J, De Santi, Susan M, Doraiswamy, P. Murali, Petrella, Jeffrey R., Aiello, Marilyn, Clark, Christopher M., Pham, Cassie, Nunez, Jessica, Smith, Charles D., Given, Curtis A., Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Ismail, M. Saleem, Brand, Connie, Richard, Jennifer, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Laubinger, Mary M., Bartzokis, George, Silverman, Daniel H.S., Lu, Po H., Graff-Radford MBBCH, Neill R, Parfitt, Francine, Johnson, Heather, Farlow, Martin, Herring, Scott, Hake, Ann M., van Dyck, Christopher H., MacAvoy, Martha G., Benincasa, Amanda L., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Graham, Simon, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Scott, Johnson, Kathleen B., Behan, Kelly E., Sperling, Reisa A., Rentz, Dorene M., Johnson, Keith A., Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Connor, Donald, Jacobson, Sandra, Killiany, Ronald, Norbash, Alexander, Nair, Anil, Obisesan, Thomas O., Jayam-Trouth, Annapurni, Wang, Paul, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Kittur, Smita, Mirje, Seema, Borrie, Michael, Lee, T-Y, Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A., Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Gandy, Sam, Marenberg, Marjorie E., Rovner, Barry W., Pearlson, Godfrey, Anderson, Karen, Santulli, Robert B., Englert, Jessica, Williamson, Jeff D., Sink, Kaycee M., Watkins, Franklin, Ott, Brian R., Cohen, Ronald, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., and Mintzer, Jacobo

Abstract

Objective:To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).Methods:The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.Results:CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.Conclusion:The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

Published
2012

4. Predicting missing biomarker data in a longitudinal study of Alzheimer disease

Author

Lo, Raymond Y., Jagust, William J., Aisen, Paul, Jack, Clifford R., Toga, Arthur W., Beckett, Laurel, Gamst, Anthony, Soares, Holly, C. Green, Robert, Montine, Tom, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Chen, Kewei, Morris, John, Lee, Virginia M.-Y., Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Buckholtz, Neil, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Mintun, Mark A., Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, Toledo-Morrell, Leylade, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn S., Pedroso, Julia, Toroney, Jaimie, Rusinek, Henry, De Leon, Mony J, De Santi, Susan M, Doraiswamy, P. Murali, Petrella, Jeffrey R., Aiello, Marilyn, Clark, Christopher M., Pham, Cassie, Nunez, Jessica, Smith, Charles D., Given, Curtis A., Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Ismail, M. Saleem, Brand, Connie, Richard, Jennifer, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Laubinger, Mary M., Bartzokis, George, Silverman, Daniel H.S., Lu, Po H., Graff-Radford MBBCH, Neill R, Parfitt, Francine, Johnson, Heather, Farlow, Martin, Herring, Scott, Hake, Ann M., Van Dyck, Christopher H., MacAvoy, Martha G., Benincasa, Amanda L., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Graham, Simon, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Scott, Johnson, Kathleen B., Behan, Kelly E., Sperling, Reisa A., Rentz, Dorene M., Johnson, Keith A., Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Connor, Donald, Jacobson, Sandra, Killiany, Ronald, Norbash, Alexander, Nair, Anil, Obisesan, Thomas O., Jayam-Trouth, Annapurni, Wang, Paul, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Kittur, Smita, Mirje, Seema, Borrie, Michael, Lee, T-Y, Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A., Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Gandy, Sam, Marenberg, Marjorie E., Rovner, Barry W., Pearlson, Godfrey, Anderson, Karen, Santulli, Robert B., Englert, Jessica, Williamson, Jeff D., Sink, Kaycee M., Watkins, Franklin, Ott, Brian R., Cohen, Ronald, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Lo, Raymond Y., Jagust, William J., Aisen, Paul, Jack, Clifford R., Toga, Arthur W., Beckett, Laurel, Gamst, Anthony, Soares, Holly, C. Green, Robert, Montine, Tom, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Chen, Kewei, Morris, John, Lee, Virginia M.-Y., Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Buckholtz, Neil, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Mintun, Mark A., Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, Toledo-Morrell, Leylade, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn S., Pedroso, Julia, Toroney, Jaimie, Rusinek, Henry, De Leon, Mony J, De Santi, Susan M, Doraiswamy, P. Murali, Petrella, Jeffrey R., Aiello, Marilyn, Clark, Christopher M., Pham, Cassie, Nunez, Jessica, Smith, Charles D., Given, Curtis A., Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Ismail, M. Saleem, Brand, Connie, Richard, Jennifer, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Laubinger, Mary M., Bartzokis, George, Silverman, Daniel H.S., Lu, Po H., Graff-Radford MBBCH, Neill R, Parfitt, Francine, Johnson, Heather, Farlow, Martin, Herring, Scott, Hake, Ann M., Van Dyck, Christopher H., MacAvoy, Martha G., Benincasa, Amanda L., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Graham, Simon, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Scott, Johnson, Kathleen B., Behan, Kelly E., Sperling, Reisa A., Rentz, Dorene M., Johnson, Keith A., Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Connor, Donald, Jacobson, Sandra, Killiany, Ronald, Norbash, Alexander, Nair, Anil, Obisesan, Thomas O., Jayam-Trouth, Annapurni, Wang, Paul, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Kittur, Smita, Mirje, Seema, Borrie, Michael, Lee, T-Y, Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A., Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Gandy, Sam, Marenberg, Marjorie E., Rovner, Barry W., Pearlson, Godfrey, Anderson, Karen, Santulli, Robert B., Englert, Jessica, Williamson, Jeff D., Sink, Kaycee M., Watkins, Franklin, Ott, Brian R., Cohen, Ronald, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., and Mintzer, Jacobo

Published
2012

5. Glucagon-like peptide-1 and its analogues act in the dorsal raphe and modulate central serotonin to reduce appetite and body weight

Author

Anderberg, Rozita H, Richard, Jennifer E, Eerola, Kim, Ferreras, Lorena Lopez, Nordbeck, Elin Banke, Hansson, Caroline, Nissbrandt, Hans, Berqquist, Filip, Gribble, Fiona M, Reimann, Frank, Wernstedt-Asterholm, Ingrid, Lamy, Christophe M., Skibicka, Karolina P, Anderberg, Rozita H, Richard, Jennifer E, Eerola, Kim, Ferreras, Lorena Lopez, Nordbeck, Elin Banke, Hansson, Caroline, Nissbrandt, Hans, Berqquist, Filip, Gribble, Fiona M, Reimann, Frank, Wernstedt-Asterholm, Ingrid, Lamy, Christophe M., and Skibicka, Karolina P

Abstract

Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase electrical activity of the DR serotonin neurons. Finally our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.

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