MIGUEL DURAN, SONJA VIRKUS, KYLIE A. MCMICHEN, YASLLE ANDRADE CAVALCANTE MORAES, ESHITA YADAV, JAGJOT K. SINGH, ZOE FOKAKIS, SAMANTHA Q. STOCKING, SAMUEL O. POOLE, CHAD S. HUNTER, KIRK M. HABEGGER, JAMES A. HARDAWAY
{"title":"104-OR: 后脑胰高血糖素样肽 1(Glucagon-Like Peptide 1)产生神经元的状态依赖性活动通过功能上相互关联的下丘脑和边缘环路调控消费行为和价值行为","authors":"MIGUEL DURAN, SONJA VIRKUS, KYLIE A. MCMICHEN, YASLLE ANDRADE CAVALCANTE MORAES, ESHITA YADAV, JAGJOT K. SINGH, ZOE FOKAKIS, SAMANTHA Q. STOCKING, SAMUEL O. POOLE, CHAD S. HUNTER, KIRK M. HABEGGER, JAMES A. HARDAWAY","doi":"10.2337/db24-104-or","DOIUrl":null,"url":null,"abstract":"Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (GcgNTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of GcgNTS neurons to consummatory and valence behavior. Methods: electrophysiology, in vivo optogenetics, fiber photometry. Results: Using electrophysiology, we observed that GcgNTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, GcgNTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, GcgNTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of GcgNTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of GcgNTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of GcgNTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that GcgNTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between GcgNTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala. Conclusions: GcgNTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala. Disclosure M. Duran: None. S. Virkus: None. K.A. McMichen: None. Y. Andrade Cavalcante Moraes: None. E. Yadav: None. J.K. Singh: None. Z. Fokakis: None. S.Q. Stocking: None. S.O. Poole: None. C.S. Hunter: None. K.M. Habegger: Research Support; Eli Lilly and Company. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Consultant; Merck & Co., Inc. Research Support; Novo Nordisk. Advisory Panel; Abvance Therapeutics. J.A. Hardaway: None. Funding K01DK115902R03DK129561P30DK079626P30DK056336","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"150 1","pages":""},"PeriodicalIF":6.2000,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"104-OR: State-Dependent Activity in Hindbrain Glucagon-Like Peptide 1—Producing Neurons Regulates Consummatory and Valence Behavior through Functionally Interconnected Hypothalamic and Limbic Circuits\",\"authors\":\"MIGUEL DURAN, SONJA VIRKUS, KYLIE A. MCMICHEN, YASLLE ANDRADE CAVALCANTE MORAES, ESHITA YADAV, JAGJOT K. SINGH, ZOE FOKAKIS, SAMANTHA Q. STOCKING, SAMUEL O. POOLE, CHAD S. HUNTER, KIRK M. HABEGGER, JAMES A. HARDAWAY\",\"doi\":\"10.2337/db24-104-or\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (GcgNTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of GcgNTS neurons to consummatory and valence behavior. Methods: electrophysiology, in vivo optogenetics, fiber photometry. Results: Using electrophysiology, we observed that GcgNTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, GcgNTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, GcgNTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of GcgNTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of GcgNTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of GcgNTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that GcgNTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between GcgNTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala. Conclusions: GcgNTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala. Disclosure M. Duran: None. S. Virkus: None. K.A. McMichen: None. Y. Andrade Cavalcante Moraes: None. E. Yadav: None. J.K. Singh: None. Z. Fokakis: None. S.Q. Stocking: None. S.O. Poole: None. C.S. Hunter: None. K.M. Habegger: Research Support; Eli Lilly and Company. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Consultant; Merck & Co., Inc. Research Support; Novo Nordisk. Advisory Panel; Abvance Therapeutics. J.A. Hardaway: None. 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104-OR: State-Dependent Activity in Hindbrain Glucagon-Like Peptide 1—Producing Neurons Regulates Consummatory and Valence Behavior through Functionally Interconnected Hypothalamic and Limbic Circuits
Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (GcgNTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of GcgNTS neurons to consummatory and valence behavior. Methods: electrophysiology, in vivo optogenetics, fiber photometry. Results: Using electrophysiology, we observed that GcgNTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, GcgNTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, GcgNTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of GcgNTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of GcgNTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of GcgNTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that GcgNTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between GcgNTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala. Conclusions: GcgNTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala. Disclosure M. Duran: None. S. Virkus: None. K.A. McMichen: None. Y. Andrade Cavalcante Moraes: None. E. Yadav: None. J.K. Singh: None. Z. Fokakis: None. S.Q. Stocking: None. S.O. Poole: None. C.S. Hunter: None. K.M. Habegger: Research Support; Eli Lilly and Company. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Consultant; Merck & Co., Inc. Research Support; Novo Nordisk. Advisory Panel; Abvance Therapeutics. J.A. Hardaway: None. Funding K01DK115902R03DK129561P30DK079626P30DK056336
期刊介绍:
Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes.
However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.