BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet
Objective: Pancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a pot...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782100096X |
| _version_ | 1818725295793897472 |
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| author | Daniela Díaz-Catalán Gema Alcarraz-Vizán Carlos Castaño Sara de Pablo Júlia Rodríguez-Comas Antonio Fernández-Pérez Mario Vallejo Sara Ramírez Marc Claret Marcelina Parrizas Anna Novials Joan-Marc Servitja |
| author_facet | Daniela Díaz-Catalán Gema Alcarraz-Vizán Carlos Castaño Sara de Pablo Júlia Rodríguez-Comas Antonio Fernández-Pérez Mario Vallejo Sara Ramírez Marc Claret Marcelina Parrizas Anna Novials Joan-Marc Servitja |
| author_sort | Daniela Díaz-Catalán |
| collection | DOAJ |
| description | Objective: Pancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. Methods: BACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. β-cell proliferation was assessed by Ki67-positive nuclei, and β-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. Results: After 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and β-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased β-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. Conclusions: Collectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity. |
| first_indexed | 2024-12-17T21:40:03Z |
| format | Article |
| id | doaj.art-e1d707b7867642fd9e5b8a8015043964 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-17T21:40:03Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-e1d707b7867642fd9e5b8a80150439642022-12-21T21:31:39ZengElsevierMolecular Metabolism2212-87782021-11-0153101251BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic dietDaniela Díaz-Catalán0Gema Alcarraz-Vizán1Carlos Castaño2Sara de Pablo3Júlia Rodríguez-Comas4Antonio Fernández-Pérez5Mario Vallejo6Sara Ramírez7Marc Claret8Marcelina Parrizas9Anna Novials10Joan-Marc Servitja11Pathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), SpainPathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), SpainPathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), SpainPathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainPathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid, Madrid, SpainCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid, Madrid, SpainNeuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; School of Medicine, Universitat de Barcelona, Barcelona, SpainPathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), SpainPathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Corresponding author. Pathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rossello 149-153, P5, 08036 Barcelona, Spain.Pathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Corresponding author. Pathogenesis and Prevention of Diabetes Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rossello 149-153, P5, 08036 Barcelona, Spain.Objective: Pancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. Methods: BACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. β-cell proliferation was assessed by Ki67-positive nuclei, and β-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. Results: After 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and β-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased β-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. Conclusions: Collectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity.http://www.sciencedirect.com/science/article/pii/S221287782100096XBACE2High-fat dietβ-cell proliferationInsulin secretionInsulin resistanceLeptin |
| spellingShingle | Daniela Díaz-Catalán Gema Alcarraz-Vizán Carlos Castaño Sara de Pablo Júlia Rodríguez-Comas Antonio Fernández-Pérez Mario Vallejo Sara Ramírez Marc Claret Marcelina Parrizas Anna Novials Joan-Marc Servitja BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet Molecular Metabolism BACE2 High-fat diet β-cell proliferation Insulin secretion Insulin resistance Leptin |
| title | BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet |
| title_full | BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet |
| title_fullStr | BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet |
| title_full_unstemmed | BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet |
| title_short | BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet |
| title_sort | bace2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet |
| topic | BACE2 High-fat diet β-cell proliferation Insulin secretion Insulin resistance Leptin |
| url | http://www.sciencedirect.com/science/article/pii/S221287782100096X |
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