BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet

Autor: Carlos Castaño, Gema Alcarraz-Vizán, Marcelina Párrizas, Sara de Pablo, Júlia Rodríguez-Comas, Joan-Marc Servitja, Mario Vallejo, Antonio Fernández-Pérez, Sara Ramírez, Daniela Díaz-Catalán, Anna Novials, Marc Claret
Přispěvatelé: Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Comisión Nacional de Investigación Científica y Tecnológica (Chile), Centro Esther Koplowitz, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Leptin
Male
T2D
Type 2 diabetes

Type 2 diabetes
TMEM27
Transmembrane protein 27

Mice
0302 clinical medicine
Hyperinsulinemia
Glucose homeostasis
Aspartic Acid Endopeptidases
Internal medicine
biology
Insulin secretion
BACE2
High-fat diet
BACE1
β-site APP-cleaving enzyme 1

Original Article
AD
Alzheimer's disease

medicine.medical_specialty
HFD
High-fat diet

CD
Chow diet

Neuropeptide
030209 endocrinology & metabolism
GSIS
Glucose stimulated insulin secretion

hIAPP
human islet amyloid polypeptide

Mice
Transgenic

03 medical and health sciences
Insulin resistance
β-cell proliferation
medicine
Animals
Obesity
BACE2
β-site APP-cleaving enzyme 2

Molecular Biology
business.industry
BKO
BACE2 knock-out

Cell Biology
medicine.disease
RC31-1245
Diet
Insulin receptor
030104 developmental biology
Endocrinology
biology.protein
Amyloid Precursor Protein Secretases
business
WT
Wild type
Zdroj: Molecular Metabolism
Digital.CSIC. Repositorio Institucional del CSIC
instname
Molecular Metabolism, Vol 53, Iss, Pp 101251-(2021)
ISSN: 2212-8778
Popis: © 2021 The Author(s).
[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.
This work was supported by projects from the Instituto de Salud Carlos III (PI17/00879 to AN and JMS) and by the Spanish Ministry of Economy and Competitiveness (BFU2017-89336-R to MV), co-funded by the Fondo Europeo de Desarrollo Regional (FEDER; A way to build Europe), and by the CERCA Programme and Generalitat de Catalunya (grant 2014_SGR_520). DDC was supported by Conicyt’s fellowship from the Government of Chile (72170321-6357/2016). SR is a recipient of a Juan de la Cierva Incorporación (IJC2018-037341-I) program from the Spanish Ministry of Science and Innovation. This work was developed at the Center Esther Koplowitz (Barcelona). CIBERDEM (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas) is an initiative of the Instituto de Salud Carlos III.
Databáze: OpenAIRE