Bace2 as a new therapeutic target in the treatment of type 2 diabetes and obesity
- Autores: Daniela Josefa Díaz Catalán
- Directores de la Tesis: Anna Novials Sardà (dir. tes.), Joan Marc Servitja Duque (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2021
- Idioma: español
- Tribunal Calificador de la Tesis: Fàtima Bosch i Tubert (presid.), Laura Herrero Rodríguez (secret.), Iván Quesada Moll (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
Type 2 diabetes (T2D) is a long-term condition closely linked to the upsurge of obesity. The pathophysiology connecting obesity and T2D is attributed to insulin resistance (IR). Obesity induces IR affecting peripheral tissues, which leads to a compensatory increase of pancreatic insulin secretion. Failure of β-cells to compensate IR will ultimately lead to T2D. Accordingly, increasing β-cell function may provide a therapeutic approach for the treatment of T2D. Inhibition of BACE2 (β-site APP-cleaving enzyme 2), a protease primarily expressed in pancreatic islets, exerts a positive effect on β-cells, enhancing their mass and function. These positive effects of BACE2 inhibition led us to hypothesize that suppressing BACE2 function may improve the pancreatic β-cell response and eventually the regulation of glucose homeostasis in an obesogenic setting. In this regard, the main objective of this thesis was to evaluate the effects on whole-body metabolism in BACE2-deficient (BKO) mice fed high fat diet (HFD).
Unexpectedly, we observed that HFD-fed BKO mice (BKO-HFD) presented an exacerbated body weight gain and hyperphagia compared to their HFD-fed wild-type (WT-HFD) littermates. In accordance with their obese phenotype, the BKO-HFD mice displayed an impaired metabolic flexibility, hepatic steatosis, inflammation in epididymal white adipose tissue and hyperleptinemia after 16 weeks of HFD feeding. Of note, the leptin-induced food intake inhibition and the hypothalamic insulin signaling were impaired in BKO mice either in chow or HF diet feeding. Despite the exacerbated increase in body weight and insulin resistance, BKO-HFD mice exhibited a similar glucose intolerance than WT-HFD mice, which was in accordance with an increase in insulin levels. In this regard, the hyperinsulinemia observed in the BKO-HFD mice was paralleled by an increase in β-cell mass and proliferation. In addition, the insulin secretory response to glucose of isolated pancreatic islets from BKO-HFD mice was also increased in relation with the WT-HFD mice. Remarkably, with only 2 weeks on HFD, before the onset of obesity, BKO-HFD mice were already glucose intolerant, insulin resistant, hyperinsulinemic, and displayed an increase in β-cell proliferation.
Taken together, these results indicate that in BACE2-deficient mice a HFD feeding induces an exacerbated increase in body weight and hyperphagia, as well as a more pronounced hyperinsulinemia and β-cell proliferation. Thus, we conclude that BACE2 inhibition should be taken into caution under settings of obesity because it aggravates the adverse effects of obesity.
