Targeting the immunoproteasome in hypothalamic neurons as a novel therapeutic strategy for high-fat diet-induced obesity and metabolic dysregulation.

Autor: Albornoz N; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Álvarez-Indo J; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., de la Peña A; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Arias-Muñoz E; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Coca A; Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile., Segovia-Miranda F; Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile., Kerr B; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Budini M; Laboratory of Molecular and Cellular Pathology, Institute in Dentistry Sciences, Dentistry Faculty, University of Chile, Santiago, Chile., Criollo A; Cell and Molecular Biology Laboratory, Institute in Dentistry Sciences, Dentistry Faculty, Universidad de Chile, Santiago, Chile.; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile., García-Robles MA; Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile., Morselli E; Department of Basic Sciences, Faculty of Medicine and Sciences, Universidad San Sebastián, Santiago, Chile., Soza A; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile. andrea.soza@uss.cl.; Centro Basal Ciencia & Vida, Universidad San Sebastián, Santiago, Chile. andrea.soza@uss.cl., Burgos PV; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile. patricia.burgos@uss.cl.; Centro Basal Ciencia & Vida, Universidad San Sebastián, Santiago, Chile. patricia.burgos@uss.cl.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Aug 02; Vol. 21 (1), pp. 191. Date of Electronic Publication: 2024 Aug 02.
DOI: 10.1186/s12974-024-03154-z
Abstrakt: Objective: Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity's deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases.
Methods: The levels of the immunoproteasome β5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome β5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of β5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay.
Results: Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the β5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA.
Conclusions: Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.
(© 2024. The Author(s).)
Databáze: MEDLINE
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